MXPA06004449A - Carbamoyl esters that inhibit cholinesterase and release pharmacologically active agents - Google Patents

Abstract

Carbamoyl esters inhibit cholinesterase activity and, upon hydrolysis release a pharmacologically active agent. In one embodiment, the carbamoyl ester has the following structure:Formula (I)wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl. The carbamoyl esters are employed in methods to treat an individual. The pharmacologically active agent obtained by hydrolysis of the carbamoyl esters can treat, for example, a nervous system condition, a cholinergic deficiency and conditions or diseases associated with a deficiency in a pharmacologically active agent, such as acetylcholine.

Description

CARBAMOILO ESTERS THAT INHIBIT COLINESTERASE AND PHARMACOLOGICALLY ACTIVE RELEASE AGENTS RELATED APPLICATION This application claims the benefit of the Provisional Application U. S. No. 60 / 512,971, filed on October 21, 2003. Its full disclosure is considered part of this, as a reference.

BACKGROUND OF THE INVENTION Several conditions and diseases in humans are accompanied by or are a consequence of disorganizations in cellular signal molecules. For example, it may be inadequate synthesis, release or reuptake of the cellular signal molecule or molecules, or disorganization in cell signaling through the molecule or molecules through receptor or non-receptor mechanisms that result in a disease or other condition. In many cases, clinical control strategies and currently available drugs are often associated with adverse side effects and must be meticulously monitored in patients. Current strategies to develop drugs to treat conditions and diseases that are accompanied by or are a consequence of disorganizations in cellular signal molecules, require significant modification of the structure-activity of a compound. In addition, currently available drugs generally do not direct the drug to particular cells or tissues and do not originate the delivery of a drug with a lasting effect. In many cases, the correction of disorganization in a simple cellular signal molecule does not effectively treat the symptoms of the disease or condition. Therefore, there is a need to develop new, improved and effective methods for the treatment of diseases or conditions that are associated with or are accompanied by disorganizations in cellular signal molecules.

SUMMARY OF THE INVENTION The present invention relates to carbamoyl esters having cholinesterase inhibitory activity and comprising an amino group which, after hydrolysis, are converted to at least one component of a pharmacologically active agent. The invention also relates to methods of using carbamoyl esters and pharmaceutical compositions of carbamoyl esters. In one embodiment, the invention is a carbamoyl ester that inhibits a cholinesterase, which after hydrolysis, is converted to at least one component of a pharmacologically active agent. In another embodiment, the invention is a carbamoyl ester having the following structure: wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and each of Ri and R2, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl. In still another embodiment, the invention is a carbamoyl ester which is not (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-l, 3a, 8-trimethyl-pyrrolo [2,3-b ] -indo-5-ol, 4-pyridinyl carbamate ester, (3aS-cis) -1, 2,3, 3a, 8, 8a, -hexahydro-l, 3a, 8-trimethyl-pyrrolo carbamate ester [2,3-b] -indol-5-ol- (2-phenyl) ethyl, carbamate ester of (3aS-cis) -1, 2, 3, 3a, 8, 8a-hexahydro-1,3, 8 -trimethyl-pyrrolo [2, 3-b] indol-5-ol [1- (1-naphthyl) ethyl], carbamate ester of 7-bromo- (3aS-cis) -1,2,3,3a, 8 , 8a-hexahydro-1, 3a, 8-trimethyl-pyrrolo [2, 3-b] -indol-5-ol-heptyl, or a tetrahydroisoquinolinium carbamate ester. In a further embodiment, the invention is a carbamoyl ester selected from the group consisting of: wherein each of R3, R4 and R5, independently or in combination, are selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, an substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl. In still another embodiment, the invention is a carbamoyl ester selected from the group consisting of: In still another embodiment, the invention is a method of treating an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase and includes an amino group which after hydrolysis becomes at least one component of a pharmacologically active agent that treats the individual for a condition of the individual. In a further embodiment, the invention is a method of treating a condition of the nervous system in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase by which the affection of the nervous system in the individual and wherein the carbamoyl ester includes an amino group which after hydrolysis, becomes at least a component of a pharmacologically active agent that also treats the affection of the nervous system in the individual. In yet another embodiment, the invention is a method of treating a condition of the central nervous system in an individual, comprising the step of administering to the individual a carbamoyl ester that inhibits acetylcholinesterase, whereby the condition of the nervous system is treated. centrally in the individual, wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent, wherein the pharmacologically active agent is selected from the group consisting of a compound of amphetamine and a methamphetamine compound, by means of which the pharmacologically active agent also treats the condition of the central nervous system in the individual. A further embodiment of the invention is a method for increasing acetylcholine in an individual, comprising the step of administering to the individual a carbamoyl ester in the individual, wherein the carbamoyl ester inhibits a cholinesterase, thereby increasing acetylcholine and includes an amino group which after hydrolysis, becomes at least one component of a pharmacologically active agent that also increases acetylcholine in the individual. In still another embodiment, the invention is a method for increasing acetylcholine in an individual, comprising the step of administering to the individual a carbamoyl ester that inhibits acetylcholinesterase, whereby the acetylcholine is increased in the individual, wherein the ester of carbamoyl includes an amino group which after hydrolysis, is converted to at least one component of a pharmacologically active agent, wherein the pharmacologically active agent is selected from the group consisting of an amphetamine compound and a methamphetamine compound. In a further embodiment, the invention is a method of treating a cholinergic deficiency in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase, thereby treating the deficiency cholinergic in the individual, and wherein the carbamoyl ester includes an amino group which, after hydrolysis, becomes at least a component of a pharmacologically active agent that also treats cholinergic deficiency in the individual. In another modality more, the invention is a method of treating memory impairment in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase thereby treating the memory impairment in the individual, and wherein the carbamoyl ester includes an amino group which after hydrolysis, becomes at least one component of an "active" pharmacologically active agent that also treats the impairment of memory in the individual. is a method of delivering a pharmacologically active agent to a tissue, comprising the step of administering to the tissue a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase and includes an amino group which after hydrolysis becomes at least in a component of a pharmacologically active agent, whereby the pharmacologically active agent is delivered to the tissue. The invention is a pharmaceutical composition comprising a carbamoyl ester that inhibits a cholinesterase, wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent. The invention described herein provides carbamoyl esters that inhibit the activity of a cholinesterase and, after hydrolysis, are converted to at least one component of a pharmacologically active agent. The methods of using carbamoyl esters can, for example, treat neurological conditions, increase the amount of an amine in a synaptic cleft, treat a cholinergic deficiency and increase transmission between neurons, supply amines in a synaptic cleft and increase the supply of pharmacologically active amines in the central nervous system. The advantages of the claimed invention include, for example, supplying a pharmacologically active agent as neurotransmitter modulators, without significant structural alteration for the pharmacologically active agent, at a synapse, which guides the neurotransmission that may be poor or diminished, thereby they treat diseases or conditions associated with neurotransmitter imbalances. The method of the invention, by employing the carbamoyl esters, can increase the amount of a pharmacologically active agent, such as a neurotransmitter, thereby compensating for a disease or condition associated with deficiency of a neurotransmitter. Accordingly, the carbamoyl esters of the invention can be employed in the treatment of diseases or other conditions associated with pharmacologically active agents and thereby stop, reverse or slow the progression of diseases or other conditions, or promote physiological processes that can be dealing with pharmacologically active agents, such pharmacologically active agents that treat the conditions associated with synaptic transmission.

