COMPOUNDS AND COMPOSITIONS AND USES THEREOF

• US 20190308990A1
• Filed: 12/10/2018
• Published: 10/10/2019
• Est. Priority Date: 07/29/2016
• Status: Active Grant

• Current Assignee: PGI Drug Discovery LLC, Sumitomo Pharma America, Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: PGI Drug Discovery LLC
• Inventors: Xie, Linghong, Heffernan, Michele L.R., Jones, Philip Glyn, Hanania, Taleen G.
• Granted Patent: US 10,927,124 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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
• CPC Class Codes: C07D 307/87 Benzo [c] furans; Hydrogenated benzo [c] furans
• CPC Class Codes: C07D 311/76 Benzo[c]pyrans
• CPC Class Codes: C07D 313/08 condensed with one six-membered ring
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

Disclosed are compounds of formula (I):

and pharmaceutical compositions containing such compounds. Methods of treating neurological or psychiatric disease and disorders in a subject in need are also disclosed.

Claims

1-74. -74. (canceled)

75. A process for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

76. The process of claim 75, wherein the deprotecting comprises treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid.

77. The process of claim 76, wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out in the presence of ethyl acetate.

78. The process of claim 76, wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out at ambient temperature.

79. The process of claim 76, wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out for about 16 h.

80. The process of claim 75, further comprising separating (S)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine and (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine.

81. The process of claim 80, wherein the separating is performed by chiral HPLC.

82. The process of claim 75, wherein tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate is prepared by a process comprising converting tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate, having the structure:

83. The process of claim 82, wherein the converting tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate to tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate comprises treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under an H₂ atmosphere.

84. The process of claim 83, wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under an H₂ atmosphere is carried out in the presence of methanol.

85. The process of claim 83, wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under H₂ atmosphere is carried out at ambient temperature.

86. The process of claim 83, wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under H₂ atmosphere is carried out for about 4 h.

87. The process of claim 82, wherein tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate is prepared by a process comprising protecting 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

88. The process of claim 87, wherein the protecting 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine comprises treating 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine with di-tert-butyl dicarbonate.

89. The process of claim 88, wherein the treating 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out in the presence of water.

90. The process of claim 88, wherein the treating 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out at ambient temperature.

91. The process of claim 88, wherein the treating 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out for about 3 h.

92. The process of claim 87, wherein 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine is prepared by a process comprising reacting 2-(2-bromo-5-fluorophenyl) ethanol, having the structure:

93. The process of claim 92, wherein the acid is trifluoromethanesulfonic acid.

94. The process of claim 92, wherein the acid is trimethylsilyl trifluoromethanesulfonate.

95. The process of claim 92, wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out in the presence of dichloromethane.

96. The process of claim 92, wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out at about 0°

C.

97. The process of claim 92, wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out for about 16 h.