Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-02
2003-07-22
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S112000
Reexamination Certificate
active
06596868
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for synthesizing an anhydroecgonine derivative that is an intermediate for synthesis of an alkaloid having the same tropane skeleton as that of cocaine having an affinity for dopamine transporters pharmacologically, and a process for synthesizing a phenyltropane derivative by using said anhydroecgonine derivative as an intermediate for the synthesis.
2. Related Art
Cocaine is an alkaloid contained in the leaves of, for example, coca (Erythroxylon coca) growing in the Andes in South America. A pure preparation of this alkaloid was isolated for the first time by Niemann et al. in 1860. Cocaine tastes bitter and its special effects such as numbness of tongue and sensory paralysis have been revealed. Freud and Koller applied cocaine to clinical use for the first time. In 1884, Freud extensively investigated the physiological effects of cocaine. On the other hand, Koller applied cocaine to a local anesthetic in the ophthalmic operation. Thereafter, local anesthesia using cocaine has rapidly come to be employed in various fields of medicine. Einhorn investigated the synthesis of a substitute for cocaine (Goodman, “Yakurisho”, 8th ed., Hirokawa Shoten Ltd.). Since cocaine has recently been found to have an affinity for dopamine transporters, it has been shown that cocaine derivatives are useful as tracer ligands, in particular, radioactive tracers for imaging agents in nuclear medicine.
Cocaine blocks the uptake of dopamine into nerve cells because of its affinity for dopamine transporters that are membrane proteins capable of re-uptake of dopamine released into synaptic clefts from dopamine nerve ending. In recent years, this mechanism of action of cocaine has been noticed in the field of nuclear medicine and attempts have been made to give a diagnosis by imaging of the dopamine transporters. Accordingly, radiolabeled products of various cocaine analogs were investigated. Neumeyer et al. found compounds such as 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)-tropane which are neuroprobes useful as radioactive tracers having an affinity for the dopamine transporters for use in single-photon emission computed tomography (SPECT) or positron emission tomography (PET) in nuclear medicine. It has been shown that the brain uptake and clearance from brain of these compounds are slower than those of cocaine itself, and that the uptake of the compounds into striatum substantially reflects the distribution of dopamine reuptake site (U.S. Pat. No. 5,310,912). In addition, Neumeyer et al. investigated various phenyltropane derivatives and consequently confirmed that N-(3-fluoropropyl)-2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)nortropane is a compound further improved, for example, in pharmacokinetic problems such as residence time as compared with 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)tropane. It has been reported that the estimation of the change of dopamine nerve cells by imaging of striatum dopamine transporters with the radioiodinated (Iodine-123) phenyltropane derivatives gives useful information for early diagnosis of Parkinson's disease and judgment on the seriousness of this disease (Booiji et al., Eur. J. Nucl. Med., 1997, 24, 68-71).
At present, as shown in the scheme A exhibited hereinafter, the tropane skeleton as basic skeleton of cocaine is obtained as anhydroecgonine methyl ester by hydrolyzing cocaine as a starting material into ecgonine, dehydrating the ecgonine, and converting the dehydrated product to methyl ester (Kozikowski et al., J. Am. Chem. Soc., 1995, 38, 3086). From this anhydroecgonine methyl ester, there can easily be synthesized a derivative having an optically active tropane skeleton having the same absolute configuration as that of natural (−)-cocaine, such as 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)tropane or N-(3-fluoropropyl)-2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)-nortropane. Cocaine, however, is designated as a narcotic because of problems such as drug dependence. For that reason, there are various difficulties in obtaining and handling cocaine. Therefore, there is desired the development of a process for synthesizing a compound analogous to cocaine which does not cause the difficulties.
Since early times, attempts have been made to synthesize a cocaine analogous (a tropane derivative) without using cocaine as a starting material. Robinson et al. synthesized tropinone by condensing a dialdehyde, methylamine and acetonedicarboxylic acid ethyl ester (Robinson et al., J. Chem. Soc., 1917, 762-768; Findlay et al., J. Org. Chem., 1957, 22, 1385-1394). Neumeyer investigated the synthesis of 2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)tropane using tropinone as a starting material (Neumeyer et al., J. Med. Chem., 1993, 36, 1914-1917). Tufariello et al. attempted stereoselective synthesis of cocaine (Tufariello et al., Tetrahedron Lett., 1978, 20, 1733-1736). However, in each of these synthetic processes, the synthesis should be carried out by producing cocaine or ecgonine methyl ester as an intermediate in the synthetic procedure. Carrying out the synthesis by replacing the substituent on the nitrogen atom with another substituent can be thought of but is disadvantageous in that it requires several additional steps. Grundmann et al. synthesized dl-ecgonidine and its ester from a cycloheptatrienecarboxylic acid derivative synthesized from benzene and a diazoacetic acid derivative, without producing an ecgonine derivative as an intermediate (Grundmann et al., Justus Liebigs Ann. Chem., 1957, 605, 24-32, and U.S. Pat. No. 2,783,235). However, no starting material other than the cycloheptatrienecarboxylic acid derivative is described in these references.
Since almost all of the above processes for synthesizing a tropane derivative are processes for synthesizing a racemic cocaine derivative, an optical resolution step is required for obtaining an optically active tropane derivative having the same absolute configuration as that of (−)-cocaine. For example, in order to obtain starting material for synthesizing various tropane derivatives, Grundmann et al. attempted the optical resolution of dl-ecgonidine ethyl ester by recrystallization and Wang et al. attempted the optical resolution of dl-carbomethoxytropinone by recrystallization. However, it is generally difficult to obtain a compound (1-form, (−)-form) having an extremely high optical purity, only by optical resolution by recrystallization. Selective synthesis of optically active anhydroecgonine methyl ester by an asymmetric synthetic method was also carried out by Davies et al. (J. Org. Chem., 1991, 56, 5696-5700, and Japanese Patent Application Kohyo No.7-504665) and Node et al. (Tetrahedron Lett., 1999, 40, 5357-5360). However, neither of their synthetic processes can give a desired compound having a satisfactory optical purity, for example, because the processes comprise a large number of steps for the synthesis.
SUMMARY OF THE INVENTION
In view of such situation, the present invention is intended to provide a process for synthesizing an anhydroecgonine derivative useful as an intermediate for synthesis of a tropane derivative, without using cocaine as a starting material, and a process for synthesizing a tropane derivative by using said anhydroecgonine derivative as an intermediate for the synthesis.
One aspect of the present invention is directed to a process for synthesizing an anhydroecgonine derivative which comprises reacting a cycloheptatriene derivative of the formula (1) shown below with a primary amine, a salt thereof or ammonia.
That is, it is directed to a process for synthesizing an anhydroecgonine derivative which comprises reacting a cycloheptatriene derivative represented by the formula (1):
wherein n is an integer of 0 or 1; and R
1
is a cyano group in the case of n being 0, and R
1
is selected from an alkyl group and an aralkyl group in the case of n being 1, with a primary amine represented by the formula (2):
R
2
NH
2
(2)
wherein R
2
is a hydrogen atom, an unsub
Itoh Osamu
Okano Kyoko
Nihon Medi+Physics Co., Ltd.
Rotman Alan L.
Sughrue & Mion, PLLC
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