BRIEF DESCRIPTION OF THE FIGURES The figure describes the mechanism of inhibition of acetylcholinesterase by the carbamoyl esters of the invention.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention, whether as steps of the invention or as combinations of parts of the invention, will now be described and pointed out more particularly in the claims. It should be understood that the particular embodiments of the invention are shown by way of illustration and not as restrictions of the invention. The main features of this invention can be used in various embodiments without departing from the scope of the invention. In one embodiment, the invention is a carbamoyl ester that inhibits a cholinesterase, comprising an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent. The term "carbamoyl ester", as used herein, refers to a carbamoyl compound having the following structural formula: 1 wherein each of Ri and R2, independently or in combination, are hydrogen or a hydrocarbon and wherein R3 is a hydrocarbon. In particular, the carbamoyl ester inhibits a cholinesterase by competing with a compound (eg, acetylcholine (ACh)) that binds to cholinesterase. As shown in the figure, the carbamoyl ester binds to the cholinesterase to form a carbamoylated enzyme. Cholinesterase is inhibited when it is prevented from inactivating a compound, such as the ACh neurotransmitter, to a degree that cholinesterase would act on the neurotransmitter in the absence of the carbamoyl ester. Hydrolysis of the carbamoylated enzyme is much slower than, for example, an acetylated enzyme, which is formed by hydrolysis of its acetylcholine from the endogenous substrate. The inhibition of cholinesterase by a carbamoyl ester molecule ceases when the carbamoylated enzyme is hydrolyzed. After hydrolysis of the carbamoylated enzyme, a released compound, such as an amino, is converted to at least one component of a pharmacologically active agent. The hydrolysis of the carbamoyl ester comprising an amino group to convert it to at least one component of a pharmacologically active agent can be by hydrolysis of an enzyme (for example, a cholinesterase) or hydrolysis by another substance than an enzyme, such as by an acid (for example, gastric acid). In one embodiment, the carbamoyl ester which inhibits a cholinesterase, comprises an amino group which, after hydrolysis by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent. The phrase "after hydrolysis by reaction with an enzyme" as used herein, refers to the two-step reaction process of the carbamoyl ester with an enzyme to form a carbamoylated enzyme, and decomposition of the carbamoylated enzyme by reaction with H20 Also, the phrase "after hydrolysis by reaction with cholinesterase", as used herein, refers to the two-step reaction process of the carbamoyl ester with the cholinesterase enzyme, to form a carbamoylated enzyme, and decomposition of the carbamoylated enzyme by reaction with H20. The cholinesterase inhibited by the carbamoyl ester of the invention can be, for example, at least one member selected from the group consisting of an acetylcholinesterase (AchE) or a butyrylcholinesterase (BuChE). The carbamoyl ester can inhibit only AChE, only BuChE, or can inhibit both AChE and BuChE in similar or different degrees. AChE is found in excitable membranes and inactive ACh. The excitable membrane can be a presynaptic neuron or a post-synaptic neuron. AChE is also called as a specific cholinesterase. BuChE is found in excitable membranes and non-neuronal tissue such as blood cells (Darvesh, S. et al., Nature Reviews 4: 131-138 (2003), whose full disclosure is considered part of this as a reference). BuChE is also referred to as pseudocholinesterase or non-specific cholinesterase. AChE and BuChE are regulators of cholinergic neurotransmission in the central nervous system (brain and spinal cord), peripheral nervous system and autonomic nervous system (parasympathetic nervous system and sympathetic nervous system). After hydrolysis of the carbamate linkage of the carbamoylated enzyme, a released compound, such as a compound including an amine, is converted to at least one component of a pharmacologically active agent. The term "becomes at least a component of a pharmacologically active agent", as used herein, refers to the release of a compound, such as an amine-containing compound, as a consequence of hydrolysis of the carbamoylated enzyme. The compound released by hydrolysis of the carbamoylated enzyme is at least a portion of a pharmacologically active agent. In one embodiment, the compound released by the hydrolysis of the carbamoylated enzyme is a prodrug. The term "prodrug", as used herein, refers to a compound, such as a carbamoyl ester of the invention, that is administered, but is not the drug actually sought in the treatment regimen and is transformed by metabolic processes in the drug actually sought in the treatment. The prodrug can then be modified to release a pharmacologically active agent. In another embodiment, the compound released by hydrolysis of the carbamoylated enzyme may, by itself, be the pharmacologically active agent. For this reason, a carbamoyl ester of the invention has a dual role as an inhibitor of a cholinesterase and as a delivery vehicle for a pharmacologically active agent. The term "pharmacologically active agent", as used herein, refers to a compound that influences biological processes by altering the activity, location and / or expression of molecules (eg, neurotransmitters, peptides, proteins). ) that are directly or indirectly involved in biological processes. The pharmacologically active agent can be a phenylethylamine, such as an amphetamine compound (1-amphetamine, d-amphetamine, 1-methamphetamine, d-methamphetamine, or any mixture of d and 1 isomers of amphetamine and methamphetamine). The pharmacologically active agent can be a prodrug or precursor that is metabolized to a compound containing a primary or secondary amine of a pharmacologically active agent, such as deprenyl which is metabolized to desmethylseleglin, 1-amphetamine and 1-methamphetamine. The pharmacologically active agent preferably alters the biological processes in a manner that results in a desired effect, for example, to improve biological processes, alleviate disease signs or symptoms, or to decrease and / or reverse the progression of the disease. . For example, after hydrolysis of the carbamoyl ester, the released amine can be converted to at least one component of a pharmacologically active agent that increases the amount of a neurotransmitter at a synapse by decreasing or stopping the degradation of a neurotransmitter, by participation in cellular events that result in the release of additional neurotransmitters, by inhibiting the reuptake of a neurotransmitter, and / or by the increased synthesis of a neurotransmitter. The pharmacologically active agent can, for example, result in an increase in ACh in the synapses of neurons of the central nervous system that can compensate for cholinergic deficiency, for example, in patients suffering from Alzheimer's disease, thereby promoting neuronal transmission for finally alleviate or improve the symptoms of Alzheimer's disease. Alzheimer's disease is accompanied by symptoms that include cognitive impairment, disoriented behavior, altered personality, difficulty in speaking and understanding and walking and damaged movements. It has been proposed that decreased cholinergic function is responsible for the symptoms of Alzheimer's disease (Benzi, G., et al., European J. Pharmacol. 346: 1-13 (1998); Korczyn, A. D., Exp. Opin. Invest. Drugs 9: 2259-2267 (2000)). The decrease in cholinergic function may be a decrease in the amount of ACh synthesized or released, the inability of a neuron to respond to ACh or the inactivation of AChE. In Alzheimer's disease, treatments include administration of compounds that increase cholinergic signaling (Jann, MW, Pharmaco therapy 20: 1-12 (2000); Bachurin, SO, Med. Res. Rev. 23: 48-88 ( 2003)). However, these compounds have low efficacy, short response time (commonly approximately 30% -50%) and numerous side effects such as nausea, gastrointestinal problems and fatigue. In one embodiment, the carbamoyl esters of the invention inhibit AChE and, after hydrolysis, are converted to at least one component of a pharmacologically active agent that increases neurotransmitters, such as ACh, at the synapses of neurons of the central nervous system. So, for example, the carbamoyl esters of the invention inhibit AChE, which degrades ACh at the synapses of neurons in patients suffering from Alzheimer's, and releases pharmacologically active agents, which, collectively or individually, increase the neurotransmitters at the synapses. . Cholinergic deficiencies also characterize other disorders such as Parkinson's disease, progressive supranuclear palsy, vascular dementia and Down syndrome (Korczyn, A.D., Exp. Opin. Invest. Drugs 9: 2259-2267 (2000)). Therefore, the carbamoyl esters of the invention can also be employed to increase the ACh in these disorders. Likewise, the pharmacologically active agent can result in an increase of the neurotransmitter dopamine in the central nervous system of patients with Parkinson's disease, thereby promoting neuronal transmission to decrease the symptoms of Parkinson's disease. The increase in dopamine may be a direct result of the hydrolysis of the carbamoylated enzyme to administer dopamine as a pharmacologically active agent, or an indirect result of the hydrolysis of the carbamoylated enzyme to administer a pharmacologically active agent that results in an increase in dopamine in synapses, for example by inhibiting dopamine reuptake, preventing dopamine degradation, increasing dopamine release or being a precursor (e.g., L-DOPA) in the synthesis of dopamine. Therefore, the pharmacologically active agent can be a pharmacologically active agent type central nervous system (brain, spinal cord). The term "central nervous system type", as used herein, refers to a pharmacologically active agent that has an effect on the central nervous system. The pharmacologically active agent can also be a pharmacologically active agent such as peripheral nervous system or a pharmacologically active agent type autonomic nervous system (parasympathetic nervous system and sympathetic nervous system). The terms "peripheral nervous system type" and "autonomic nervous system type", as used herein, refer to a pharmacologically active agent that has an effect on the peripheral nervous system and the autonomic nervous system, respectively. The pharmacologically active agent can include a prodrug and other structural derivatives (e.g., isomers or stereoisomers, such as stereoisomers d, 1, di, R, S, and RS) and functional derivatives thereof in which, preferably, a Primary or secondary amine is available for substitution. In another embodiment, the carbamoyl ester has the following structure: II wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and each of Ri and R2, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl. The term "alkyl", used alone or as part of a larger portion, includes both saturated, straight, branched, or cyclic hydrocarbon chains containing from one to twelve carbon atoms. A heteroalkyl, as used herein, is an alkyl group in which one or more carbon atoms are replaced by a heteroatom. The term "aryl", used alone or as part of a larger portion as in "aralkyl" or "aralkoxy", are carbocyclic aromatic ring systems (e.g. phenyl), fused polycyclic aromatic ring systems (e.g., naphthyl and anthracenyl) ) and aromatic ring systems fused to carbocyclic non-aromatic ring systems (eg, 1, 2, 3, 4-tetrahydronaphthyl and indanyl) having from five to about fourteen carbon atoms. The term "heteroaryl", used alone or as part of a larger portion as in "heteroaralkyl" or "heteroarylalkoxy", refers to the aromatic ring system having five to fourteen members and having at least one heteroatom. Preferably a heteroaryl has from one to about four heteroatoms. Preferred heteroalkyls are those in which the heteroatom is selected from the groups consisting of oxygen, sulfur, nitrogen, phosphorase and halides. Examples of heteroaryl rings include pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, purinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, thienyl, 4,6-dihydro-thieno [3, 4 -c] pyrazolyl, 5,5-dioxide-4,6-dihydrothieno [3,4- c] pyrazolyl, tianaphtenyl, 1,4,5,6-tetrahydrocyclopentapyrazolyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl , quinolinyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, and benzoisazolyl. Preferred heteroaryl groups are pyrazolyl, furanyl, pyridyl, guinolinyl, indolyl and imidazolyl. An aralkyl group, as used herein, is an aryl substituent that is linked to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. A heterocycloalkyl group, as used herein, is a substituent that is linked to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. A heteroaralkyl group, as used herein, is a heteroaryl substituent that is linked to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. An aryl (including aralkyl, aralkoxy and the like) or heteroaryl (including heteroaralkyl and heteroaralkoxy and the like) may contain one or more examples of suitable substituents including aliphatic groups, aryl groups, haloalkoxy groups, heteroaryl groups , halo and hydroxyl. In a further embodiment, the carbamoyl ester is not (3aS-cis) -1, 2, 3, 3a, 8, 8a-hexahydro-l, 3a-8-trimethyl-pyrrolo [2, 3-b] -indole 5-ol, 4-pyridinyl-carbamate ester, (3aS-cis) -1,2, 3, 3a, 8, 8a-hexahydro-l, 3a, 8-trimethyl-pyrrolo [2, 3-b] indole 5-ol, (2-phenyl) ethyl carbamate ester, (3aS-cis) -1,2, 3, 3a, 8, 8a-hexahydro-1,3,8-trimethyl-pyrrolo carbamate ester [2 , 3-b] indol-5-ol [1- (1-naphthyl) ethyl], 7-bromo- (3aS-cis) -1, 2,3, 3a, 8, 8a-hexahydro-1, 3a, 8 -trimethyl-pyrrolo [2, 3-b] indol-5-ol, n-heptyl carbamate ester, or a tetrahydroisoquinolinyl carbamate ester. Examples of aromatic esters of carbamoyl are described in Brossi, A., et al. , Aust. J. Chem. 49: 171-181 (1996); Trabace, L., et al. , CNS Drug Reviews 8: 53-69 (2992); De Sarno, P., et al. , Neurochem. Res. 14: 791-977 (1989); U.S. Patent Nos. 4,971,107; 4,948,807; 5,187,165; 5,302,721; 5,409,948; 5,455,354; 5,602,176; 5,665,880; 5,677,457; international patents WO 97/14694 and WO 97/23484, the entire disclosure of which is considered part of the present, by way of reference. The nitrogen of the carbamate bond of the aromatic carbamoyl ester may be substituted. Particular examples of aromatic esters of carbamoyl are myotin, eserin (also called physostigmine), geneserin, neostigmine, fenserin (Brossi, A., et al., Aust. J. Chem. 49: 171-181 (1996), the entire disclosure of which it is considered part of this, as reference), CHF2819 (Trabace, L., et al., CNS Drug Reviews: 8: 53-69 (1992), whose full disclosure is considered part of this, as a reference) and heptylphisostigmine (DeSarno, P., et al., Neurochem, Res. 14: 971-977 (1989), whose entire disclosure is considered part of this, as a reference). In one embodiment, the aromatic esters of carbamoyl are known compounds, such as stigmines, which have been modified. The modification may include, for example, substitutions in the nitrogen of the carbamate linkage. These compounds are collectively referred to as "substituted stigmines". In another embodiment, the carbamoyl ester may include an isomer or stereoisomer (ie, d, 1, di, R, S, or RS). In all the structures shown herein, it should be understood that, if a compound is represented as (+, -), (±), di (DL) or (R) (S), the invention is intended to include racemic mixtures, or pure compositions of a compound form, for example "d" or "1", "R" or "S", unless otherwise specified. Methods for making the carbamoyl esters of the invention, such as carbamoyl aromatic esters, are within the knowledge of those skilled in the art (see, for example, U.S. Patent Nos. 5,665,880; 5,677,457; and WO 97; / 14694, whose full disclosure is considered part of this, as a reference). In one embodiment, the synthesis of aromatic esters of carbamoyl can be achieved by activation of an amino group of a compound to form an activated amine. The activated amine can be isolated and reacted with a phenol group of another compound to form the carbamoyl ester. For example, a primary amine can be converted to an isocyanate. Alternatively, the amines can be converted to carbamoyl chlorides. The amines can also be activated and used in situ for the formation of the carbamoyl ester, such as by reacting an amine with activating agents containing carbonyl chlorides (for example phosgene), by reacting the amine with activating agents containing nitrophenyloxycarbonyl groups (for example bis-4-nitrophenylcarbonate, 4-nitrophenylchloroformate), or by the reaction of the amine with carbonyldiimidazole The individual steps of the amine activation and the formation of the carbamoyl ester can be catalyzed by various agents, such as acids, bases, and nucleophiles, separately or in combination.

