WO2004002462A2 - Use of an alpha2delta ligand such as gabapentin or pregabalin for treating ttention deficit hyperactivity disorder - Google Patents
Use of an alpha2delta ligand such as gabapentin or pregabalin for treating ttention deficit hyperactivity disorder Download PDFInfo
- Publication number
- WO2004002462A2 WO2004002462A2 PCT/IB2003/002666 IB0302666W WO2004002462A2 WO 2004002462 A2 WO2004002462 A2 WO 2004002462A2 IB 0302666 W IB0302666 W IB 0302666W WO 2004002462 A2 WO2004002462 A2 WO 2004002462A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aminomethyl
- methyl
- acid
- phenyl
- alkyl
- Prior art date
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 60
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960002870 gabapentin Drugs 0.000 title claims abstract description 11
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 9
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 7
- 208000013403 hyperactivity Diseases 0.000 title description 4
- 230000006735 deficit Effects 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 94
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 28
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims description 108
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- -1 3-amino-methyl-bicyclo[3.2.0]hept-3-yl Chemical group 0.000 claims description 61
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 229940124530 sulfonamide Drugs 0.000 claims description 9
- 150000003456 sulfonamides Chemical group 0.000 claims description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 8
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 8
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical group C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 7
- 150000001408 amides Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- NDDZVQRQVFTNSN-UHFFFAOYSA-N 2-[3-(aminomethyl)-3-bicyclo[3.2.0]heptanyl]acetic acid Chemical compound C1C(CN)(CC(O)=O)CC2CCC21 NDDZVQRQVFTNSN-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- ONKWZNBXHSMMDK-UHFFFAOYSA-N 2-[2-(aminomethyl)-1,3,3a,4,5,6,7,7a-octahydroinden-2-yl]acetic acid Chemical compound C1CCCC2CC(CN)(CC(O)=O)CC21 ONKWZNBXHSMMDK-UHFFFAOYSA-N 0.000 claims description 4
- GSBZRDSCOPXLJJ-UHFFFAOYSA-N 2-[2-(aminomethyl)-3,3a,4,5,6,6a-hexahydro-1h-pentalen-2-yl]acetic acid Chemical compound C1CCC2CC(CN)(CC(O)=O)CC21 GSBZRDSCOPXLJJ-UHFFFAOYSA-N 0.000 claims description 4
- CWSXPZYRFGYVBO-UHFFFAOYSA-N 4-methyl-2-(2h-tetrazol-5-ylmethyl)pentan-1-amine Chemical compound CC(C)CC(CN)CC1=NN=NN1 CWSXPZYRFGYVBO-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- BIGWXAGEQONZGD-UHFFFAOYSA-N 2h-oxadiazol-5-one Chemical compound O=C1C=NNO1 BIGWXAGEQONZGD-UHFFFAOYSA-N 0.000 claims description 2
- BWBQMUPZKXFEIP-UHFFFAOYSA-N 3-(1-aminoethyl)-5-methylheptanoic acid Chemical compound CCC(C)CC(C(C)N)CC(O)=O BWBQMUPZKXFEIP-UHFFFAOYSA-N 0.000 claims description 2
- IRQCKMBXGOKUDW-UHFFFAOYSA-N 3-(1-azaniumylethyl)-5-methylhexanoate Chemical compound CC(C)CC(C(C)N)CC(O)=O IRQCKMBXGOKUDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- PPIQMYQQPKTQBZ-UHFFFAOYSA-N n-[2-[1-(aminomethyl)cyclohexyl]ethyl]methanesulfonamide Chemical compound CS(=O)(=O)NCCC1(CN)CCCCC1 PPIQMYQQPKTQBZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 10
- 229940098779 methanesulfonic acid Drugs 0.000 description 10
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- 229960001171 acetohydroxamic acid Drugs 0.000 description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
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- 125000004122 cyclic group Chemical group 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000012154 double-distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229910018828 PO3H2 Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000007514 bases Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
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- 239000000021 stimulant Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- IASDTUBNBCYCJG-YUMQZZPRSA-N (3r,4s)-3-(azaniumylmethyl)-4,5-dimethylhexanoate Chemical compound CC(C)[C@H](C)[C@H](CN)CC(O)=O IASDTUBNBCYCJG-YUMQZZPRSA-N 0.000 description 2
