MXPA00011284A - Methods for increasing levels of acetylcholine - Google Patents

Abstract

The current invention relates to a method for increasing levels of acetylcholine comprising administering to a mammal in need thereof, an effective amount of a compound of formula (I), and optionally an AChE inhibitor.

Description

METHODS TO INCREASE ACETILCOLINE LEVELS Description of the Invention The present invention concerns the disciplines of medicinal chemistry, neurophysiology, and neuropharmacology. Specifically, the present invention relates to the increase of acetylcholine levels by the administration of 2-aryl-3-aroylbenzo [b] thiophenes. Cholinergic neurons constitute a major neuronal system of the central and peripheral nervous systems. Cholinergic neurons are associated especially with the neurotransmitter acetylcholine. In the central nervous system, acetylcholine is a neurotransmitter that can be found in, among other places, the hippocampus and the frontal cortex of the brain.

It is believed that the area of the hippocampus in the brain, particularly those areas known to involve cholinergic neurons, have functions associated with the process of knowledge, learning and memory. Degenerative diseases with symptoms such as Ref: 123743 the loss of knowledge, learning, and memory have been linked to a loss of cholinergic neurons. For example, it is known that in patients suffering from Alzheimer's disease, there is a marked decrease in the level of cholinergic neurons of the hippocampus. The progressive loss of those cholinergic neurons seems to reflect the progressive loss of memory and cognitive functions in those patients. It is believed that one reason for the decrease of those neurons is the loss or decreased function of the acetylcholine transmitter. Various potential therapies that are designed to increase acetylcholine levels are being evaluated clinically. The level of acetylcholine in a neuron is determined basically where the balance between its biosynthesis and its biodegradation is found. The enzyme choline acetyltransferase (ChAT) is primarily responsible for its synthesis and acetylcholine esterase (AChE) for its degradation. A therapeutic strategy to increase the level of acetylcholine is based on blocking its degradation by inhibiting AChE, for example, by using AChE inhibitors such as physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride and what it looks like Although there are some encouraging results with the clinical use of AChE inhibitors, especially in the early stages of Alzheimer's disease, these agents usually have side effects undesirable, due to its non-specific systemic action Currently, tacrine has been approved for the early treatment of Alzheimer's symptoms, (see "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", Ed. Gilman, et al., Pergamon Press, 8th Ed., Chap 7, (1990) and the references cited there.) Another therapeutic strategy to increase acetylcholine levels is based on the regulated acceleration of ChAT in neurons, which has been found to be hormone, estrogen, increases the level of acetylcholine for the accelerated regulation of ChAT in the hippocampus of the rat (see "Immunochemical demonstration of increased cholme acetyltransfe rase concentration in rat preoptic area after estradiol administration ", Luine et al. , Brain Res. , 191: 213-211, 1980, "Estradiol Increases Choline Acetytransferase Activity in Specific Basal Forebrain Nuclei and Projection Areas of Female Rats ", Luine, V., Exp. Neurology, 89: Ib4-490, 1985," Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Da law rats ", Singh , M., et al., Brain Res., 644: 305-312, 1994.) Therefore, it has been speculated, and confirmed by the preliminary clinical information, that post-menopausal women who undergo treatment with therapy Hormone replacement (estrogen with or without progestins) may be less likely to succumb to Alzheimer's disease or have existing symptoms relieved., estrogen therapy has undesirable side effects, which include uterotrophic effects, a possible increase in the incidence of breast cancer, swelling, resumption of menses, etc., which limits patient compliance. Therefore, there is a possibility for new and improved therapeutic interventions to increase acetylcholine levels. The current invention relates to a method for the accelerated regulation of choline acetyltransferase (ChAT) in mammals It comprises administering to a mammal in need thereof an effective amount of a compound of the formula I: I? or