In another embodiment, the synthesis of the carbamoyl esters can be achieved by activation of a phenol group of a compound to form an activated phenol. The activated phenol is reacted with an amino group of another compound. The activation of the phenol can be carried out in various ways, such as by the reaction of the phenol with activating agents containing carbonyl chlorides (for example, phosgene, triphosgene), by the reaction of the phenol with activating agents containing nitrophenyloxycarbonyl groups (by example, bis-4-nitrophenylcarbonate, 4-nitrophenylchloroformate), or by the reaction of phenol with carbonyldiimidazole. The individual steps of phenol activation and formation of the carbamoyl ester can be catalyzed by various agents, such as acids, bases, and nucleophiles, separately or in combination. Carbamoyl esters can be analyzed by well-known analytical methods, including NMR. The carbamoyl esters can be synthesized, for example, by reaction of the phenolic hydroxyl group in eseroline (16 g) with carbonyldiimidazole (CDl) (15.1 g) (94 mmol) in 100 ml of ethyl acetate, then the addition of 14.8 ml. of acetic acid and 90 mmol of the amine resulting in the formation of the carbamoyl aromatic ester (Gao et al., J. Heterocyclic Chem 37: 331-333 (2000), the entire disclosure of which is considered part of the present, as reference) The formation of aromatic esters of carbamoyl from eseroline has been described using carbamoyl chlorides (Marta, et al., Bichimica et Biophysica Acta 1120: 262-266 (1992); Marta, et al., Biomed Biochem Acta 47: 285 -288 (1998); Marta, et al., Life Sci. 43: 1921-1928 (1988), whose full disclosure is considered part of this, as a reference).

The reaction of a phenolic hydroxyl group with carbamoyl chlorides has also been described for the synthesis of aromatic esters of carbamoyl (Toda, et al., Bioorg Med Chem 11: 1935-1955 (2003), Kogen, et al., Org. Lett. 4: 3359-3362 (2002), Mustazza, et al., Eur. J. Med Chem 37: 91-109 (2002) and Sterling, et al., J Med Chem 45: 5260-5279 (2002), whose exposure integral is considered part of this, as a reference).

Phiovenine analogues were prepared by reaction of fisovenol with alkyl isocyanates in anhydrous diethyl ether in the presence of a minimum amount of sodium (Yu, et al., Helvética Chimica Acta, 74: 761-766 (1991), whose full disclosure is considered is part of this, as a reference).

