MXPA97005390A - Use of the 3,4-difenil-chromanos for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of debenerative disorders cerebra - Google Patents

Abstract

The present invention provides the novel uses of the compounds of the general formula (I), wherein R1, R4 and R5 are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of cerebral degenerative disorders

Description

USE OF THE 3,4-DIFENILCROMANOS PAPA THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR TREATMENT OR PROPHYLAXIS OF BRAIN DEGENERATIVE DISORDERS FIELD OF THE INVENTION The present invention relates to the use of the compounds of the general formula I for the treatment of patients suffering from cerebral degenerative disorders, for example, Alzheimer's disease, and prophylaxis thereof. The present invention also encompasses pharmaceutical compositions comprising these compounds and methods for using the compounds and their pharmaceutical compositions.

BACKGROUND OF THE INVENTION In the classification of diseases of the nervous system, it is customary to designate a group of them as degenerative, indicating that they are characterized by slowly progressive neuronal death, of gradual evolution, which occurs for reasons that are still unknown. The identifications of these diseases depend on the REF: 25039 exclusion of possible causal factors such as infections, metabolic deterioration, and intoxications. A considerable proportion of the disorders classified as degenerative are genetic. Others, however, occur only sporadically as isolated cases in a given family. The classification of degenerative disorders can not be based on any exact knowledge of the etiology or pathogenesis; its subdivision into individual syndromes lies in the descriptive criteria based mainly on neuropathological and clinical aspects. Many of the degenerative diseases of the nervous system progress not influenced by therapeutic measures. Alzheimer's disease (AD) is perhaps the most important of all degenerative diseases due to its frequent onset and devastating nature. AD is a degenerative brain disorder clinically characterized by progressive loss of memory, cognition, reasoning, judgment and emotional stability, which gradually leads to profound mental deterioration and ultimately death. AD is the most common cause of progressive mental failure (dementia) in the elderly, and is thought to represent the fourth most common medical cause of death in the United States. It is estimated that currently the disease affects approximately two to three million individuals in the United States alone. To date, many of the degenerative diseases of the nervous system, including AD, progress not influenced by any therapeutic measures. The most prominent pathological feature is death and the disappearance of nerve cells in the cerebral cortex. This eventually leads to extensive convolutional atrophy, especially in the frontal, parietal and mid temporal regions. Two types of microscopic lesions are distinctive for the disease. The first, originally described by Alzheimer's, consists of intraneuronal accumulations of filamentous material in the form of curls, spirals or entangled masses called neurofibrillary tangles of Alzheimer's. Its exact nature is currently under active research, but neuropathological evidence strongly suggests that these fibrillar masses of a nature to iloidogenic are of major importance in triggering the death of neurons. The second histopathological change that characterizes AD is the presence of intracortical clusters of thickened neuronal processes, axons and dendrites. Several lines of evidence indicate that the progressive cerebral deposition of particular amyloidogenic proteins, β-amyloid proteins (βAP), plays an important role in the pathogenesis of AD, and may precede cognitive symptoms by years or decades (Selkoe DJ, Neuron 6: 487, 1991). Recently, ßAP has been shown to be released from neuronal cells developed in the brain culture, and is present in the cerebrospinal fluid (SCF) of normal individuals and patients with AD (Seubert et al., Nature 359: 325, 1992). Biochemical studies show that choline acetyltransferase, the key enzyme required for the synthesis of acetylcholine, is decreased in the cerebral cortex in AD. The main source of cholinergic innervation of the neocortical is a group of neurons located in the basal part of the anterior brain just below the striatum, the basal nucleus of Meynert. This nucleus is a site of major neuronal loss and frequent neurofibrillary tangles of Alzheimer's. In this way, the deterioration of cholinergic transmission may play a role in the clinical expression of the disease. However, the therapy attempted with colmomimetic agents has not been widely successful. In contrast, recent studies have indicated that estrogen influences cholinergic function through stimulation of choline acetyltransferase (Kaufman H et al., Brain Res 453: 389, 1988) and that it also increases receptor binding sites. hypothalamic nicotinic acetylcholine (Morley BJ et al., Brain Res 278: 262, 1983). Furthermore, it has been suggested that low-dose estrogen replacement therapy may have a beneficial effect on AD (Okura T et al., Menopause 1: 125, 1994). However, the effects of estrogen in rats show difference by sex: the administration of estradiol increased the activity of choline acetyltransferase in nuclei in females that had undergone oophorectomy, but had a decrease or no effect in castrated males (Luine VN & amp; amp; amp;; McEwen BS, Neuroendrocrinology 36: 36: 475, 1983). In addition, there are significant side effects of estrogen replacement therapy, with the largest disturbance being the well established correlation with endometrial and breast cancers. The incidence of carcinoma is dependent on dose and duration. Avoiding the risk of cancer has been achieved by the concomitant use of a progestogen with estrogen. This combination, however, causes menstruation to return, which many women find unacceptable. A further disadvantage is that the long-term effects of the progestogen have not been fully determined. There is still a need in the art for compositions and methods that are useful in the treatment or prophylaxis of degenerative brain disorders including Alzheimer's disease. There is an additional need for compositions that lack the undesirable side effects of estrogen. The centroman is a. A non-steroidal compound known to have antiestrogenic activity. This is in use in India as an oral contraceptive (see, for example, Salman et al., US Patent Specification No. 4,447,622; Singh et al., Acta Endocrinol.