- FEWJHICLKRAPHS-OCCSQVGLSA-N (3s,5r)-3-(aminomethyl)-5-methyl-7-phenylheptanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CCC1=CC=CC=C1 FEWJHICLKRAPHS-OCCSQVGLSA-N 0.000 description 2
- KKXFMWXZXDUYBF-BDAKNGLRSA-N (3s,5r)-3-(aminomethyl)-5-methyloctanoic acid Chemical compound CCC[C@@H](C)C[C@H](CN)CC(O)=O KKXFMWXZXDUYBF-BDAKNGLRSA-N 0.000 description 2
- JBBFMHZVKGOWPT-YPMHNXCESA-N (3s,5s)-3-(aminomethyl)-5-methyl-6-phenylhexanoic acid Chemical compound OC(=O)C[C@@H](CN)C[C@H](C)CC1=CC=CC=C1 JBBFMHZVKGOWPT-YPMHNXCESA-N 0.000 description 2
- QIQWRCNAPQJQLL-COALEZEGSA-N (z)-but-2-enedioic acid;5-[(1r,2r)-2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1h-imidazole Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)CCC#C[C@@H]1C[C@H]1C1=CN=CN1 QIQWRCNAPQJQLL-COALEZEGSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC1(*)C*(*)**C1 Chemical compound CC1(*)C*(*)**C1 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QFLSQUNSWXMJBE-UHFFFAOYSA-N [1-(aminomethyl)cyclohexyl]methylphosphonic acid Chemical compound OP(=O)(O)CC1(CN)CCCCC1 QFLSQUNSWXMJBE-UHFFFAOYSA-N 0.000 description 2
- CJMFUZSVUFPYJR-UHFFFAOYSA-N [2-(aminomethyl)-4-methylpentyl]phosphonic acid Chemical compound CC(C)CC(CN)CP(O)(O)=O CJMFUZSVUFPYJR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
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- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Definitions
- This invention relates to a method of preventing or treating attention deficit hyperactivity disorder ("ADHD") by administering a compound that exhibits activity as an alpha2delta ligand ( ⁇ 2 ⁇ ligand).
- ADHD attention deficit hyperactivity disorder
- ⁇ 2 ⁇ ligand alpha2delta ligand
- Such compounds have affinity for the 2 ⁇ subunit of a calcium channel.
- Such compounds have also been referred to in the literature as gamma-aminobutyric acid (GABA) analogs.
- ADHD Attention deficit hyperactivity disorder
- Clonidine an ⁇ 2 -adrenoceptor agonist, treats the aggressive and oppositional symptoms. There is a potential for significant side effects with both methylphenidate and clonidine, making it important to identify other drugs that have similar or better efficacy with reduced side effects.
- ADHD can be characterized as a dysregulation of catecholaminergic neurotransmission in executive brain regions like prefrontal cortex, it is possible that drugs acting to modulate this neurotransmission may be of potential relevance to treat ADHD.
- alpha delta ligands including gabapentin and pregabalin may be efficacious in treating this disorder. This hypothesis is based on our previous observation that gabapentin and pregabalin appear to preferentially attenuate neurotransmitter release induced by stimuli considered pathological in nature (J. Pharmacol. Exp. Ther. 295:1086-1093, 2000). Therefore, ADHD may also be an indication sensitive to alpha 2 delta ligands either alone or in combination with stimulants (e.g., Ritalin) or non-stimulants (e.g., atomoxetine,
- ADHD is one of the most common childhood psychiatric disorders and appears to be a common, often underrecognized, psychiatric disease in adults as well (Spencer T, 1998). This disorder, which begins in childhood, may be followed by a lifelong expression of symptoms (e.g., hyperactivity and/or impulsivity) (Schweitzer JB, 2001). ADHD may change its manifestations as it develops from preschool through adult life (Cantwell DP, 1996; Elia J, 1999; Nolan EE, 2001). The diagnosis of ADHD is based on clinical evaluation (Dulcan M, 1997;
- the essential feature of ADHD is a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparative level of development
- DSM- IN Diagnostic and Statistical Manual of Mental Disorders
- patients In order to be diagnosed with ADHD, patients must demonstrate symptoms of ADHD that cause impairment before the age of seven years, and symptoms must have been ongoing for longer than six months in at least two settings (e.g., school [or work] and home). (See DSM-IV).