Fenserin and its analogs have been made by reaction of eseroline with an isocyanate (US Patent No. 6,495,700, the entire disclosure of which is considered part of the present, by reference), by reaction in dimethoxyethane under an argon atmosphere in the presence of of catalytic amounts of n-butyllithium n-hexanes.

The isocyanates were also used by Mustazza, et al. , Eur J Med Chem 37: 91-109 (2002) and Yuv et al. , J Med Chem 44: 4062-4071 (2001), whose full disclosure is considered part of this, as a reference.

In yet another embodiment, the aromatic carbamoyl ester is selected from the group consisting of: VI wherein each of R3, R4 and R5, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl.

In yet another embodiment, the carbamoyl ester of γ is selected from the group consisting of: XVI In a further embodiment, the carbamoyl ester is selected from the group consisting of: In yet another embodiment, the carbamoyl ester is selected from the group consisting of: In one embodiment, the pharmacologically active agent is a memory facilitating agent. In another embodiment, the pharmacologically active agent is a cognitive facilitating agent. The term "memory facilitating agent", as used herein, refers to a compound that promotes memory in an individual, prevents or minimizes memory impairment in an individual or participates in biological processes that are involved in the function of memory. In a preferred embodiment, the memory facilitating agent is an amphetamine compound. The amphetamine compound may be d-amphetamine, 1-amphetamine or a mixture, such as a racemic mixture, of d-amphetamine and 1-amphetamine. In another preferred embodiment, the memory facilitating agent is methamphetamine. The methamphetamine compound may be d-methamphetamine, 1-methamphetamine or a mixture, such as a racemic mixture, of d-methamphetamine and 1-methamphetamine. Memory processes that can be facilitated by the memory facilitating agent can be the consolidation of memory, the process of storing new information in long-term memory ("Neuroscience: Exploring The Brain", Bear, MF et al. al., Williams &Wilkins, Baltimore, Maryland, Ch. 19, pp. 517-545 (1996), McGaugh, JL Science 287: 248-251 (2000), whose entire disclosure is considered part of the present, as reference); short-term memory (also called "working memory"), the process by which newly acquired information is maintained for short periods and newly acquired information is made available for further processing of information ("Neuroscience: Exploring The Brain" , Bear, MF et al., Williams &Wilkins, Baltimore, Maryland, Ch. 19, pp. 517-545 (1996); McGaugh, J.L. Science: 248-251 (2000); Becker, J.T., et al. , Brain and Cognition 41: 1-8 (1999), whose full disclosure is considered part of this, as a reference); declarative memory, which is the memory of events and events ("Neuroscience: Exploring The Brain ", Bear, M. F. et al., Williams &Wilkins, Baltimore, Maryland, Ch. 19, pp. 517-545 (1996); McGaugh, J.L. Science 287: 248-251 (2000); Tulving, E., et al. , Science 247: 301-306 (1990); Squire, L.R., et al. , Proc. Nati Acad. Sci. 93: 13515-13522 (1996), whose full disclosure is considered part of this, as a reference); procedural memory (also called "tacit knowledge" or "implicit knowledge"), which is memory for experiences or behavior ("Neuroscience: Exploring The Brain", Bear, MF et al., Williams &Wilkins, Baltimore, Maryland, Ch. 19 , pp. 517-545 (1996); McGaugh, JL Science 287: 248-251 (2000), whose entire disclosure is considered part of the present, as a reference); or attention, acquisition, recovery or retention. Someone skilled in the art would be able to identify and evaluate the agents that would be suitable as memory facilitators. In another embodiment, the pharmacologically active agent is a cognitive facilitating agent. The term "facilitating agent of cognition", as used herein, refers to a compound that promotes activities associated with thinking, learning and acquiring knowledge in an individual, prevents or minimizes impairment in thinking, learning and Acquisition of knowledge in an individual or participates in biological processes that are involved in thinking, learning and acquiring knowledge. Impaired thinking, learning and acquired knowledge (a cognitive disorder) may be a consequence of or associated with another disease (eg, Alzheimer's disease) or central nervous system, or peripheral or autonomic condition. The cognitive process that can be facilitated by the facilitating agent of cognition can be evaluated by behavioral criteria and behavioral tests, which, in turn, can define more where the facilitating agents of cognition are acting in the learning process. of thought, and the acquisition of knowledge. Someone with experience in the technique would be able to identify and evaluate agents that would be suitable as facilitators of cognition.