a pharmaceutical salt of acid addition or solvate thereof; wherein: R1 and R3 are each hydrogen, methyl, benzoyl, substituted benzoyl, or C (0) - (C6-C6 alkyl); R2 is selected from the group consisting of pyrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; wherein the group R2 is optionally the N-oxide; and optionally a choline esterase inhibitor. In addition, the present invention relates to a method for increasing acetylcholine levels in the cortex and / or hippocampal regions of the brain in mammals, which comprises administering to a mammal in need thereof, an effective amount of a compound of the formula I, or a pharmaceutical salt of acid addition or solvate thereof; and optionally a choline esterase inhibitor. In addition, the present invention relates to a method for inhibiting detrimental conditions or effects caused by a deficiency of choline acetyltransferase and / or acetylcholine in the frontal cortex or in the hippocampal regions of the mammalian brain, which comprises administering to a mammal with the need for this, an effective amount of a compound of the formula I, or a pharmaceutical salt or solvate thereof; and optionally a choline esterase inhibitor. Moreover, the present invention relates to a pharmaceutical formulation comprising a compound of the formula I, or a pharmaceutical acid addition salt or solvate thereof, an acetylcholine esterase inhibitor (AChE); and a pharmaceutical carrier, diluent or excipient. The current invention is related to the discovery of a select group of 2-aryl-3- aroylbenzo [bjhiophenes, that is, the compounds of formula I, which are useful for the accelerated regulation of ChAT, and, therefore, are useful for increasing acetylcholine levels in neurons containing acetylcholine and ChAT. A preferred embodiment of all methods of the present invention is wherein the mammal to be administered a compound of formula I is a human, particularly a female human, and more particularly when the human female is deficient in estrogen. However, human males are also referred to under the term "mammals," particularly males who are deficient in testosterone. Another preferred embodiment of the present invention is wherein the condition caused by a decrease in choline acetyltransferase and / or acetylcholine in the frontal cortex and / or hippocampal regions of the brain is due to Alzheimer's disease. Moreover, another preferred embodiment for all methods of the present invention is the use of a pharmaceutical acid addition salt and a compound of the 4 I 'formula I wherein R 1 is hydrogen, R 3 is methyl, and R 2 is pyrrolidin-1-yl. More preferably, the salt is the hydrochloride. This most preferred compound is called 2- (4-hydroxyphenyl) -3- (- [2- (pyrrolidin-1-yl) ethoxy] phenoxy] -6-hydroxybenzo [b] thiophene hydrochloride, an even more preferred mode of all The methods of the present invention is the use of a pharmaceutical acid addition salt and a compound of the formula I wherein R 1 is hydrogen, R 3 is methyl, and R 2 is piperidin-1-yl. More preferably, the salt is the This more preferred compound is called 2- (4-hydroxyphenyl) -3- (4- [2- (piperidin-1-yl) ethoxy] phenoxy] -6-hydroxybenzo [b] thiophene hydrochloride. the optional use of currently known AChE inhibitors such as physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride and the like, as well as agents that are later found to be AChE inhibitors. , the term "effective amount" means an amount of a compound of the formula I which is a z to be used for regulation Accelerated ChAT and / or Increase acetylcholine levels in the hippocampus and regions of the frontal cortex of the brain and / or inhibit the most damaging conditions or effects caused by a decrease in choline acetyltransferase and / or acetyl in mammals . When a compound of formula I is administered simultaneously with an AChE inhibitor the term "effective amount" also means an amount of this agent capable of inhibiting AChE. The term "estrogen-free" refers to a condition, whether it occurs naturally or chemically induced, where a woman can not produce enough estrogen hormones to maintain estrogen-dependent functions, for example, menses, homeostasis muscle mass, neuronal function, cardiovascular conditions, etc. These estrogen-free situations manifest themselves of, but are not limited to, menopause and surgical or chemical ovarectomy that includes its functional equivalent, for example, medication with antagonists or GnRH agonists, ICI 182780, and what it looks like.