- alpha2delta ligands are known.
- Gabapentin a cyclic alpha2delta ligand
- ⁇ eurontin® Warner-Lambert Company
- Such cyclic alpha2delta ligands are described in US Patent No. 4,024,175, which issued on May 17, 1977, and US Patent No. 4,087,544, which issued on May 2, 1978.
- Other series of alpha2delta ligands are described in US Patent No. 4,024,175, which issued on May 17, 1977, and US Patent No. 4,087,544, which issued on May 2, 1978.
- Other series of alpha2delta ligands are described in US Patent
- This invention provides a method of preventing or treating ADHD in a mammal suffering therefrom, comprising administering a therapeutically effective amount of an alpha2delta ligand or a pharmaceutically acceptable salt thereof.
- the foregoing method is sometimes referred to herein as the "invention method”.
- a preferred embodiment of the invention method utilizes an alpha2delta ligand that is a cyclic amino acid compound of Formula I
- Rj is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof.
- An especially preferred embodiment utilizes a compound of Formula I where Rj is hydrogen and n is 5, which compound is l-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin.
- Other preferred alpha2delta ligands, or a pharmaceutically acceptable salt thereof are compounds of Formula I wherein the cyclic ring is substituted, for example with alkyl such as methyl or ethyl. Typical of such compounds include (l-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-
- the invention method utilizes an alpha2delta ligand of Formula II
- Ri is a straight or branched unsubstituted alkyl of from 1 to 6 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to 6 carbon atoms;
- R2 is hydrogen or methyl;
- R3 is hydrogen, methyl, or carboxyl. Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention method.
- An especially preferred embodiment of the invention method employs a compound of Formula U where R2 and R3 are both hydrogen, and R j is
- a more preferred embodiment of the invention method utilizes a compound of Formula II named 3-aminomethyl-5-methyl-hexanoic acid, or especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin.
- Pregabalin is also known as "CI-1008" and "S-(+)-3-IBG.”
- Another preferred embodiment of the invention method utilizes a compound of Formula II named 3-(l-aminoethyl)-5-methylheptanoic acid or 3 -( 1 -aminoethyl)-5 -methylhexanoic acid.
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand that is a compound of the Formula III, IIIC, IH , DIG, or ILTH
- n is an integer of from 0 to 2; m is an integer of from 0 to 3; R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid; with the proviso that R can not be sulfonic acid when m is 2 and n is 1; Rj to Rj4 are each independently selected from hydrogen or straight or branched alkyl of from 1 to 6 carbons, unsubstituted or substituted benzyl or phenyl which substituents are selected from halogen, alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro; A' is a bridged ring selected from
- ⁇ to Z4 are each independently selected from hydrogen and methyl; o is an integer of from 1 to 4; and p is an integer of from 0 to 2.
- Another preferred embodiment of the invention method utilizes a compound of Formulas HI, IJIC, IDE, IDG, or DTH selected from:
- Another preferred embodiment of the invention method utilizes a compound of the Formula HI, HIC, Hi , HIG, or HHI, wherein preferred compounds are those wherein R is a sulfonamide selected from -NHSO2R ⁇ or -SO2NHR.I5 wherein Rl5 is straight or branched alkyl or trifluoromethyl.
- Another preferred embodiment of the invention method utilizes a compound of the Formula Dl, DIC, IDF, DIG, or DTH, wherein especially preferred is N-[2-(l-aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide.
- Another preferred embodiment of the invention method utilizes a compound of the Formula ID, DIC, IDF, IDG, or DIH, wherein other preferred compounds are those wherein R is a phosphonic acid, -PO3H2.
- Another preferred embodiment of the invention method utilizes a compound of the Formula ID, DIC, HIE, ⁇ iG, or DTH, wherein especially preferred are (l-aminomethyl-cyclohexylmethyl)-phosphonic acid and (2-aminomethyl-4-methyl-pentyl)-phosphonic acid.