In a preferred embodiment, the cognition facilitating agent is an amphetamine compound. The amphetamine compound can be amphetamine or methamphetamine. The amphetamine can be d-amphetamine, 1-amphetamine, a racemic mixture of d-amphetamine and 1-amphetamine or any mixture of d- and 1-amphetamine. In another preferred embodiment, the facilitating agent of cognition is methamphetamine. The methamphetamine can be d-methamphetamine, 1-methamphetamine, a racemic mixture of d-methamphetamine and 1-methamphetamine or any mixture of d- and 1-methamphetamine. The term "amphetamine", as used when referring to "1-amphetamine" and "d-amphetamine", means a compound represented by Formula XXII, which includes pro drugs and other structural and functional derivatives thereof wherein the Primary amine group is available for substitution. In a preferred embodiment, amphetamine is the compound represented by Formula XXII: The dextroenantiomer of amphetamine is referred to as the isomer d, (+), D or S and is represented by the following structural formula: The levoenantiomer of amphetamine may be referred to as (-), L or R and is represented by the following structural formula : Racemic mixtures of d-amphetamine and 1-amphetamine are referred to as di, (+, -), (±), or DL or (R) (S). An (R) - (-) -amphetamine employed in the methods of the invention is represented by the structural formula: Formula XXV is also called levo-amphetamine sulfate or 1-amphetamine sulfate. Formula XXV has the molecular formula C? 8H28N20S and a molecular weight of 368.50. The chemical name according to the International Union of Pure and Applied Chemistry (IUPAC) of Formula XXV is methyl-2-phenylethylamine sulfate (2: 1) and the chemical name according to the Chemical Extracts Service (CAS) is methylphenethylamine sulfate ( 2: 1). The term "methamphetamine", as used when referring to "1-methamphetamine" and "d-methamphetamine", means a compound represented by Formula XXVI: The (R) - (-) -methamphetamine can be represented by the structural formula: Formula XXVII also refers to levomethamphetamine-HCl, 1-methamphetamine or levomethamphetamine-HC1. Formula XXVII has the molecular formula CioHieNCl. In another modality, the (R) - (-) -methamphetamine can be represented by the structural formula: Formula XXVIII also refers to levo-methamphetamine, levo-deoxyeedrine, or levomethamphetamine. Formula XXVIII has the molecular formula C10H15N and a molecular weight of 149.24. In yet another embodiment, the pharmacologically active agent is at least one member selected from the group consisting of a cholinergic agent (also referred to as ACh), an adrenergic agent (also called epinephrine), a noradrenergic agent (also called ñorepinephrine), a dopaminergic agent , a serotonergic agent (also called 5-hydroxytryptamine), a glutamatergic agent, a GABAergic agent (gamma-aminobutyric acid), a histaminergic agent (e.g., HTMT, antamina, imepip, and alpha-methylhistamine (Tocris, Ellisville, MO) ), an inhibitor of mono-amino-oxidase, a catechol-O-methyl-transferase (COMT) inhibitor, a beta-secretase inhibitor, a gamma-secretase inhibitor, a potassium channel blocker, a channel blocker of calcium (e.g., nimodipine), an adenosine receptor modulator, a cannabinoid receptor modulator (e.g., virodamine), a nootropic agent (e.g., enhancement agent), or of cognition) (eg, safinamide, minaprine, indeloxazine), a modulator of the neuropeptide pathway, a neurotrophic (eg, an agent that induces neuronal cell growth), phosphodiesterase (PDE) inhibitor IV, an inhibitor of phosphatase / calcineurin, a carbonic anhydrase inhibitor (eg, brinzolamide, dorzolamide), a traffic regulator of the receptor, a modulator of the trace amine receptor, a sigma receptor modulator, imidazoline receptor modulator, a sodium / calcium exchange blocker (also called Na + Ca + 2 or NCX exchanger), ACE inhibitors (Angiotensin Conversion Enzyme), antioxidants and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). The pharmacologically active agent can also be a tracer amine neurotransmitter, such as phenylethylamine, octopamine, tyramine, and tryptamine. Phenylethylamine also refers to a natural amphetamine (Janssen, P.A.J., et al., Int. J. Neuropsychopharmacol., 2: 229-240 (1999), whose entire disclosure is considered part of the present, as a reference). Phenylethylamine is deaminated by the mono-amino-oxidases (Yang, H.-YT, et al., J. Pharmacol. Exp. Ther., 187: 365-371 (1973), whose entire disclosure is considered part of this , as reference) . A carbamoyl ester which, after hydrolysis, for example, by reaction with a cholinesterase, is converted to phenylethylamine may be less susceptible to initial monoamine oxidation, thereby facilitating the supply of phenylethylamine to the nervous system of an individual. An "agent", as used herein, refers to a compound that can produce a physical, chemical or biological effect that can be a stimulator (e.g., an activating agent) or an inhibitor (e.g., a blocking agent). The agents that are stimulators can be agonists. The agents that are inhibitors can be antagonists or inverse agonists. Reverse agonists are compounds or molecules that down-regulate the activity activated by the receptor, thereby acting in a manner opposite to that of an agonist for the receptor. Therefore, exposure or administration of an inverse agonist can result in a decreased response compared to the exposure or administration of an agonist. A cholinergic agent can be, for example, a compound that stimulates the action of ACh, thereby mediating cell signaling mediated by ACh between two cells (a cholinergic agonist). The stimulation may be, for example, the result of facilitating the binding of ACh to a cell surface receptor, the interference with ACh degradation, the stimulation of ACh release, the stimulation of ACh synthesis, the activation of seconds. messengers (eg, phospholipase C, inositol 1, 4, 5-triphosphate, protein kinase C, protein kinase A) that mediates cell signaling with ACh, the alteration of ion channels (eg, sodium, potassium) in target cells. An agent can also inhibit or prevent one or more of these effects (e.g., a cholinergic antagonist). The carbamoyl ester of the invention can become a pharmacologically active agent that can specifically affect the two subtypes of ACh receptors, muscarinic cholinergic receptors and nicotinic cholinergic receptors, so it focuses on a particular receptor subtype that mediates a biological process particular. In one embodiment, the cholinergic agent is selected from the group consisting of a muscarinic cholinergic receptor agonist, (Cutler, N.R., et al., CNS Drugs 3: 467-481 (1995); Korczyn, AD, Drugs 9: 2259-2267 (2000), the entire disclosure of which is hereby incorporated by reference), an antagonist of the muscarinic cholinergic receptor, a cholinergic nicotinic receptor agonist, a nicotinic cholinergic receptor antagonist, an acetylcholinesterase inhibitor, a cholinergic antagonist, an allosteric modulator of a cholinergic receptor and an open channel blocker. An agonist or antagonist of the muscarinic cholinergic receptor can mediate effects in various tissues, including smooth muscle, cardiac muscle, exocrine glands, and the nervous system of individuals. An agonist or antagonist of the nicotinic cholinergic receptor can also mediate effects by altering the biological, physical or chemical components of ganglia in the autonomic nervous system, in neuromuscular junctions of the peripheral or autonomic nervous system and in the central nervous system. In another embodiment, the hydrolysis of the carbamoyl ester, by reaction with a cholinesterase, results in the formation of a cholinergic agonist selected from the group consisting of RJR2403 (Methyl- (4-pyridin-3-yl-but-3-enyl) - amine) (also referred to as TC2403), A85380 (3- (Azetidin-2-ylmethoxy) -pyridine), anatoxin A, epibatidine and anabasine (Tocris, Ellisville, MO); and TC1734 ([4- (5-Isopropoxy-pyridin-3-yl) -1-methyl-but-3-enyl] -methylamine) (Obinu, MC et al., Progress in Neuropsychopharmacol. &Biol. Psychiatry 26: Obinu, MC et al., Internatl., J. Neuropsychopharmacology 3: Suppl 1 (S361) (2003), Lipiello, PM et al., Soc. Neurosci. Abstr 24: 88 (Part 1) (1998); Gatto, G. , et al., CNS Drug Reviews 10: 147-166 (2004)). In a further embodiment, the hydrolysis of the carbamoyl ester, by reaction with a cholinesterase, causes the formation of an adrenergic agent selected from the group consisting of an alpha receptor agonist (eg, ±, a 2) a beta receptor agonist. (for example, ßx, ß 2, ß 3), an alpha receptor antagonist, and a beta receptor antagonist. Adrenergic agents can modulate neurons and receptors involved in the actions of adrenaline and any neuronal or hormonal function that is mediated or affected by adrenaline. Since noradrenaline can also act through the alpha and beta receptors, pharmacologically active agents can affect biological, chemical or physical processes associated with norepinephrine. In a preferred embodiment, the adrenergic agent is a primary or secondary amine. The adrenergic agents include at least one member selected from the group consisting of oxymetazoline, cirazoline, clonidine, A61603, agmatine, atenolol, betaxolol, bisoprolol, BRL 37344, BRL 44408, picoterol, dobutamine, efaroxan, formoterol, HEAT, ICI 118551, ICI89406 , ICL215001, idazoxan, pindolol, practolol, procaterol, pronetalol, propranolol, RX821002, SB206606, SR59230A, sotalol, WB4101, xamoterol, ZD7114, efaroxan and clenbuterol (Tocris, Ellisville, MO); and adrenaline, brimonidine, dipifevrin, and metipranolol. In yet another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a noradrenergic agent selected from the group consisting of a norepinephrine reuptake inhibitor and a norepinephrine releasing agent. The norepinephrine reuptake inhibitor can prevent or minimize the elimination of norepinephrine from a synapse, thereby increasing the amount of norepinephrine in the synapse. The prevention of norepinephrine elimination can be active (for example, by blocking a cellular process involved in reuptake) or passive (for example, by stabilizing norepinephrine). The norepinephrine agent can result in the release of norepinephrine from a cell (e.g., a nerve cell, a secretory cell, an epithelial cell). Other compounds referred to herein as "reuptake inhibitors" and "release agents", act similarly, but specific to the particular pharmacologically active agent, as a neurotransmitter. The norepinephrine reuptake inhibitor can be, for example, viloxazine, and / or nisoxetine (Tocris, Ellisville, MO); maprotiline, atomoxetine, MCI225 (4- (2-fluoro-phenyl) -6-methyl-2-piperazin-1-yl-thieno [2,3-d] pyrimidine) hydrochloride, oxaprotiline, reboxetine, talopram, talsupram, and tionisoxetine; and amoxapine, desipramine, methylphenidate, nomifensin, nortriptyline, and protriptyline (Sigma Chemical Co., St. Louis, MO). In yet another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a serotonergic agent selected from the group consisting of a serotonergic antagonist, a serotonergic agonist, a serotonergic reuptake inhibitor and an agent of serotonin release. Serotonergic agents can, for example, affect neurotransmission or the hormonal release of endocrine glands. Serotonergic agents may include at least one member selected from the group consisting of pindolol, quipazine, fluoxetine, anpirtoline, N- (4-bromobenzyl) -5-methoxytryptamine, BW 723C86, 5-carboxamidotriptamine, m-CPP, N-demethylclozapine, Desmethylcitalopram, isamoltane, L-694247, MDL 72832, MDL 73005EF, alpha-methyl-5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine, mianserin, MK212, 5-nonyloxytryptamine, 6-nitroquipazine, urophluoxetine, RS 67333, RS 67506, RS 23597-190, RS 39604, RU 24969, sertraline, desmethylsertraline, SR 57227, and fluvoxamine (Tocris, Ellisville, MO); and MAI, RS17017 (1- (4-amino-5-chloro-2-methoxy-phenyl) -5-piperidin-1-yl-pentan-1-one), RS 66331, SB271046 (4-methoxy-3-piperazin-1 hydrochloride 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid) -yl-phenyl), SB 399885, and SL65.0155 (5- (8-amino-7-chloro-2,3-dihydro-benzo [1,4] dioxin-5-yl) -3- (l-phenethyl-piperidin-4-yl) -3H- hydrochloride 1,3,4] oxadiazol-2-one).