The term "inhibitory" in the context of inhibitory conditions or detrimental effects caused by a deficiency of ChAT and / or acetylcholine in the frontal cortex and / or regions of the hippocampus in the brain includes the generally accepted meanings, ie, prohibit, restrict, alleviate, improve, decrease, stop, or reverse the progression or severity of a decrease in ChAT and acetylcholine and the pathological sequelae, that is, symptoms resulting from this event. The term "accelerated regulation of ChAT" refers to increasing the enzymatic activity of ChAT, that is, promoting the conversion of choline to acetylcholine. This increase includes an increase in the efficiency and / or reaction rate of ChAT and choline and / or an increase in the amount of ChAT that is present at the site of action. This increase in the amount of the present enzyme can be seen in gene regulation or in another synthetic step of enzyme formation and / or in a decrease in the deactivation and metabolism of the enzyme.

The general terms used in the description of the compounds described herein have their usual meanings. For example, "C?-C6 alkyl" refers to straight or branched aliphatic cyclic chains of 1 to 6 carbon atoms including methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, pentyl, hexyl and the like. look like The term "substituted benzoyl" refers to a benzoyl group having from 1 to 5 substituents independently selected from the group consisting of C.sub.C alkyl, C.sub.1 -C.sub.2 alkoxy, hydroxyl, nitrogen, chlorine, fluorine, or tri (chloro). or fluoro) methyl The term "pharmaceutical" when used herein as an adjective means that it is substantially non-toxic and substantially non-detrimental to the recipient.The term "pharmaceutical formulation" is also intended to mean that the carrier, solvent, excipient and salt should be compatible with the active ingredient of the formulation (a compound of formula I).

The term "acid addition salt" refers to a salt of a compound of the formula I which is prepared by the reaction of a compound of the formula I with an optional organic acid. For the exemplification of pharmaceutical acid addition salts see, for example, Berge, S.M., Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci. , 66: 1, 1977. The term "solvate" represents an aggregate comprising one or more solute molecules, such as a compound of formula I, with one or more molecules of a pharmaceutical solvent, such as water, ethanol, and what it looks like. The compounds of the formula I wherein R and / or R3 are hydrogen or methyl can be prepared according to the known procedures, such as those detailed in U.S. Patent Nos. 5,510,357, 5,723,474, and 5,731,342, teachings of the which are incorporated here for your reference. The compounds of the formula I which are carboxylic esters (R1 and / or R3 are C (O) - (C6-C6 alkyl), benzoyl, or substituted benzoyl) can be prepared from the compounds of the formula I wherein R and / or R3 are hydrogen essentially mediant &methods described in Patent No. E. U. A. 5.39 ^ 763, the teachings of which are incorporated herein by reference. The acid addition pharmaceutical salts of the invention are typically formed by reacting a compound of formula I with an equimolar or excess amount of an acid. The reagent is generally combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like. The salts are usually precipitated from the solution approximately within one hour to 10 days and can be isolated by filtration and other conventional methods. The acids commonly used to form the acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and so forth, and organic acids such as p-toluenesulfonic acid. methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, acid succinic acid, citric acid, tartaric acid, benzoic acid, acetic acid, and whatever it looks like. Physostigmine salicylate, tacnna hydrochloride, donepezil hydrochloride and other AChE inhibitors are commercially available. The pharmaceutical formulations can be prepared by methods known in the art. For example, a compound of the formula I, and optionally an AChE inhibitor, can be formulated with common excipients, diluents, or carriers and can be formed into tablets, capsules, and the like. Therefore, a compound of the formula I and an AChE inhibitor can be formulated and administered together. A compound of the formula I and an AChE inhibitor can also be administered separately. Examples of excipients, diluents and carriers that are suitable for the formulation include the following fillers and expanding agents such as starch, sugars, mannitol, silicic derivatives, binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatins, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as agar, calcium carbonate, and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonia compounds; active surface agents such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonide; and lubricants such as talc, calcium and magnesium stearate and solid polyethylglycols. The final pharmaceutical forms can be pills, tablets, powders, dragees, syrups, aerosols, sachets, tablets, elixirs, suspensions, emulsions, ointments, suppositories, sterile injectable solutions, or sterile packaged powders, depending on the type of excipient used. In addition, the compounds of the formula I are suitable for the formulation in the form of sustained release dosage forms. The formulations may also be constituted so as to release the active ingredient only or preferably in a particular region of the intestinal tract, possibly over a period of time. These formulations involve coatings, covers, or protective matrices that can be made from polymeric or wax substances. The particular dose that is required of a compound of formula I for the accelerated regulation of ChAT, and optionally the dose of an AChE inhibitor that is required to inhibit AChE, according to this invention, depends on the particular circumstances of the conditions to be treated. Conditions such as dosage, route of administration, and frequency of dosing are best decided by the attending physician. Generally, a minimum effective dose for oral or parenteral administration of a compound of the formula I is about 1., 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about 800, 100, 60, 50, or 40 mg. More typically, the doses range between 5 mg and 60 mg (which are expressed as the amount of free base of a compound of the formula I). These doses are administered to a patient in need of treatment from 1 to 3 times each day or as often as needed for the effective accelerated regulation of ChAT, and / or increase the levels of acetylcholine in the cortex frontal and / or in the hippocampal regions of the brain and / or inhibiting the conditions or deleterious effects characterized by a deficiency of choline acetyltransferase and / or acetylcholine in the frontal cortex and / or hippocampal regions of the brain. The following formulations are given for the purposes of illustration and are not intended to be limiting in any way. The total active ingredients in these formulations comprise from 0.01% to 99.9% by weight of the formulation. The term "active ingredient" means a compound of the formula I, or a pharmaceutical salt or solvate thereof, and optionally an AChE inhibitor. Preferably, the compound of formula I is the hydrochloride salt wherein R 1 is hydrogen, R 3 is methyl, and R 2 is pyrrolidin-1-yl. Even a more preferred formulation of a compound of the formula I is the hydrochloride salt wherein R 1 is hydrogen, R 3 is methyl, and R 2 is piperidin-1-yl.