- Another preferred embodiment of the invention method utilizes a compound of the Formula Dl, DIC, DTP, HIG, or DIH, wherein other preferred compounds are those wherein R is a heterocycle selected from:
- Another preferred embodiment of the invention method utilizes a compound of the Formula Dl, HIC, IHF, HIG, or HHI, wherein especially preferred are C-[l-(lH-tetrazol-5-ylmethyl)cyclohexyl]-methylamine and 4-methyl-2-(lH-tetrazol-5-ylmethyl)-pentylamine.
- An especially preferred embodiment of the invention method utilizes a compound of the Formula IH wherein: m is an integer of from 0 to 2; p is an integer of 2; and
- an embodiment of the invention method which utilizes a compound of the Formula ID, IDC, DIE, HIG, or HHI named 3-(l-aminomethyl-cycloheptylmethyl)-4H-[l,2,4]oxadiazol-5-one hydrochloride. Also preferred is an embodiment of the invention method which utilizes a compound of the Formula Dl, IHC, DH% IDG, or DDT named C-[l-(lH-tetrazol- 5-ylmethyl)-cycloheptyl]-methylamine, or a pharmaceutically acceptable salt thereof.
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand that is a compound of the Formula IV
- Ri is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl
- R2 is straight or branched alkyl of from 1 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkyl OH -alkylphenyl,
- Ri is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R ⁇ is methyl. Preferred is an embodiment of the invention method employing a compound of Formula IV wherein Ri is hydrogen, and R ⁇ is alkyl.
- Another preferred embodiment of the invention method employing a compound of Formula IV wherein R* is methyl, and R ⁇ is alkyl.
- Still another preferred embodiment of the invention method utilizes a compound of Formula IV wherein R is methyl, and R ⁇ is methyl or ethyl.
- 3S,5S ⁇ 3-Aminomethyl- 5-(4-methoxy-phenoxy)-hexanoic acid; 3S,5S; ⁇ 3-Aminomethyl- 5-(3-methoxy-phenoxy)-hexanoic acid; 3S,5S •3-Aminomethyl- 5-(2-methoxy-phenoxy)-hexanoic acid; 3S,5S; •3-Aminomethyl- 5-(4-nitro-phenoxy)-hexanoic acid; 3S,5S; ⁇ 3-Aminomethyl- 5-(3-nitro-phenoxy)-hexanoic acid; (3S,5S •3-Aminomethyl- 5-(2-nitro-phenoxy)-hexanoic acid; 3S,5S •3-Aminomethyl- 6-hydroxy-5 -methyl-hexanoic acid; 3S,5S -3-Aminomethyl- 6-methoxy-5-methyl-hexanoic acid; 3S,5S; -3-
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand which is a compound of the Formula (IXA) or (IXB)
- n is an integer of from 0 to 2;
- R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid;
- A is hydrogen or methyl
- R'3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl wherein benzyl or phenyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro.
- a more preferred embodiment of the invention method utilizes an alpha2delta ligand which is a compound of the Formula (IXA) or (LXB), wherein R is a sulfonamide selected from -NHSO2R i ⁇ and -SO2NHRI wherein R 5 i s straight or branched alkyl or trifluoromethyl.
- An especially preferred embodiment of the invention method utilizes a compound of the Formula (IXA) or (IXB) selected from: 4-Methyl-2-(lH-tetrazol-5-ylmethyl)-pentylamine; 3-(2-Aminomethyl-4-methyl-pentyl)-4H-[l,2,4]oxadiazole-5-thione, HC1; (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid; 3-(3- Amino-2-cyclopentyl-propyl)-4H- [ 1 ,2,4] oxadiazol-5-one;
- Another preferred embodiment of the invention method utilizes a compound of the Formula (IXA) or (IXB), wherein R is a phosphonic acid, -PO 3 H 2 .
- Another preferred embodiment of the invention method utilizes a compound of the Formula (IXA) or (IXB), wherein R is
- an embodiment of the invention method that utilizes a compound of the Formula (LXA) or (LXB) that is 3-(2-aminomethyl-4-methyl- pentyl)-4H-[l ,2,4]oxadiazol-5-one hydrochloride.
- Another embodiment utilizes an alpha2delta ligand that is a compound of the Formula V, VI, VD, or VDI
- n is integer of from 1 to 4, where there are stereocenters, each center may be independently R or S.