In yet another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a glutamatergic agent selected from the group consisting of an NMDA receptor agonist (N-methyl D-aspartate), an NMDA receptor antagonist, an NMDA-glycine site agonist, an NMDA-glycine site antagonist, an AMPA receptor agonist (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and a AMPA receptor antagonist, a cainate receptor agonist and a kainate receptor antagonist. Additionally, or alternatively, the glutamatergic agent may include an NMDA ion channel modulator, an NMDA-polyamine site agonist, a NMDA-polyamine site agonist, an AMPA / kainate agonist, an AMPA / kainate antagonist, a metabotropic glutamate receptor agonist Group I, a metabotropic glutamate receptor antagonist Group I, a metabotropic glutamate receptor agonist Group II, a metabotropic glutamate receptor antagonist Group II, a metabotropic glutamate receptor agonist Group III, a metabotropic glutamate receptor antagonist, Group III, an AP6 agonist sensitive to quisqualate, an antagonist of the AP6 site responsive to quisqualate and an inhibitor of the uptake of excitatory amino acids.

Examples of metabotropic glutamate receptor compounds include 2-methyl-6- (phenylethynyl) -pyridine (MPEP), trans-ACPD, ACPT-I, ACPTII, ACPTIII, TADA, AIDA, AP3, AP4, AP6, (2R, 4R ) -APDC, APICA, 3-carboxy-4-hydroxyphenylglycine, 4-carboxy-3-hydroxyphenylglycine, 4-carboxyphenylglycine, L-CCG-I, CHPG, CPPG, 1-cysteinsulfinic acid, DCG IV, 3,4-DCPG, 3,5-DHPG, E4CPG, EGLU, L-3'F2CCG-I, l-glutamic acid, homoAMPA, 3-hydroxyphenylglycine, ibotenic acid, LY307452, LY341495, LY367385, MAP4, MCCG, MCPG, MPPG, MSOP, MSPG, MTPG, alpha-methyl-3-carboxymethylphenylglycine, o-phospho-1-serine, PPG, quisqualic acid, s-fulfo-1-cysteine, UBP1112, and spargic acid (Tocris, Ellisville, MO). Other glutamate receptor compounds include lamotrigine, riluzole, and salsolinol-1-carboxylic acid (Tocris, Ellisville, MO). NMDA agents may include aspartic acid, D-cycloserine, ACBC, trans-ACBD, cis-ACPD, AP4, AP5, AP7, aspartic acid, 4-carboxyphenylglycine, CGP37849, CGP39551, CGS19755, CGP78608, chlorfeg, CPP, L acid -cysteinsulfinic acid, glutamic acid, glycine, HA-996, N- (4-hydroxyphenylacetyl) spermine, N- (4-hydroxyphenylpropanol) spermine, ibotenic acid, L689560, LY 235959, MK 801, NMDA, SDZ 220-040, SDZ 220 -581, d-serine, (tetrazol-5-yl) glycine, memantine, spermine and spermidine (Tocris, Ellisville, MO); and amantadine (Sigma Chemical Co., St. Louis, MO). AMPA / kainate agents may include L-quisqualic acid, domoic acid, kainic acid, AMPA, ATPA, CFM-2, (S) -CPW 399, 5-fluorowillardine, 5-yodowillardin, willardin, GAMS, GYKI, 52466, IDRA 21, SYM 2081, and SYM 2206 (Tocris, Ellisville, MO). An inhibitor of the uptake of excitatory amino acids can be dihydrocaine acid, cis-ACBD, L-CCG-II, chlorfeg, dihydrocainic acid, threo-3-methylglutamic acid, MPDC, trans-2, 4-PDC, SYM2081, and TBOA ( Tocris, Ellisville, MO). The NMDA receptor antagonist can be memantine (Tocris, Ellisville, MO) (Parsons, CG, et al., Neuropharmacol., 38: 735-767 (1999), the entire disclosure of which is considered part of the present, as a reference ). The NMDA-glycine receptor agonist can be D-cycloserine (Sigma Chemical Company, St. Louis, MO) (Land, C, et al., Neurobiol, Learning Mem., 72: 158-168 (1999), whose full disclosure is considered part of this, as a reference). In yet another embodiment, hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a GABAergic agent which is selected from the group consisting of a GABAergic receptor antagonist, a GABAergic receptor agonist, a Benzodiazepine site agonist, a benzodiazepine site antagonist, a benzodiazepine site inverse agonist, and a GABA uptake inhibitor. GABAergic may include, for example, muscimol, baclofen, saclofen, l-amino-5-bromouracil, CACA, CGP35348 (3-amino-propyl) -dietoxymethyl-phosphinic acid), CGP46381 (3-amino-propyl) -cyclohexylmethyl-phosphinic acid), CGP 52432, CGP 54626, CGP 55845, GABA, GBLD 345, 2-hydroxisaclofen, isoguvacine, faclofen, SB 205384, SCH 50911, SKF 97541, TACA THIP, TPMPA, and tracazolate (Tocris, Ellisville, MO ); SR 95531 and SGS742 (3-amino-propyl) -butyl-phosphinic acid) (Kerr, DIB et al., J. Ong. Pharmac.Ther.67: 187-246 (1995); Froestl, W., et al. ., Biochem. Pharmacol., 68: 1479-1487 (2004)). In another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a dopaminergic agent selected from the group consisting of a dopaminergic antagonist, dopaminergic agonist, a dopaminergic reuptake inhibitor, a release agent dopaminergic, dopamine and L-DOPA (levo dopa) (3,4-dihydroxyphenylalanine, 3-hydroxytyrosine). Since dopamine is an intermediate in the synthesis of noradrenaline, adrenaline and melanin, any agent that affects dopamine can produce physical, chemical or biological effects in the biological processes associated with or mediated by noradrenaline, adrenaline and melanin. The dopaminergic agent can affect dopamine as a hormone or dopamine as a neurotransmitter. The dopaminergic agent may include, for example, dihydrexidine, A68930 (l-aminomethyl-3-phenyl-isochroman-5,6-diol), SKF 38393, AJ 76, 4-phenyl-1,2,3,4-tetrahydroisoquinoline, and rimcazole (Tocris, Ellisville, MO); and A77636 (3-adamantan-l-yl-l-aminomethyl-isochroman-5,6-diol), adrogolide, and SKF81297 (6-chloro-l-phenyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepin-7,8-diol); pergolide (Sigma Chemical Company, St. Louis, MO) and pramipexole (also called MIRAPEXMR). A "modulator", as used herein, refers to a compound that regulates, adjusts or adapts a biological pathway or receptor-mediated signal transduction pathway. Modulators can stimulate or inhibit a biological pathway or receptor-mediated signal transduction pathway. For example, an adenosine receptor modulator can increase the ability of adenosine to bind to the receptor, decrease the ability of adenosine to bind to the receptor, bind directly to the receptor (e.g., an agonist or inverse agonist) and have an effect or interact otherwise with the receptor to regulate, adjust or adapt a biological pathway associated with a signal transduction pathway mediated by adenosine receptor. In another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of at least one member selected from the group consisting of a mono-amino-oxidase inhibitor, COMT inhibitor, beta inhibitor. -secretase or a gamma-secretase inhibitor. An inhibitor prevents an enzyme from participating in a biological process or decreases the activity of the enzyme in the biological process. For example, a beta-secretase inhibitor or a gamma-secretase inhibitor can prevent the formation of beta-amyloid protein from amyloid precursor protein in the brain of a human. The accumulation of beta-amyloid protein is associated with Alzheimer's disease in humans. Therefore, the decrease in beta-amyloid protein can improve, prevent or reduce the onset or progression of Alzheimer's disease. In a particular embodiment, the monoamino oxidase inhibitor is at least one member selected from the group consisting of desmethylseleglin (Heinonen, EH, et J. Clin Pharmacol, 37: 602-609 (1997), whose entire exposure is considered as part of this, as a reference), rasagiline (Kupsch, A., Curr Opin Opin, Investigation Drugs 3: 794-979 (2002), whose full disclosure is considered part of this, as a reference), 1 - (benzofuran-2-yl) -2-propylaminopentane, 5-benzyloxy-2-indolmethylamino, lazabemide, CHF3381 (2- (indan-2-ylamino) -acetamide), milacemide, ofegelin, brofaromine, Ro-41-1049, RS-1636; and bifemelano, and tetrindol (Tocris, Ellisville, MO). In another embodiment, the hydrolysis of the carbamoyl ester, for example, by reaction with a cholinesterase, causes the formation of a potassium ion channel blocker, such as 4-amino-pyridine. Since the selective permeability of a potassium channel, it is important for the resting membrane potential of a cell, the blocking of a potassium ionic channel can potentiate or prolong the depolarization of a membrane, by which cellular signaling, for example, of neurons, is increased. The pharmacologically active agents can affect the cells of the central nervous system, peripheral nervous system, autonomic nervous system and other tissues (e.g., smooth muscle, cardiac muscle, skeletal muscle) and organs (e.g., endocrine glands, exocrine glands). In one embodiment, the pharmacologically active agent can be an exogenous agent (originated or produced outside the individual). In another embodiment, the pharmacologically active agent can be an endogenous agent(originated or produced within the individual) that has been purified from a biological source, obtained from an individual. The physical, chemical or biological effect that can be stimulated or inhibited by the carbamoyl esters of the invention and the pharmacologically active agents of the invention can be between two or more cells. In one embodiment, those two or more cells are two or more nerve cells (presynaptic neurons, post-synaptic neurons). The nerve cells can be in the central nervous system, the peripheral nervous system or the autonomic nervous system. In another embodiment, those two or more cells can be at least one muscle cell (smooth muscle, skeletal muscle, cardiac muscle) and at least one nerve cell (presynaptic neurons, post-synaptic neurons). In yet another embodiment, the two or more cells can be at least one nerve cell and at least one non-neuronal cell (e.g., a secretory cell of the adrenal medulla, a cell of an exocrine gland or endocrine gland, an epithelial cell of an organ or tissue). The two or more cells can be in vitro cells (e.g., cell culture) or cells in vivo (e.g., in an individual). The pharmacologically active agent can be a nootropic agent (i.e., a cognition enhancing agent), a neurotrophic agent (i.e., an agent that induces neuronal cell growth) and / or a neuroprotective agent. In yet another embodiment, the invention is a method of treating an individual. The method includes administering to the individual a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase and includes an amino group which after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent that treats the individual for a condition of the individual. The pharmacologically active agent released by the carbamoyl ester is at least one member selected from the group consisting of a cholinergic agent, an adrenergic agent, a noradrenergic agent, a dopaminergic agent, a serotonergic agent, a glutamatergic agent, a GABAergic agent, a histaminergic agent, a mono-amino-oxidase inhibitor, a COMT inhibitor, a beta-secretase inhibitor, a gamma-secretase inhibitor, a potassium channel blocker, a calcium channel blocker, a receptor modulator of adenosine, a modulator of the cannabinoid receptor, a nootropic, a modulator of the neuropeptide pathway, a neurotrophic, a PDE IV inhibitor, a phosphatase / calcineurin inhibitor, a regulator of the receptor traffic and an amine receptor modulator in traces The carbamoyl ester of the invention can inhibit cholinesterase activity, which can be expressed as an IC50. The term "IC50", as used herein, refers to the concentration of a drug, compound, molecule or carbamoyl ester that inhibits an activity or effect by 50%, for example, by reducing the frequency of a condition , as 50% memory or cognitive loss; by reducing the binding of a competing molecule to a protein (e.g., a receptor) by 50%; or by reducing the level of an activity (eg, cholinesterase activity) by 50%. As used herein, an "individual" is any mammal. A mammal can be a rodent (like a rat, mouse or guinea pig), a domesticated animal (like a dog or cat), a ruminant animal (like a horse or a cow) or a primate (like a monkey or a human). In a preferred embodiment, the individual is a human. The condition of the individual who is treated by the