Formulation I Gelatin Capsules Ingredient Quantity (mg / capsule) Active Ingredient 50-600 Starch NF 0-500 Starch powder with 0-500 flowable Centistoke 350 fluid 0-15 silicone The ingredients are mixed, passed through a U sieve. No. 45 mesh, and filled into hard gelatin capsules.

Formulation 2 Tablets Ingredient Amount (mg / tablet) Active Ingredient 50-600 Starch 10-50 Cellulose, microcrystalline 10-20 Polyvinylpyrrolidone (as a 5 to 10% solution in water) Sodium carboxymethylcellulose 5 Magnesium stearate 1 Talc 1-5 The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 14 mesh US sieve. The granules thus produced are dried at 50-60 ° C and passed through a US sieve. No. 18 mesh. Sodium carboxymethyl cellulose, magnesium stearate, and talc, which were previously passed through a No. 60 mesh US sieve, are added to the above granules and thoroughly mixed. The resulting material is compressed into a tablet-forming machine to produce the tablets.

Formulation 3 Aerosols Ingredient Weight% Active Ingredient 0 -.50 Ethanol 29.50 Propellant agent 22 70.00 (Chlorodifluoromethane) The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The quantity that is required is then fed into a stainless steel container and diluted with the rest of the propellant. Then the valve units are adjusted in the container.

Formulation 4 Suspension Ingredient Weight / Volume Active Ingredient 100 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mL Benzoic acid solution (0.1M) 0.10 mL Saborizante c.b. Colorant c.b. Purified water up to the total 5 mL The suspensions each contain 100 mg of a compound of formula I per 5 mL of doses which are prepared as follows: the active ingredient is passed through a U.? Screen. No. 45 mesh and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. The solution of the benzoic acid, the flavoring, and the dye diluted in water are added and the mixture is stirred thoroughly. Additional water is added to make the entire mixture have the required volume.

The following demonstration of the methods of the present invention is presented for purposes of illustration and is not intended in any way to limit the scope of this invention. Forty female Sprague-Da ley rats (weight range 300 to 325 g, six months old) are obtained from Harian. The animals are bilaterally ovaricectomized (OVX) or exposed to a Sham surgical procedure, and then shipped after one week. Upon arrival, they are accommodated in metal cages Hanging in groups of 3 or 4 per cage and have ad libium access for food and water for 2 weeks. They are kept at room temperature of 22.2 ° + 1.7 ° C with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours of light and 12 hours of darkness. The animals are dosed daily by subcutaneous injection or forced feeding with either compound 1 (2- (4-hydroxyphenyl) -3- (4- [2- (piperidin-1-yl) ethoxy] phenoxy] - 6-hydroxybenzo [b] thiophene), at 3 mg / kg / day in a vehicle containing 10% cyclodextrin, estradiol benzoate at 0.03 or 0.3 mg / kg / day, or the control vehicle. To the animals are treated for 3 or 10 days. There are 20 animals for each dosage regimen. During the appropriate time intervals, the animals are sacrificed and their brains are dissected. The particular portions of the brains are homogenized and evaluated. The homogenate of the hippocampus and the frontal cortex is processed and the determination is made for ChAT activity by a radio-label analysis for the biosynthesis of acetylcholine. This procedure can be found in Schoepp et al. , J. Ne? Ral Transmiss. , 78: 183-193, 1989, of which the teachings are incorporated herein for reference. As expected, in animals with OVX, ChAT levels are reduced > 50% (p <0.01) compared to controls operated by Sham. In contrast to this, the animals receiving Compound I or the estradiol benzoate have significantly increased levels (p <0.05) of ChAT against the OVX controls and a negligible difference of the Sham controls. Therefore, the present invention provides methods for the treatment and prophylaxis of syndromes related to memory loss, learning, and cognitive functions, which are commonly observed in women who are devoid of estrogen, especially in postmenopausal women. An example of this syndrome is senile dementia of the Alzheimer's type. The beneficial effects, such as a decrease in memory loss, associated with the administration of the compound of this invention become apparent after chronic administration. For example, post-menopausal women suffering from Alzheimer's disease can expect an improvement in their disease after 2-12 months from the administration of 2- (4-hydroxyphenyl) -3- (4- [2- (piperidin-1-yl) ethoxy] phenoxy] -6-hydroxybenzo [b] thiophene The methods of the present invention can also be used in the prophylactic modality, for example, a group of peri- or post-menopausal women. They can sustain their cognitive and memory functions evaluated by means of conventional analyzes After the establishment of this reference line, women are administered 2- (4-hydroxyphenyl) -3- (4- [2- (piperidin-1) hydrochloride. -yl) ethoxy] phenoxy] -6-hydroxybenzo [b] thiophene for a period of 1-5 years At the end of this period, The evaluations of cognitive and memory functions that are made through conventional analyzes show a decrease in the loss of these functions in relation to an equal group of patients who were not given a placebo during the same period of time.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (16)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The use of a compound of the formula I: I? or a pharmaceutical salt of acid addition or solvate thereof; characterized in that: R1 and R3 are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C (0) - (C6-C6 alkyl); R2 is selected from the group consisting of pyrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; wherein the group R2 is optionally the N-oxide, and optionally an inhibitor of the acetylcholine esterase (AChE); in the preparation of a drug useful for the accelerated regulation of choline acetyltransferase (ChAT) in mammals.