- a preferred embodiment of the invention method utilizes a compound of the Formula V, VI, VH, or VDI, wherein n is an integer of from 2 to 4.
- Another preferred embodiment of the invention method utilizes a compound of the Formula V.
- a still more preferred embodiment of the invention method utilizes a compound of the Formula V, VI, VII, or VDI that is selected from:
- Another still more preferred embodiment of the invention method utilizes a compound of the Formula V, VI, VD, or VDI that is selected from: (l ⁇ ,5 ⁇ )(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, (l ,5 ⁇ )(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
- a more preferred embodiment of the invention method utilizes an alpha2delta ligand of the Formula V, VI, VH, or VHI that is
- a still more preferred embodiment of the invention method utilizes an alpha2delta ligand of the Formula V, VI, VH, or VHI that is (l ,3 ,5 ⁇ )(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid hydrochloride.
- alpha2delta ligand that is employed is selected from the following compounds and their pharmaceutically acceptable salts:
- Another preferred embodiment of the invention method utilizes the cyclic amino acids of the Formula I. These are described in US Patent No. 4,024,175 and
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand of the Formula H, and these compounds are described in US Patent 5,563,175, which is incorporated herein by reference in its entirety.
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand of the Formula III, HIC, HIE, DIG, or HIH. These compounds are described in PCT Patent Application No. WO 99/31075, which is incorporated herein by reference in its entirety.
- Another preferred embodiment of the invention method utilizes an alpha2delta ligand of the Formula IV, which are described in PCT Patent Application No. WO 00/76958, which is incorporated herein by reference in its entirety.
- alpha2delta ligands to be utilized in the invention method are compounds of the Formula (LXA) and (LXB), which are described in PCT
- alpha2delta ligands that can be used in preferred embodiments of the present invention method are described in PCT Patent Application No. WO 99/31057, which is incorporated herein by reference in its entirety.
- al ⁇ ha2delta ligands are compounds of the Formulas (XII) and (XIH)
- n is an integer of from 0 to 2; R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid; and X is -O-, -S-, -S(O)-, -S(O) 2 -,or NR'i wherein R' ⁇ is hydrogen, straight or branched alkyl of from 1 to 6 carbons, benzyl, -C(O)R'2 wherein R'2 is straight or branched alkyl of 1 to 6 carbons, benzyl or phenyl or -CO2R'3 wherein R'3 is straight or branched alkyl of from 1 to 6 carbons, or benzyl wherein the benzyl or phenyl groups can be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, trifluoromethyl, and nitro.
- alpha2delta ligands that may be utilized in preferred embodiments of the invention method are described in PCT Patent Application No. WO 98/17627, which is incorporated herein by reference in its entirety.
- alpha2delta ligands are compounds of the formula
- R is hydrogen or lower alkyl
- R is hydrogen or lower alkyl
- X is -O-, -S-, -NR3_ wherein
- R3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl; wherein phenyl and benzyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, amino, and nitro.
- alpha2delta ligands that can be utilized in preferred embodiments of the invention method are described in PCT Patent Application No. WO 99/61424, which is incorporated herein by reference in its entirety. Such alpha2delta ligands are compounds of the formulas (1), (2), (3), (4), (5), (6), (7), and (8)
- Rj to RiQ Qie each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; m is an integer of from 0 to 3; n is an integer of from 1 to 2; o is an integer of from 0 to 3; p is an integer of from 1 to 2; q is an integer of from 0 to 2; r is an integer of from 1 to 2; s is an integer of from 1 to 3; t is an integer of from 0 to 2; and u is an integer of from 0 to 1.
- alpha2delta ligands that can be utilized in preferred embodiments of the invention method are described in United States Provisional Patent Application No. 60/353,632, filed on January 31, 2002.
- alpha2delta ligands are compounds of the formulas X, XA, XB, XI, XIA, XD3 and XB-1, as described below.