pharmacologically active agent is at least one condition selected from the group consisting of a condition of the central nervous system, a condition of the peripheral nervous system and a condition of the autonomic nervous system. In a particular embodiment, the individual treated with the carbamoyl ester has a central nervous system condition. A "central nervous system condition", as used herein, refers to any disease or malaise that affects the individual's brain or spinal cord. The affections of the central nervous system, treated with the carbamoyl esters of the invention, can, for example, be a consequence of a genetic disease, environmental exposure to a compound or disease or disease secondary to primary. The condition of the central nervous system may be characterized or be a consequence of inadequate neurotransmitter release, synthesis, processing, reuptake or cell signaling. The condition of the central nervous system may be in additional form, or alternatively characterized or be a consequence of insufficient or inadequate neuronal transmission by interruptions in the ion channels. In a particular embodiment, the central nervous system condition is treated with a carbamoyl ester that includes a substituted stigmine. The carbamoyl esters of the invention can be used to treat conditions including depression, anxiety and mental retardation. The conditions of the central nervous system in an individual, treated by the carbamoyl esters of the invention may be Parkinson's disease, a deterioration of memory and a cognitive deterioration. The deterioration of memory can be in a human individual. Memory impairments that can be treated by the carbamoyl esters of the invention include Alzheimer's disease, memory loss caused by age, deterioration in memory consolidation, deterioration in short-term memory, mild cognitive impairment. , deterioration in declarative memory and memory impairments associated with or as a consequence of multiple sclerosis and / or Parkinson's disease. The deterioration of the memory treated by the carbamoyl esters of the invention may be a consequence of exposure to an antagonist of the muscarinic cholinergic receptor. In one embodiment, the muscarinic cholinergic antagonist of the receptor is atropine. In another embodiment, the muscarinic cholinergic antagonist of the receptor is scopolamine. In yet another embodiment, the muscarinic cholinergic antagonist of the receptor is homatropine. An antagonist of the muscarinic cholinergic receptor includes any substance that blocks, decreases, attenuates, inhibits, cleaves, limits, reduces, restricts or interferes with the action of ACh, thereby interrupting ACh-mediated cell signaling between presynaptic and post-synaptic neurons. The antagonist may, for example, oppose the action of ACh by acting in a manner that prevents ACh from binding to a cholinergic muscarinic receptor in a post-synaptic neuron, from the mediation of post-synaptic events and after the binding from ACh to a cholinergic muscarinic receptor, interfering with the degradation of ACh by acetylcholinesterase in the synaptic cleft or interfering with the release of ACh from presynaptic neurons. In yet another embodiment, the carbamoyl esters of the invention can be used to treat a condition of the peripheral nervous system in an individual. The affection of the peripheral nervous system may, for example, be a disease or condition produced by or associated with neurons that supply innervation to a skeletal muscle (e.g., Myasthenia Gravis). Peripheral nervous system disorders may be, for example, a deterioration in the release of acetylcholine from neurons in the neuromuscular junction of skeletal, smooth or cardiac muscle. The carbamoyl esters of the invention can be used to treat a condition of the autonomic nervous system (sympathetic nervous system, parasympathetic nervous system) in an individual. The conditions of the autonomic nervous system can be affections that affect the smooth muscle of viscera, glands (endocrine glands, exocrine glands), blood vessels or cardiac muscle. The conditions of the autonomic nervous system treated using the carbamoyl esters of the invention can be post-operative distention and urinary retention. The conditions of the autonomic nervous system can be a deterioration in a function associated with the autonomic nervous system, for example, an impairment in the release of norepinephrine from sympathetic neurons or ACh from parasympathetic neurons at a synapse with a cell (eg, epithelial, nerve, muscle, connective tissue) in an organ, blood vessel or gland. Any person skilled in the art would be capable of diagnosing an individual with a condition of the central nervous system, affection of the peripheral nervous system and a condition of the autonomic nervous system. In one embodiment, after hydrolysis, for example, with a cholinesterase, the carbamoyl ester used to treat the individual with a condition (central nervous system, peripheral nervous system, autonomic nervous system) is converted to an amphetamine compound (1-) amphetamine, d-amphetamine) and / or a methamphetamine compound (d-methamphetamine, 1-methamphetamine). A "deterioration of memory or cognition," as used herein, refers to a diminished capacity of memory and / or cognitive processes in the human. Cognitive processes and / or memory and impairments of cognitive processes and / or memory can be evaluated or determined by established techniques. For example, memory may be evaluated before, at the same time or after treatment of the individual with the carbamoyl esters of the invention, by means of one or more well-established tests by those skilled in the art. Such tests include the Passive Avoidance Test (Principles of Neuropsychopharmacology), R. S. Feldman, et al. , Sinauer Assoc, Inc., Sunderland, MA (1997), whose full disclosure is considered part of this, as a reference); Rey Auditory Verbal Learning Test (RAVLT); a Wechsler Memory Scale; Wechsler's Revised Memory Scale (Wechsler, D., Wechsler Memory Scale-Revised Manual, NY, NY, The Psychological Corp. (1987)); California Verbal Learning Test, Second Edition (Delis, D.C., et al., The California Verbal Learning Test, Second Edition, Adult Version, Manual, San Antonio, TX: The Psychological Corporation (2000)); Wesnes Computerized Assessment Battery for Cognitive Drug Research (CDR); Buschke Selective Recall Test (Buschke, H., et al., Neurology 24: 1019-1025 (1974)); Short Test of Revised Visual-Space Memory; and Everyday Care Test (Perry, R.J., et al., Neuropsychologia 38: 252-271 (2000)). In a particular embodiment, the memory of the human before, during or after the administration of the carbamoyl esters of the invention is evaluated or determined by a recall test of words such as RAVLT. In another embodiment, the invention described herein provides a method of treating a condition of the nervous system in an individual. The method includes administering to the individual a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase by which the condition of the nervous system of the individual is treated. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent that also treats the affection of the nervous system in the individual. The pharmacologically active agent can, for example, maintain the inhibition of cholinesterase which was inhibited by the carbamoyl ester. The pharmacologically active agent can also treat nervous system involvement, for example, by supplying a compound to a neuron or synapse, maintaining the polarization of a neuron, preventing the reuptake of a neurotransmitter, stimulating or maintaining the synthesis or release of a neurotransmitter. a neurotransmitter. In a particular embodiment, the administration of the carbamoyl ester treats a condition of the central nervous system in an individual. The carbamoyl ester inhibits acetylcholinesterase, whereby the condition of the central nervous system in the individual is treated. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with acetylcholinesterase, is converted to at least one component of a pharmacologically active agent that also treats the condition of the central nervous system in the individual. The pharmacologically active agent is selected from the group consisting of an amphetamine compound and a methamphetamine compound. Yet another embodiment of the invention is a method for increasing acetylcholine in an in vitro sample. The method includes administering a carbamoyl ester to the sample in vitro. The carbamoyl ester inhibits a cholinesterase, which increases the acetylcholine in the sample in vitro. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with cholinesterase, is converted to at least one component of a pharmacologically active agent that further increases acetylcholine in the sample in vitro. The in vitro sample can be a sample without cells or a sample containing cells. The cells used can be mammalian cells (e.g., CHO cells), insect cells or bacterial cells. The method can be used to evaluate the ability of the carbamoyl ester to inhibit cholinesterase and the pharmacologically active agent in order to influence biological, chemical or physical processes before being used in an individual. The method can be packaged in a kit as a test to classify the carbamoyl esters with respect to the cholinesterase activity and the pharmacological activity of the converted carbamoyl ester agents after hydrolysis. Another embodiment of the invention is a method for increasing acetylcholine in a tissue. The method includes administering a carbamoyl ester to the tissue. Carbamoyl ester inhibits a cholinesterase, whereby acetylcholine is increased in the tissue and includes an amino group which, after hydrolysis, for example, by reaction with cholinesterase, becomes at least one component of a pharmacologically active agent that also increases acetylcholine in the tissue. The tissue may be a nervous tissue, a muscle tissue (cardiac, skeletal, smooth muscle) or a set of one or more tissue types selected from the group consisting of nerve tissue, muscle tissue, epithelial tissue and connective tissue. The tissue may be isolated (removed from the individual). A further embodiment of the invention is a method for increasing acetylcholine in an individual. The method includes administering to the individual a carbamoyl ester in the individual. The carbamoyl ester inhibits a cholinesterase (eg, AchE, BuChE), so acetylcholine is increased. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent that also increases the acetylcholine in the individual. In one embodiment, the pharmacologically active agent increases acetylcholine in the central nervous system of the individual. In another embodiment, the pharmacologically active agent increases the acetylcholine in the peripheral nervous system of the individual. In yet another embodiment, the carbamoyl ester increases acetylcholine in the autonomic nervous system of the individual. The techniques for evaluating the increase of ACh in an in vitro sample, in a tissue and in an individual are well known to those skilled in the art. (See, for example, Day, J.C., et al., Methods 23: 21-39 (2001), whose full disclosure is considered part of this, as a reference). In a preferred embodiment, the pharmacologically active agent in the methods of the invention is an amphetamine compound and / or a methamphetamine compound. The additional increase in acetylcholine may be a mediated increase in a manner similar to the increase mediated by the carbamoyl ester (inhibition of AChE) or an increase in ACh, for example, by increasing the release of ACh, increasing the synthesis of ACh or otherwise to prevent the inactivation of ACh. In still another embodiment, the invention is a method of increasing the transmission between two or more neurons.