2. The use of a compound of the formula I: or a pharmaceutical salt of acid addition or solvate thereof, characterized in that: R1 and R3 are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C (O) - (Ci-Cß alkyl); R2 is selected from the group consisting of N-pyrol? Din-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; wherein the group R2 is optionally the N-oxide; and optionally an acetylcholine esterase inhibitor (AChE); in the preparation of a medicine useful for increase acetylcholine levels in the frontal cortex and / or hippocampal regions of the mammalian brain.

3. The use of a compound of the formula I: i; or a pharmaceutical salt of acid addition or solvate thereof; characterized in that R1 and R3 are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C (O) - (C-Cd alkyl); R2 is selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; wherein the group R2 is optionally the N-oxide; and optionally an acetylcholine esterase inhibitor (AChE); in the preparation of a medicine useful for inhibit the conditions or detrimental effects caused by a deficiency of choline acetyltransferase and / or acetylcholine in the frontal cortex and / or hippocampal regions of the brain in mammals.

4. The use according to any of claims 1-3, characterized in that the mammal is a female human.

5. The use according to claim 4, characterized in that the female human is deficient in estrogen.

6. The use according to claim 5, characterized in that the compound of the formula I is a pharmaceutical salt of acid addition, R1 is hydrogen, R3 is methyl and R2 is piperidin-1-yl.

7. The use according to claim 6, characterized in that the compound of the formula I is the hydrochloride salt.

8. The use according to claim 5, characterized in that the compound of the formula I is a pharmaceutical salt of acid addition, R1 is hydrogen, R3 is methyl and R2 is pyrolidin-1-yl.

9. The use according to claim 8, characterized in that the compound of the formula I is the hydrochloride salt.

10. The use according to claim 3, characterized in that the mammal is a human and the inhibited condition is Alzheimer's disease.

11. The use according to claim 10, characterized in that the human is a female deficient in estrogen.

12. The use according to claim 11, characterized in that the compound of the formula I is a pharmaceutical acid addition salt, R1 is hydrogen, R3 is methyl and R2 is piperidin-1-yl.

13. The use according to claim 12, characterized in that the compound of the formula I is the hydrochloride salt.

14. The use according to either of claims 2 or 3, characterized in that the acetylcholine esterase inhibitor (AChE) is selected from the group consisting of physostigmine salicylate, tacrine hydrochloride, and donepezil hydrochloride.

15. A pharmaceutical formulation comprising a compound of the formula I: i; or a pharmaceutical salt of acid addition or solvate thereof, characterized in that: R1 and R3 are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C (0) - (C6-C6 alkyl); R2 is selected from the group consisting of N-pyrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; wherein the group R2 is optionally the N-oxide; and optionally an acetylcholine esterase inhibitor (AChE); and a carrier, diluent, or pharmaceutical excipient.

16. The formulation according to claim 15, characterized in that the acetylcholine esterase inhibitor (AChE) is selected from the group consisting of physostigmine salicylate, tacrine hydrochloride, and donepezil hydrochloride.