- Compounds of the formula X have the formula
- Ri is hydrogen or ( -C ⁇ a kyl optionally substituted with from one to five fluorine atoms; R is hydrogen or (C 1 -C 3 )alkyl optionally substituted with from one to five fluorine atoms;
- R 3 is (Ci-Qdalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 3 )alkyl, phenyl, phenyl-(C 1 -C 3 )alkyl, pyridyl, pyridyl-(C 1 -C 3 )alkyl, phenyl-N(H)-, or pyridyl-N(H)- , wherein each of the foregoing alkyl moieties can be optionally substituted with from one to five fluorine atoms, preferably with from zero to three fluorine atoms, and wherein said phenyl and said pyridyl and the phenyl and pyridyl moieties of said phenyl-(CrC 3 )alkyl and said pyridyl-(d-C 3 )alkyl, respectively, can be optionally substitute
- lower alkyl means a straight or branched alkyl group or radical having from 1 to 6 carbon atoms, and includes methyl, ethyl, 7 ⁇ -propyl, z ' -propyl, n-butyl, /-butyl, sec-butyl, tert-butyl, n- ⁇ pentyl, «-hexyl, and the like.
- alkyl is a straight or branched group of from 1 to 8 carbon atoms, unless stated otherwise, including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, and octyl.
- Alkyl can be unsubstituted or substituted by hydroxy or from 1 to 3 fluorine atoms.
- Preferred groups are methyl and ethyl.
- alkenyl is a straight or branched group of from 2 to 8 carbon atoms containing 1 or 2 or 3 double bonds including but not limited to ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, l-hexen-3-yl, and hept-l,3-dien-7-yl. Alkenyl can be unsubstituted or substituted by from 1 to 3 fluorine atoms.
- cycloalkyl means a cyclic group of from 3 to 7 carbon atoms including but not limited to cyclopropyl, cyclobutyl, and cycloheptyl.
- the benzyl and phenyl groups may be unsubstituted or substituted with from 1 to 3 groups each independently selected from halogen, especially fluoro, alkoxy, alkyl, and NH2-
- Halogen includes fluorine, chlorine, bromine, and iodine.
- alkoxy means the group -O-alkyl wherein alkyl is as defined above.
- Sulfonamides are those of formula or -SO2NHR.15 wherein
- Rl5 is a straight or branched alkyl group of from 1 to 6 carbons or a trifluoromethyl.
- Amides are compounds of formula -NHCORI ⁇ wherein RI2 is straight or branched alkyl of from 1 to 6 carbons, benzyl, and phenyl.
- Phosphonic acids are -PO3H2.
- Sulfonic acids are -SO3H .
- Hydroxamic acid is Heterocycles are groups of from 1 to 2 rings, the monocyclic rings having from 4 to 7 ring members and the bicyclic ring having from 7 to 12 ring members, with from 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur.
- alkyl is a straight or branched group of from 1 to 11 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl except as where otherwise stated.
- the cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unless otherwise stated.
- the benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF3, nitro, alkyl, and alkoxy. Preferred are fluorine and chlorine.
- Carboalkoxy is -COOalkyl wherein alkyl is as described above. Preferred are carbomethoxy and carboethoxy.
- the degree of binding to the 2 ⁇ subunit can be determined using the radioligand binding assay using [3H] gabapentin and the ⁇ 2 ⁇ subunitderived from porcine brain tissue, as described by N. S. Gee et al., J. Biol. Chem., 1996, 277:5879-5776.
- All that is required to practice the method of this invention is to administer an alpha2delta ligand, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective to treat ADHD.
- Such ADHD-treating amount will generally be from about 1 to about 300 mg/kg of subject body weight. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight.
- regulatory agencies such as, for example, the Food and Drug Administration ("FDA") in the U.S. may require a particular therapeutically effective amount.
- an effective amount or a therapeutically effective amount of an alpha2delta ligand, or a pharmaceutically acceptable salt thereof, for treating ADHD according to the invention method, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, published clinical studies, the subject's (ie, mammal's) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by the subject.
- the administered dose may fall within the ranges or concentrations recited above, or may vary outside, i.e., either below or above, those ranges depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of the alpha2delta ligand that are less than optimum for a particular subject. Thereafter, the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
- compositions of an alpha2delta ligand, or a pharmaceutically acceptable salt thereof are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier.
- dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses.
- suitable pharmaceutical carriers including pharmaceutical diluents
- suitable pharmaceutical carriers are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations.
- compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts.