(Copenh) 126 (1992), 444-450; Grubb, Curr. Opin.

Obstet. Gynecol. 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Hindu Patent Specification No. 129187). Centcroman has also been investigated as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781-783). Recently, it has been found that centchroman as a racemate is potent as a pharmaceutical product that lowers cholesterol, expressed by a significant decrease in serum concentrations (SD Bain et al., J. Min. Bon. Res. 9 (1994), 394). U.S. Patent No. 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts. An object of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of disorders of cerebral degeneration, for example, Alzheimer's disease.

BRIEF DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the general formula I as set forth in claim 1 can be used in the treatment or prophylaxis of disorders of cerebral degeneration, for example, Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based in part on the discovery that a representative 3, 4-diarylchroman, centroman (3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1) -yl) ethoxy) phenyl] -7-methoxy chroman) is effective against cerebral degenerative disorders, for example Alzheimer's disease, among others in mice or Fisher rats. Centroman is a racemic mixture. These animal models are generally recognized models for example of degenerative brain disorders, for example Alzheimer's disease. These data thus indicate that the 3, 4-diarylchromans of the formula I are useful as therapeutic and preventive agents against degenerative brain disorders, for example Alzheimer's disease, in mammals, including primates such as humans. Within the present invention, the compounds of the formula I as set forth in claim 1 are administered as drugs against cerebral degenerative disorders, for example, Alzheimer's disease. Within the formula I, R ', R4 and RD are individually hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R2 and RJ are individually hydrogen or lower alkyl. As used herein, the term "lower alkyl" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-prolyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "lower alkoxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec. -amiloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includes chlorine, fluorine, bromine and iodine. The tertiary amino radical can be an N, N-dialkylamine such as N, N-dimethylamine, N, N-diethylamine, N, N-dipropylamine and N, N-dibutylamine or a polymethyleneimine, for example, piperidine, pyrrolidine, N- methylpiperazine or orpholine. In the present, the term "(tertiary amino) (lower alkoxy)" is a lower alkoxy group which is substituted by a tertiary amino group. Preferred compounds include those in which R ~ is lower alkoxy; R2 and R3 are lower alkyl, especially methyl; R4 is hydrogen; and R "is (tertiary amino) (lower alkoxy) of the polymethyleneimine type. Within the particularly preferred embodiments, R1 is in the 7-position and is lower alkoxy, particularly methoxy; each of Rz and R3 is methyl, R4 is hydrogen, and R5 is in the 4-position and is a radical (tertiary amino) (lower alkoxy) such as 2- (pyrrolidin-1-yl) ethoxy. To be included by this invention are all pharmaceutically acceptable salts of the aforementioned compounds of the formula I. It is preferred to use the compounds of the formula I in the trans configuration. These compounds can be used as racemic mixtures, or the isolated stereoisomers can be used, for example, d- or 1-enantiomers. Trans-d-enantiomers are more preferred. A particularly preferred compound for use within the present invention is cent-chroman consisting of 1-centchroman and d-centchroman. Probably, 1-centchroman has the formula IV. the 3, 4-diachromagnes are prepared according to known methods, such as those described in US Patent Specification No. 3,340,276 to Carney et al., US Patent Specification No. 3,822,287 to Bolger, and Ray et al., J. Med. Chem. 18 (1976), 276-279, the contents of which are incorporated by reference herein. The conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is described in US Patent Specification No. 3,822,287. The optically active d and 1 enantiomers can be prepared as described by Salman et al. In US Patent Specification No. 4,447,622 (incorporated by reference herein) by the formation of an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. If R2 is different from R3 and R4 is different from R ", general formula I covers 8 optical isomers Within the present invention, the 3,4-diarylchromans of the formula I can be prepared in the form of pharmaceutically acceptable salts, especially salts by addition of acid, including the salts of organic acids and mineral acids Examples of such salts include organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, acid oxalic, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like The appropriate inorganic acid addition salts include the salts of hydrochloric, hydrobromic, sulfuric and phosphoric acids, and the like. salts by addition of acid can be obtained as the direct products of the synthesis of the compound.In an alternative, the free base can be dissolved see in an appropriate solvent containing the appropriate acid, and the salt is isolated by evaporation of the solvent or otherwise the salt and the solvent are separated.

