Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-12-10
2004-06-01
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S307000
Reexamination Certificate
active
06743949
ABSTRACT:
The present invention refers to a new process for obtaining S-cetamine from racemic cetamine, by means of procedures of selective crystallization of its enantiomers with the aid of a chiral resolution agent employed in special concentration conditions, which confer stability and reproducibility on the precipitation of tartrate salts.
The (R,S)-2-(2-chlorophenyl)-2-methylamin cyclohexanone is known in Brazil with the generic name of cetamine.
Cetamine is a drug with sedative, analgesic and anesthesic properties, which molecular structure presents a chiral center (asymmetric carbon), thus having two enantiomers, known as S-cetamine and R-cetamine,
FIG. 1: Molecular formula of cetamine, with the representation of its asymmetric carbon.
Since it was introduced in the market, more than 20 years ago, it is commercialized in its racemic form, which consists of a mix in equal proportions of both enantiomers.
The last ten years of development of new drugs were marked by a deep change in the comprehension of the activity associated to the special molecular structure of new molecules and their receivers within the organism.
The three-dimension mapping of several specific receivers and enzymes, revealed the importance of development of enantiomeric defined drugs, as the different enantiomers of a given substance present differences on distribution of their ligands at three-dimension level. This different distribution of these ligands can provide different degrees of complementarity between these enantiomers and the activity sites.
In the cases where one of the enantiomers presents a high degree of complementarity with the action site, it is named eutomer. The eutomer, when exerting this activity, usually interferes with the action of his antipode, the distomer.
The distomer, however, is not always a passive component in the biological environment. It can actuate as agonist, antagonist, and it can exert activity on other receivers, can produce undesirable side effects and can even exert an activity complementary to the activity exerted by eutomer. (Williams K, Lee E—Importance of Drug Enantiomers in Clinical Pharmacology—Drugs, 30: 333-354 (1985)).
The development of new drugs in this last ten years has practically postulated that in cases where distomer do not contribute to the overall effect of one drug, he can be considered as an undesirable impurity, because, as it is a different entity from its eutomer, he can be potentially toxic. (Sheldon RA—Chirotechnology—Industrial Synthesis of Optically Active Compounds—pg. 50 (1993)).
Among several other well known drugs, we can mention some examples where distomers present undesirable side effect, which are not characteristics of their eutomers: Penicilamine is an anti-arthritis agent, where eutomer is the S-isomer, and its distomer is the R-isomer, which is highly toxic (mutagenic); the S,S-etambulol presents tuberculostatic activity 200 times superior to its distomer (R,R-etambulol), which causes optic neuritis that can result in blindness; L-dopa, used to the Parkinson Disease, is commercialized in this form, as its distomer produces severe side effects, such as granulocytopenia; and certainly, the most remarkable example of a drug formerly commercialized in its racemic form presenting the distomer associated with severe side effects, is talidomide. Commercialized during the sixties, as sedative, from the two enantiomers present in it, R-talidomide is the one who is effectively sedative, while its distomer (S-talidomide) is highly teratogenic, causing severe abnormalities for the phoetus. (Sheldon RA—Chirotechnology—Industrial Synthesis of Optically Active Compounds, pg 53 (1993)).
These new concepts are reformulating the use of drugs developed and commercialized in the form of racemic mixtures, due the fact that, in ancient times, it is not known the complexity of the interaction of different enantiomers in biological environment.
Cetamine is one of these drugs developed prior to the clarification of this new concepts. Recently, researches discovered that side effects post-anesthesia seen with its use, among them hallucinations and restiveness, are mainly associated to its R-enantiomer, while its S-enantiomer (eutomer) is the effectively anesthesic one, exerting this activity with a power about three or four times higher to its distomer. (Puu G, Koch M, Artursson E—Biochemical Pharmacology, 41(12): 2043-2045(1991); Sheldon, R. A.—Chirotechnology—Industrial Synthesis of Optically Active Compounds, p. 53 (1993)).
Feasibility of commercialization of this pure enantiomer from cetamine, S-cetamine, depends on the development of processes industrially efficient for its obtainment.
Among the available references that present procedures of obtaining S-isomer from cetamine, we have the procedure described in the patent DE 2062620 (Hudyma T W, Holmes S W e Hooper I R, de 1971), in which the obtainment of the S-cetamine is effected from racemic cetamine by means of the procedure of resolution with acid L-(+)-tartaric. The reaction medium consists of acetone and water and a reagent, the base racemic cetamine and the tartaric acid are employed in equivalent amounts in mol. The diastereomer salt separated in this procedure is recrystallized twice from acetonitrile, the isolated basis (S-cetamine) is also recrystallized and its chloridrate also suffers a rechrystallization to finally present a high enantiomeric purity with a low overall yield.
The consecutive recrystallization to which the several intermediate products and the final product are submitted, show a low enantiomeric purity of the tartrate salt from S-cetamine initially separated.
Industrially, the use of this procedure presents some disadvantages, among them the extensive purifications due to the low enantiomeric purity of the S-cetamine tartrate initially separated during the resolution process. Another disadvantage is associated to the solvent used in the purification of this salt, which is the acetonitrile, a toxic solvent which use in high proportions is not recommended.
In addition to these factors, experimentally this procedure shows a great variation of the enantiomeric purity of the precipitated S-cetamine tartrate, which interferes directly on the purification procedures for this salt. In some cases, also, the procedure is not efficient to separate enantiomers, occurring the crystallization on both forms, i.e. the S-cetamine and the R-cetamine tartrates, in proportions almost equivalent. The success of the recrystallization in acetonitrile is directly dependent on the enantiomeric purity of the salt initially precipitated, which, when low, presents separation of the product in the form of oil, which crystallizes slowly, without effective increments of this enantiomeric purity, becoming an additional problem in the adequacy of the method to a industrial scale production.
The patent WO 97/43244 (Gangkafner S, Grunenwald J, Steiner K, de 1997) describes a procedure almost identic to the patent DE 2062620 mentioned above, where the author only replaces the recrystallization solvent of S-cetamine tartrate, acetonitrile, by a mix of acetone and water.
It describes also some variants effected for this procedure, changing solvents used, and also the use of the resolution agent in amounts not proportional to the racemic base cetamine molar equivalent, this resolution agent being used in amount superior to the molar equivalent amount of the base cetamine.
As in the above reference, this procedure presents large variations in the precipitated amounts and in the separated salt enantiomeric purity, the S-cetamine tartrate. Due to the low enantiomeric purity of the precipitated salt, the product of the optical resolution needs to undergo reprocessing via recrystallization, in order to reach a higher enantiomeric purity, and this recrystallization represents the addition of one more phase in the procedure of obtaining S-cetamine, increasing the cost for the productive process.
There is also the patent WO 95/08529 (Grover E R, Mazzeo J R, Merion M, Petersen J S, Schwartz M E, de 1995), where
Mannochio de Souza Russo Elisa
Russo Valter Freire Torres
Birch & Stewart Kolasch & Birch, LLP
Cristália Produtos Químicos e Farmacêuticos Ltda.
Davis Brian
LandOfFree
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