- the compositions can, if desired, also contain other therapeutic agents commonly employed to treat ADHD. Further, the compositions can, if desired, also contain other therapeutic agents commonly employed to treat secondary symptoms such as, for example, depression or anxiety that may or may not accompany ADHD.
- the compositions may contain sertraline, fluoxetine, or other antidepressant or antianxiety agents.
- the percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition.
- the most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, up to about 95%.
- Preferred routes of administration of an alpha2delta ligand, or a pharmaceutically acceptable salt thereof are oral or parenteral.
- a useful intravenous dose is between 5 and 50 mg
- a useful oral dosage is between 20 and 800 mg.
- the alpha2delta ligand, or a pharmaceutically acceptable salt thereof may be administered in any form. Preferably, administration is in unit dosage form.
- a unit dosage form of the alpha2delta ligand, or a pharmaceutically acceptable salt thereof, to be used in this invention may also comprise other compounds useful in the therapy of diseases resulting in ADHD.
- the invention method is useful in human and veterinary medicines for treating or preventing ADHD in a mammal.
- Some of the compounds utilized in a method of the present invention are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts.
- the acid addition salts are formed from basic compounds, whereas the base addition salts are formed from acidic compounds. All of these forms are within the scope of the compounds useful in the method of the present invention.
- Pharmaceutically acceptable acid addition salts of the basic compounds useful in the method of the present invention include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
- organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic
- Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
- salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts,” /. ofPharma. Sci, 1977;66:1).
- An acid addition salt of a basic compound useful in the method of the present invention is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner.
- the free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner.
- the free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the compounds and their respective acid addition salt forms are equivalent for purposes of the present invention.
- a pharmaceutically acceptable base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
- a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
- suitable metal cations include sodium cation (Na + ), potassium cation (K + ), magnesium cation (Mg2+), calcium cation (Ca ⁇ ), and the like.
- a base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner.
- the free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner.
- the free acid forms of the compounds useful in the method of the present invention differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
- Certain of the compounds useful in the method of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Certain of the compounds useful in the method of the present invention possess one or more chiral centers, and each center may exist in the R or S configuration.
- a method of the present invention may utilize any diastereomeric, enantiomeric, or epimeric form of an alpha2delta ligand, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof. Additionally, certain compounds useful in the method of the present invention may exist as geometric isomers such as the Seven (E) and sixteen (Z) isomers of alkenyl groups. A method of the present invention may utilize any cis, trans, syn, anti,
- Certain compounds useful in the method of the present invention can exist as two or more tautomeric forms. Tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization and the like.
- a method of the present invention may utilize any tautomeric form of an alpha2delta ligand, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof.
- compositions containing a ADHD treating effective amount of an alpha2delta ligand and a pharmaceutically acceptable carrier, diluent, or excipient.
- the examples are representative only, and are not to be construed as limiting the invention in any respect.
- the tablets of Formulation Example 1 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
- the pH of a solution of 500 g of gabapentin and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid.
- the solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 25 mg of gabapentin.
- a mixture of 25 g of (l ⁇ ,3 ⁇ ,5 ⁇ )(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)- acetic acid hydrochloride, 100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured into molds, and allowed to cool.
- Each suppository contains 25 mg of (l ⁇ ,3 ⁇ ,5 ⁇ )(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid hydrochloride.
- Ampoules A solution of 2.5 kg of gabapentin is dissolved in 60 L of double-distilled water. The solution is sterile filtered, and the filtrate is filled into ampoules. The ampoules are lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 25 mg of gabapentin.
