| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 23, 1996 |
| PATENT TITLE |
Geneserine derivatives processes as cholinesterase inhibitors |
| PATENT ABSTRACT |
Geneserine homologs of formula I ##STR1## in which R is a straight or branched C.sub.2 -C.sub.20 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, an unsubstituted phenyl or benzyl group, or a phenyl or benzyl group substituted by a C.sub.1 -C.sub.4 alkyl group, a halogen atom or a C.sub.1 -C.sub.4 alkoxy group, or a salt with an organic or inorganic non-toxic acid, exhibit anticholinesterase activity and may be useful in the treatment of Alzheimer disease and other conditions due to a neurological deficiency. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 3, 1994 |
| PATENT CT FILE DATE | August 4, 1992 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | February 18, 1993 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Robinson et al, Journal of Pharmacy and Pharmacology, 1968, 20S, 213S-217S. Ligny et al, Chemical Abstracts 90: 162,308, abstract of French Patent FR 2 374 908 issued Jul. 1978. Shishido et al, Journal of chemical Society, Perkin Trans., 1(11), Nov. 1987, 2491-2495. Robinson et al., Journal of the Chemical society, Section C: Organic Chemistry, No. 15, 2077-2078, 1970. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A compound of formula I: ##STR6## wherein R is a straight or branched C.sub.4 -C.sub.12 alkyl group, an unsubstituted phenyl or benzyl group, or a phenyl substituted by a C.sub.1 -C.sub.4 alkyl group, and a salt thereof with an organic or inorganic non-toxic acid. 2. The compound according to claim 1 wherein R is a straight C.sub.4 -C.sub.12 alkyl group. 3. The compound according to claim 1 wherein R is n-heptyl or n-octyl. 4. The compound according to claim 1 wherein R is an unsubstituted benzyl or phenyl, or a phenyl substituted by a C.sub.1 -C.sub.2 alkyl group. 5. The compound according to claim 1 which is a salt with tartaric, hydrochloric or salicylic acid. 6. A pharmaceutical composition containing as the active ingredient a compound according to claim 1 in admixture with a compatible carrier. 7. The method of treatment of a patient in need of a medicament having cholinesterase-inhibiting activity which consists of administering to said patient 10-1000 mgs daily of a compound of formula I ##STR7## wherein R is a straight or branched C.sub.4 -C.sub.12 alkyl group, an unsubstituted phenyl or benzyl group, or a phenyl substituted by a C.sub.1 -C.sub.4 alkyl group, and a salt thereof with an organic or inorganic non-toxic acid. |
| PATENT DESCRIPTION |
The present invention relates to geneserine derivatives, a process for the preparation thereof and pharmaceutical compositions containing them. The compounds of the invention have the following general formula I: ##STR2## wherein R is a straight or branched C.sub.2 -C.sub.20 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, a phenyl or benzyl group, optionally substituted with C.sub.1 -C.sub.4 alkyl groups, halogen atoms, C.sub.1 -C.sub.4 alkoxy groups. Preferably R is an alkyl group having 4 to 12 carbon atoms, most preferably 6 to 8 carbon atoms. Compound I, in which R is an n-heptyl group, is particularly preferred. The invention also comprise s the salts of compounds I with pharmaceutically acceptable acids, particularly hydrochloric, sulfuric, tartaric, succinic, maleic, citric, methanesulfonic, fumaric, acetic, lactic, salicylic acids. The compounds of formula I and the pharmaceutically acceptable salts thereof have inhibiting activity against cholinesterase and they can usefully be administered to patients suffering from Alzheimer disease or from various other conditions deriving from a neurologic deficiency. Alzheimer disease is a form of progressive dementia clinically characterized by loss of memory and impairment of the intellective activities. The importance of the cholinergic system in Alzheimer disease is well known and the loss of the cholinergic function has been found to be related to both the presence of neuropathologic lesions and a severe loss of the cognitive functions. On the basis of such evidences, one of the most studied therapeutical approaches is the cholino-mimetic one, intended to improve and increase the cholinergic activity. The most promising results were obtained using cholinesterase inhibitors, particularly physostigmine and tacrine. EP-A-0154864 and EP-A-0298202 disclose physostigmine derivatives characterized by an increased lipophilia, due to the presence of long-chain alkyl or aryl residues on the carbamoyl group which is typical of this class of alkaloids. Geneserine, even though it has been known for many years as an anticholinergic agent and used in therapy as a gastrointestinal antispastic, has never been the object of studies in order to verify its capability to restore the cholinergic function at the level of central nervous system. Now it has been found that geneserine derivatives of formula I have pharmacological properties which are particularly interesting and advantageous compared with the prior art compounds. Compounds of formula I can be prepared by oxidizing compounds of formula II ##STR3## wherein R is as defined above. The oxidation is preferably carried out by means of organic peracids or peroxides, such as m-chloroperbenzoic acid, monoperphthalic acid, peracetic acid, hydrogen peroxide, in inert solvents such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide. The preparation of compounds of formula II from physostigmine is known from EP-A-0154864 and EP-A-0298202, cited above. Alternatively, compounds I can be obtained starting from geneserine by hydrolysis of the methylaminocarbonyloxy group and subsequent O-acylation with reagents capable of introducing the desired function ##STR4## wherein R is as defined above. Examples of acylating reagent s which can conveniently be used for this purpose comprise alkylisocyanates of formula R-NCO, wherein R is as in formula I, or in alternative substituted imidazolureas of formula III ##STR5## which can be prepared from carbonyldiimidazole and amines of formula RNH.sub.2, wherein R is as defined above. Hydrolysis of geneserine can be carried out analogously to that of physostigmine, by reaction with alkali alkoxides, whereas the O-acylation with the substituted imidazolureas is carried out in a strictly anhydrous medium, in the presence of metal sodium. The resulting compounds I can then be salified with organic or inorganic non-toxic acids, according to the conventional techniques. Compounds I, for the envisaged therapeutical uses, will be formulated according to conventional techniques and excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., New York U.S.A., 18.sup.ma Ed. The average daily dosage will depend, of course, on many factors, but generally it will range from 10 to 1000 mg of compounds I or the salts thereof. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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