Use of d4 and 5-ht2a antagonists, inverse agonists or partial agonists

• US 20070078162A1
• Filed: 12/02/2004
• Published: 04/05/2007
• Est. Priority Date: 12/02/2003
• Status: Active Grant

• Current Assignee: Pharmaneuroboost N.V.
• Original Assignee: Pharmaneuroboost N.V.
• Inventors: Buntinx, Erik
• Granted Patent: US 8,304,431 B2
• Time in Patent Office: Days
• US Class Current: 514/316
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

The present invention relates to the use of compounds and compositions of compounds having D4 and 5-HT2A antagonistic, partial agonistic or inverse agonistic activity for the treatment of the underlying dysregulation of the emotional functionality of mental disorders (i.e. affect instability-hypersensitivity-hyperaesthesia-dissociative phenomena-etc). The invention also relates to methods comprising administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) compounds having D4 antagonistic, partial agonistic or inverse agonistic activity and (ii) compounds having 5-HT2A antagonistic, partial agonistic or inverse agonistic, and (iii) any known medicinal compound and compositions of said compounds. The combined D4 and 5-HT2A antagonistic, partial agonistic or inverse agonistic effects may reside within the same chemical or biological compound or in two different chemical and/or biological compounds.

Claims

1-81. -81. (canceled)

82. A method for treating mood disorders or anxiety disorders comprising administering to a patient pipamperone, or a pharmaceutically acceptable salt thereof, in a dose ranging between 5 and 15 mg per day of the active ingredient, and administering said pipamperone simultaneously with, separate from or sequential to a second compound, to augment the therapeutic effect of said second compound or to provide a faster onset of the therapeutic effect of said second compound, wherein said second compound is selected from the group consisting of:

selective serotonin, nor-adrenaline and dopamine re-uptake inhibitors (SNDRI), selective serotonin and nor-adrenaline re-uptake inhibitors (SNRI) and selective serotonin re-uptake inhibitors (SSRI).

83. The method according to claim 82, wherein said pipamperone is administered daily at least one day before administering said second compound.

84. The method according to claim 82, wherein said second compound is a selective serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound.

85. The method according to claim 84, wherein said selective serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound is selected from the group consisting of NS 2330, McN 5652, DOV 216,303 and DOV 21,947, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

88. The method according to claim 82, wherein said second compound is a selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound.

89. The method according to claim 88, wherein said selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound is selected from the group consisting of venlafaxine, tomoxetine, tandamine, talsupram, talopram, nefazodone, milnacipran, LY 113.821, duloxetine, desvenlafaxine and amoxapine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

90. The method according to claim 89, wherein said venlafaxine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging between 75 and 300 mg of the active ingredient.

91. The method according to claim 89, wherein said tomoxetine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging between 0.475 and 3.8 mg/kg of the active ingredient.

92. The method according to claim 89, wherein said milnacipran, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging between 50 and 200 mg of the active ingredient.

93. The method according to claim 89, wherein said duloxetine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging between 40 and 60 mg of the active ingredient.

100. The method according to claim 82, wherein said second compound is a selective serotonin re-uptake inhibitor (SSRI) compound.

101. The method according to claim 100, wherein said selective serotonin re-uptake inhibitor (SSRI) compound is selected from the group consisting of YM 992, VPI-013 (OPC-14523), sertraline, paroxetine, LY 214.281, LU AA 21-004, Lu 35-138, litoxetine, ifoxetine, fluvoxamine (controlled release formulation), fluvoxamine, fluoxetine, femoxetine, escitalopram, EMD 68843, cyanodothepine, citalopram, venlafaxine, milnacipran, duloxetine, ademethionine (preferably s-adenosylmethionine) and cericlamine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

102. The method according to claim 101, wherein said selective serotonin re-uptake inhibitor (SSRI) compound is fluvoxamine (controlled release formulation), or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging between 100 and 300 mg of the active ingredient.

103. The method according to claim 101, wherein said selective serotonin re-uptake inhibitor (SSRI) compound is escitalopram, or a pro-drug or an active metabolite thereof, and is administered in a daily dose ranging between 10 and 20 mg of the active ingredient.

104. The method according to claim 101, wherein said selective serotonin re-uptake inhibitor (SSRI) compound is citalopram, or a pro-drug or an active metabolite thereof, and is administered in a daily dose ranging between 10 and 40 mg of the active ingredient.

86. A pharmaceutical composition comprising (a) pipamperone, and (b) a selective serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound, as a combined preparation for simultaneous, separate or sequential use for treating mood disorders or anxiety disorders, wherein said pipamperone is provided in a unitary dose of between 5 and 15 mg of the active ingredient.

87. The pharmaceutical composition according to claim 86, wherein said selective serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound is selected from the group consisting of NS 2330, McN 5652, DOV 216,303 and DOV 21,947, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

94. A pharmaceutical composition comprising (a) pipamperone and (b) a selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound as a combined preparation for simultaneous, separate or sequential use for treating mood disorders or anxiety disorders, wherein said pipamperone is provided in a unitary dose of between 5 and 15 mg of the active ingredient.

95. The pharmaceutical composition according to claim 94, wherein said selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound is selected from the group consisting of venlafaxine, tomoxetine, tandamine, talsupram, talopram, nefazodone, milnacipran, LY 113.821, duloxetine, desvenlafaxine and amoxapine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof,

96. The pharmaceutical composition according to claim 95, wherein said venlafaxine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, provided in a unitary dose of between 75 and 300 mg of the active ingredient.

97. The pharmaceutical composition according to claim 95, wherein said tomoxetine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 38 and 304 mg of the active ingredient.

98. The pharmaceutical composition according to claim 95, wherein said milnacipran, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 50 and 200 mg of the active ingredient.

99. The pharmaceutical composition according to claim 95, wherein said duloxetine, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 40 and 60 mg of the active ingredient.

105. A pharmaceutical composition comprising (a) pipamperone and (b) a selective serotonin re-uptake inhibitor (SSRI) compound as a combined preparation for simultaneous, separate or sequential use for treating mood disorders or anxiety disorders, wherein said pipamperone is provided in a unitary dose of between 5 and 15 mg of the active ingredient.

106. The pharmaceutical composition according to claim 105, wherein said selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound is selected from the group consisting of YM 992, VPI-013 (OPC-14523), sertraline, paroxetine, LY 214.281, LU AA 21-004, Lu 35-138, litoxetine, ifoxetine, fluvoxamine (controlled release formulation), fluvoxamine, fluoxetine, femoxetine, escitalopram, EMD 68843, cyanodothepine, citalopram, venlafaxine, milnacipran, duloxetine, cericlamine and ademethionine (preferably s-adenosylmethionine), or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.

107. The pharmaceutical composition according to claim 106, wherein said fluvoxamine (controlled release formulation), or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 100 and 300 mg of the active ingredient.

108. The pharmaceutical composition according to claim 106, wherein said escitalopram, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 10 and 20 mg of the active ingredient.

109. The pharmaceutical composition according to claim 106, wherein said citalopram, or a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable salt thereof, is provided in a unitary dose of between 10 and 40 mg of the active ingredient.