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IL16559303A IL165593A0 (en) | 2002-06-27 | 2003-06-16 | Use of an alpha2delta ligand such as gabapentin orpregabalin for treating attention deficit hyperac tivity disorder |
JP2004517096A JP2005534678A (en) | 2002-06-27 | 2003-06-16 | How to treat attention-deficit / hyperactivity disorder |
EP03732941A EP1515709A2 (en) | 2002-06-27 | 2003-06-16 | Use of an alpha2delta ligand such as gabapentin or pregabalin for treating attention deficit hyperactivity disorder |
CA002488566A CA2488566A1 (en) | 2002-06-27 | 2003-06-16 | Use of an alpha2delta ligand such as gabapentin or pregabalin for treating attention deficit hyperactivity disorder |
AU2003239752A AU2003239752A1 (en) | 2002-06-27 | 2003-06-16 | Use of an alpha2delta ligand such as gabapentin or pregabalin for treating ttention deficit hyperactivity disorder |
BR0312240-9A BR0312240A (en) | 2002-06-27 | 2003-06-16 | Method of Treatment of Attention Deficit Hyperactivity Disorder |
MXPA04012922A MXPA04012922A (en) | 2002-06-27 | 2003-06-16 | Use of an alpha2delta ligand such as gabapentin or pregabalin for treating ttention deficit hyperactivity disorder. |
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US39214002P | 2002-06-27 | 2002-06-27 | |
US60/392,140 | 2002-06-27 |
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EP (1) | EP1515709A2 (en) |
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AU (1) | AU2003239752A1 (en) |
BR (1) | BR0312240A (en) |
CA (1) | CA2488566A1 (en) |
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Cited By (4)
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WO2008095253A1 (en) * | 2007-02-07 | 2008-08-14 | Gosforth Centre (Holdings) Pty Ltd | Treatment of adhd |
AU2008213908B2 (en) * | 2007-02-07 | 2013-07-25 | Gosforth Centre (Holdings) Pty Ltd | Treatment of ADHD |
US10028971B2 (en) | 2008-08-06 | 2018-07-24 | Gosforth Centre (Holdings) Pty Ltd. | Compositions and methods for treating psychiatric disorders |
US10590140B2 (en) | 2016-05-06 | 2020-03-17 | Esteve Pharmaceuticals, S.A. | Tetrahydropyrimidodiazepine and dihydropyridodiazepine compounds for treating pain and pain related conditions |
Families Citing this family (3)
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CN1094757C (en) | 1996-07-24 | 2002-11-27 | 沃尼尔·朗伯公司 | Isobutylgaba and its derivatives for the treatment of pain |
PT1622569E (en) | 2003-04-24 | 2016-03-03 | Incyte Corp | Aza spiro alkane derivatives as inhibitors of metallproteases |
US7910108B2 (en) | 2006-06-05 | 2011-03-22 | Incyte Corporation | Sheddase inhibitors combined with CD30-binding immunotherapeutics for the treatment of CD30 positive diseases |
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- 2003-06-16 JP JP2004517096A patent/JP2005534678A/en not_active Withdrawn
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008095253A1 (en) * | 2007-02-07 | 2008-08-14 | Gosforth Centre (Holdings) Pty Ltd | Treatment of adhd |
EP2505197A1 (en) * | 2007-02-07 | 2012-10-03 | Gosforth Centre (Holdings) Pty Ltd | Treatment of ADHD |
AU2008213908B2 (en) * | 2007-02-07 | 2013-07-25 | Gosforth Centre (Holdings) Pty Ltd | Treatment of ADHD |
US8957099B2 (en) | 2007-02-07 | 2015-02-17 | Gosforth Centre (Holdings) Pty Ltd. | Treatment of ADHD |
US9649297B2 (en) | 2007-02-07 | 2017-05-16 | Gosforth Centre (Holdings) Pty Ltd. | Treatment of ADHD |
US10028971B2 (en) | 2008-08-06 | 2018-07-24 | Gosforth Centre (Holdings) Pty Ltd. | Compositions and methods for treating psychiatric disorders |
US10590140B2 (en) | 2016-05-06 | 2020-03-17 | Esteve Pharmaceuticals, S.A. | Tetrahydropyrimidodiazepine and dihydropyridodiazepine compounds for treating pain and pain related conditions |
Also Published As
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ZA200409848B (en) | 2005-06-23 |
US20040006073A1 (en) | 2004-01-08 |
AU2003239752A1 (en) | 2004-01-19 |
WO2004002462A3 (en) | 2004-03-11 |
TW200400025A (en) | 2004-01-01 |
MXPA04012922A (en) | 2005-03-31 |
JP2005534678A (en) | 2005-11-17 |
CA2488566A1 (en) | 2004-01-08 |
BR0312240A (en) | 2005-04-12 |
IL165593A0 (en) | 2006-01-15 |
CN1678298A (en) | 2005-10-05 |
EP1515709A2 (en) | 2005-03-23 |
PL375090A1 (en) | 2005-11-14 |
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