The 3, 4-diarylchromans of the formula I and their salts are useful in the field of human and veterinary medicine, for example, in the treatment or prophylaxis of patients suffering from degenerative brain disorders, for example, Alzheimer's disease . For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal administration or transdermal, according to conventional methods. The formulations may also include one or more diluents, fillers,? emulsifiers, preservatives, buffers, excipients, etc. and can be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release dermal implants, tablets, etc. One of C experience in this technique can formulate the compounds of formula I in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton. , 5 PA, 1990.

Oral administration is preferred. Thus, the active compound of the formula I is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound of the formula I is combined with a carrier and molded in the form of a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate, and the like. Such compositions may also include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives, etc. Pharmaceutical compositions containing a compound of the formula I can be administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against degenerative brain disorders, for example, Alzheimer's disease. Such amounts will depend, in part, on the particular condition to be treated, the age, weight and general health of the patient, and other factors evident to those skilled in the art. 1 Pharmaceutical compositions containing a compound of formula I can be administered in unit dosage form one or more times per day or week. In the alternative, these may be provided as controlled release formulations appropriate for the dermal implant. The implants are formulated to provide the release of the active compound over the desired period of time, which may be up to several years. Controlled release formulations are described, for example, in Sanders et al., J. Pharm. Sci. 73 (1964), 1294-1297, 1984; US Patent Specification No. 4,489,056; and US Patent Specification No. 4,210,644, which are incorporated by reference herein. Examples of the preferred compounds of formula I are centchroman as a racemic mixture and as 1-centchroman and d-centchroman. In addition, a preferred compound is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychroman. The most preferred compound is 1-3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxy chroman. The present invention is further illustrated by the following examples which, however, are not to be considered as limiting the scope of protection. The features described in the foregoing description and in the following examples may, either separately and in any combination thereof, be the material for carrying out the invention in various forms thereof.

Examples Test 1 Transgenic mice overexpressing the β-amyloid precursor protein V717F were purchased from Athena Neurosciences, Inc. San Francisco, California, USA. Only heterozygous animals are used. Histopathological examination of the brains of these animals shows deposits of human amyloid β-peptide (Aβ) in the hippocampus, in the corpus callosum and in the cerebral cortex after 6 to 9 months. The accumulation of peptide increases with age and after 9 months the pattern resembles that observed in Alzheimer's disease.

