Amino Acid Conjugates of Quetiapine, Process for Making and Using the Same
The presently described technology provides a novel class of prodrugs of quetiapine that can be synthesized by chemically conjugating amino acids to quetiapine. The present technology also provides methods of treating patients, pharmaceutical compositions and methods of synthesizing conjugates of the present technology.
1 - 134 . (canceled)
135 . A composition for treating a psychiatric disorder in a subject, comprising a conjugate of 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) or an active metabolite thereof and an amino acid, a salt thereof, a derivative thereof or their combination.
136 . The composition of claim 135 , wherein the amino acid is a standard amino acid, a non-standard amino acid, a natural amino acid, a synthetic amino acid or a combination thereof.
137 . The composition of claim 135 , wherein the amino acid is valine and the conjugate is 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl L-valine, 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl D-valine, their active metabolites and/or derivatives, pharmaceutically acceptable salts or their combination.
138 . The composition of claim 135 , wherein the amino acid is phenylalanine and the conjugate is 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl L-phenylalanine, 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl D-phenylalanine, their active metabolites and/or derivatives, pharmaceutically acceptable salts or their combination.
139 . The composition of claim 135 , wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally.
140 . The composition of claim 135 , wherein the composition is formulated for oral or suppository administration.
141 . The composition of claim 140 , wherein the composition formulated for oral administration is a tablet, capsule, caplet, pill, troche, lozenge, liquid solution, suspension, elixir or oral thin film.
142 . The composition of claim 135 , wherein the conjugate of quetiapine or an active metabolite and/or an active derivative thereof and an amino acid, a salt thereof, a derivative thereof or their combination is present in an amount of between about 1 mg and 2000 mg per unit dose.
143 . The composition of claim 141 , wherein the conjugate of quetiapine or an active metabolite and/or an active derivative thereof and an amino acid, a salt thereof, a derivative thereof or their combination is present in an amount of between about 150 and 800 mg per unit dose.
144 . The composition of any one of claim 142 or 143 , wherein the presence of quetiapine, an active metabolite and/or an active derivative thereof is based on molar equivalent of unconjugated quetiapine or unconjugated active metabolite thereof.
145 . The composition of claim 135 , wherein the psychiatric disorder is schizophrenia, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, restless legs syndrome, autism, alcoholism, depression, insomnia or Tourette syndrome.
146 . The composition of claim 135 , wherein the subject is a human or a mammal subject.
147 . The composition of claim 135 , wherein the subject has not been diagnosed with schizophrenia or bipolar disorder.
148 . The composition of claim 135 , further comprising one or more of: lithium, divalproex, antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents and sweeteners.
149 . The composition of claim 135 , wherein the salt of the conjugate of quetiapine or an active metabolite and/or an active derivative thereof and an amino acid is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate or a mixture thereof.
150 . The composition of claim 149 , wherein the organic acid salt is a mesylate salt, a besylate salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate salt, a citrate salt, a malate salt, or a tartarate salt.
151 . A composition for treating a psychiatric disorder in a subject comprising, a conjugate of quetiapine or an active metabolite and/or an active derivative thereof and an amino acid, a salt thereof, a derivative thereof or their combination wherein the composition is represented by any one of the following structures of formulas I-IV:
a pharmaceutically acceptable salt thereof, a derivative thereof or their combination.
152 . A composition for treating a psychiatric disorder in a subject comprising, a conjugate of quetiapine or an active metabolite and/or an active derivative thereof and an amino acid, a salt thereof, a derivative thereof or their combination wherein the composition is represented by any one of the following structures of formulas V-VIII:
a pharmaceutically acceptable salt thereof, a derivative thereof or their combination.
153 . A method of treating a psychiatric disorder requiring the binding of dopamine receptor(s), serotonin receptor(s), or both in a subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of quetiapine, an active metabolite and/or an active derivative thereof, conjugated to an amino acid, a pharmaceutically acceptable salt or derivative thereof, thereby binding a dopamine receptor, a serotonin receptor, or both.
154 . The method of claim 153 , whereby the amino acid is a standard amino acid, a non-standard amino acid, a natural amino acid, a synthetic amino acid or a combination thereof.