- Stereoisomers with high affinity for adrenergic receptors
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The present invention provides stereoscopically-pure diastereomers of Formula I: 1In a preferred embodiment, the stereoisomers of the present invention are of Formula II, depicted below: 2R2, R3 and le are independently H, OH, OCH3, CH2OH, NHCONH2, NH2, halogen or CF3, and R1 is pyridine, or an amine which may be substituted with hydrogen, lower alkyl, lower alkylenearyl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, or a similar functional group. TV is hydrogen, hydroxyl or methyl; R6 is hydrogen, lower alkyl, lower alkylenaryl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, and the like. For both Formula I and Formual II, the firs carbon on the side chain progressing from the ring is preferably in the R-configuration. The second carbon atom on the side chain of Formula II, which is attached to IV, may or may not be a chiral center. However, when the second carbon atom is a chiral center, it is preferably in the S-configuration. The present invention contemplates each stereoisomer of Formula I and II in substantially-pure form. The present invention also provides methods of relieving nasal, sinus and bronchial congestion and of treating attention deficit hyperactivity disorder and obesity. The present stereoisomers may also be used to induce pupil dilation. These methods include administering to a mammal a composition containing a therapeutically effective amount of a stereoscopically-pure stereoisomer of Formula I or II with a pharmaceutically acceptable excipient.
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- Stability of oxetacain and the structure of its degradation products
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Refluxed acid aqueous solutions of oxetacain (1) show 3 degradation products. 1 is decomposed at room temperature (20 °C, 480 d) 10%. 7 degradation products of crystalline 1 are detectable in the temperature-moisture test. At room temperature no other product than 1 appears. Under normal storage conditions a 5-year stability for acid aqueous solutions and a more than 10-year stability for crystalline 1 are estimated. Small amounts of the degradation products were isolated by TLC and HPLC. According to MS, UV and IR analysis their structures are mephentermin (2), a morpholinone derivative (3), a carboxylic acid derivative of 1 (4), a mono-C-demethyl-1 (5) and a mono-N-de(1-phenyl-2-methyl-propyl)-1 (6). The structures of 2 other degradation products are unknown. MS fragmentation mechanisms are discussed.
- Gober,Franke,Lisowski
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p. 584 - 587
(2007/10/02)
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- In vitro stability and biotransformation of 3'-hydroxy-2-[N-methyl-N-(1,1-dimethyl-2-phenethyl)amino] acetophenone (TVX 960)
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3'-Hydroxy-2-[N-methyl-N-(1,1-dimethyl-2-phenethyl)amino]acetophenone (TVX 960) is shown to be only partially stable in solution; hydrolysis occurs at neutral to alkaline pH-values. Proteolytic splitting in artificial intestinal liquid with pancreatin is particularly strong while in artificial stomach juice practically no breakdown occurs. In vitro studies show TVX 960 to be extensively stable in dog plasma. Approx. 95% of the compound is intact after 160 min, the rest is being broken down to mephentermine. In whole blood, however, more than 50% is broken down under the same conditions. In liver homogenates of dogs and rats, a strong breakdown occurs at approx. the same rates; the proportion of mephentermine in the liver homogenate of dogs is, however, lower than that in the liver homogenate of rats. In vivo studies in man show that following oral administration of equimolar quantities of TVX 960 and mephentermine certain differences exist with regard to renal elimination. No intact or glucuronide-conjugated TVX 960 are excreted. The amounts of mephenterine, phentermine and other basic metabolites over the first 4 h following administration of TVX 960 is approx. 4 times as high as following administration of mephentermine. Over the period from 8-60 h, however, the proportion of renally eliminating amines following administration of mephentermine is higher than following administration of TVX 960. Blood level determination in man shows that TVX 960 has a higher rate of absorption than mephentermine. The elimination (from blood) is also quicker following administration of TVX 960 than following mephentermine. The degree of N-demethylation differs following administration of the 2 compounds. Despite the hydrolytic or proteolytic instability of TVX 960 the proportion of phentermine in the blood is higher at first. From the differing phentermine/mephentermine ratios in the blood it can be seen that the N-demethylation occurring in vivo represents mainly the primary breakdown step of TVX 960. The phentermine/mephentermine ratio in the urine confirms that N-demethylation is to be regarded as the primary breakdown step.
- Dell,Donik,Jacobi,Kamp
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p. 1138 - 1144
(2007/10/02)
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