Between 10 and 50 transgenic mice are used for the disease. The animals are housed in hanging metal cages in groups of two, and have ad libitum access to food and water for a week. The ambient temperature is maintained at 20 ° ± 1.5 ° C with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours of light and 12 hours of darkness. After one week of the acclimation period the animals are randomly divided into five treatment groups of between 2 and 10 animals, and daily oral treatment with the test compound is initiated. The test compound is given in four different doses between 0 and 75 mg / kg / day for one month. After the dosing period the animals are weighed and slaughtered by asphyxia with C02. The brain is removed, weighed and immediately frozen in cold isopentane. The brains are sectioned in series in a cryostat (sections of 10-50 μm thickness) and mounted on glass slides marked and coated with poly-L-lysine. Brain sections from mouse are labeled with antiserum R1280 generated against synthetic human Aβ 1-40 peptide. The standard rabbit IgG kit with peroxidase (Vector Labs) is used as recommended, with 3, 3'-diaminobenzidine (DAB) as the chromogen. Positive plates are counted and measured quantitatively using stereological techniques. The activity is indicated by a decrease in the size and number of plaques in the brain.

Test 2 Five to fifty women are selected for the clinical study. Women are postmenopausal, for example, having stopped menstruating for between 6 and 12 months before the start of studies, and who have been diagnosed with early stage Alzheimer's disease (AD), and are expected to have symptoms of worsening AD within the study period, but otherwise they are in good general health. The study has a placebo control group, for example, women are divided into two groups, one of which receives the active agent of this invention and the other receives the placebo. Patients are evaluated for memory, cognition, reasoning and other symptoms associated with AD. Women in the test group recite between 1-1000 mg of the active agent per day by the oral route.

They continue therapy for 6-36 months. Accurate records are kept for the symptoms evaluated in both groups and at the end of the study these results are compared. The results are compared between the members of each group and also the results for each patient are compared to the symptoms for each patient before beginning the study. The activity of the test result is illustrated by an inhibition of any or more of the symptoms of AD in the patients taking the test drug.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (16)

1. The use of the compounds of the general formula I characterized in that R ', R4 and Rs are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower (lower tertiary) amino); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of cerebral degenerative disorders, eg, the disease of Alzheimer's

2. The use according to claim 1, characterized in that the compound has the general formula III: wherein R ", R2, R3, R4 and R" each have the meaning in accordance with claim 1.

3. The use according to claim 1 or 2, characterized in that R1 is lower alkoxy, preferably methoxy.

4. The use according to any of the preceding claims, characterized in that R 'is lower alkyl, preferably methyl.

5. The use according to any of the preceding claims, characterized in that R- is lower alkyl, preferably methyl.

6. The use according to any of the preceding claims, characterized in that R4 is hydrogen.

7. The use according to any of the preceding claims, characterized in that RD is (tertiary amino) (lower alkoxy), preferably 2- (pyrrolidin-1-yl) ethoxy.

8. The use according to any of the preceding claims, characterized in that the compound is a stereoisomer, for example an isolated d- or 1-enantiomer.

9. The use according to any of the preceding claims, characterized in that the compound is an isolated d-enantiomer.

10. E use according to claim 1, characterized in that the compound is 3, 4-trans-2, 2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxy chroman.

11. The use according to the preceding claim, characterized in that the compound is a d- or 1-enant isolated from 3,4-trans-2, 2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin -1-yl) ethoxy) phenyl] -7-methoxy chroman.

12. The use according to claim 11, characterized in that the compound is 1-3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl ] -7-methoxychroman.

13. The use according to any of the preceding claims, characterized in that the composition is in a form suitable for oral administration.

14. The use according to any of the preceding claims, characterized in that the compound is administered as a dose in a. range of about 0.001 to 75, preferably in a range of 0.01 to 75, more preferably in a range of 0.01 to 50, and especially in the range of about 0.1 to 25, mg / kg of the patient per day.

15. The use according to any of the preceding claims, characterized in that the composition is administered one or more times per day or week.

16. The use according to any of the preceding claims, characterized in that the composition is in the form of a dermal implant.