The method includes exposing the neurons to a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase, so that the transmission between the two or more neurons is increased. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent that further increases the transmission between the two or more neurons. The additional increase in transmission may be, for example, in a manner similar to the carbamoyl ester (by cholinesterase inhibition) or by any other means mediated by the pharmacologically active agent, such as by stimulating the release or synthesis of a neurotransmitter. , the inhibition of the reuptake of a neurotransmitter, the alteration of the ion channels of neurons. The transmission between two or more neurons can be increased in vitro or in vivo. The techniques for determining an increase in transmission in vitro and in vivo are well known to those skilled in the art. For example, changes in the depolarization of postsynaptic neurons can be recorded by electrophysiological methods. The carbamoyl ester can increase the transmission between two or more neurons, for example, by increasing the amount of a neurotransmitter (eg, cholinergic, adrenergic, noradrenergic, dopaminergic, serotonergic, glutamatergic, GABAergic, histaminergic) or by decreasing or prevention of the degradation of a neurotransmitter (for example, by inhibiting mono-amino-oxidase, COMT) at the synapse. Additionally, or alternatively, the carbamoyl ester can increase transmission between two or more neurons, by modulating a neurotransmitter receptor (eg, adenosine receptor, cannabinoid receptor, trace amine receptor) or blocking channels ionic (for example, the potassium channel, the sodium channel) in the neurons. In addition, the carbamoyl ester can increase transmission between two or more neurons by inhibiting PDE IV, phosphatase / calcineurin inhibitor or regulating a receptor trafficking molecule, by inhibiting a phosphodiesterase or a phosphatase or by Modulation of receptor traffic molecules (eg, BARK, arrestin, ubiquitin E3 ligase). An increase in transmission in an individual can minimize or alleviate the conditions of the central or peripheral nervous system, such as memory and cognitive impairments. For example, an increase in cholinergic (eg post-synaptic) transmission in a human individual can minimize or alleviate the symptoms associated with Alzheimer's disease. An increase in dopaminergic (eg post-synaptic) transmission in a human individual can minimize or alleviate the symptoms associated with Parkinson's disease. A carbamoyl ester can, after hydrolysis with a cholinesterase, become, for example, dopamine or a dopaminergic agent which can increase transmission (pre- or post-synaptic) in the central nervous system in human individuals with Parkinson's disease , thereby providing an alternative to L-DOPA (Levo dopa). The lipophilic phenyl carbamate, for example, of the carbamoyl ester can facilitate the penetration of the carbamoyl ester through the blood brain barrier, thus allowing the delivery of a pharmacologically active agent, in particular, dopamine, into the central nervous system. One skilled in the art can determine, using known techniques, the effect of the pharmacologically active agent on a human individual with a central or peripheral nervous system condition. Another embodiment of the invention is a method of treating a cholinergic deficiency in an individual.

The method includes administering to the individual a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase which is used to treat cholinergic deficiency in the individual. The carbamoyl ester includes an amino group that, after hydrolysis, for example, by reaction with cholinesterase, it becomes at least a component of a pharmacologically active agent that also treats cholinergic deficiency in the individual. Additional treatment may be, for example, by inhibiting AChE / or BuChE, or by increasing the release or synthesis of ACh. Cholinergic deficiency can be a deficiency of the nervous system. For example, the carbamoyl esters of the invention can be used to treat a human individual who has Alzheimer's disease. Presynaptic neurons degenerate rapidly in Alzheimer's disease, which limits the efficacy of ChE inhibition as the disease progresses (Cutler, N.R., et al., CNS Drugs 3: 467-481 (nineteen ninety five) ) . ChE continues to be present at the synapse of neurons in an individual with Alzheimer's disease, hydrolyzing the small amount of ACh that may be present at the synapse. For this reason, the carbamoyl esters of the invention can be converted into a cholinergic agonist, thereby improving cholinergic deficiency by increasing ACh-mediated synaptic transmission in the central nervous system of individuals suffering from Alzheimer's disease, mild cognitive impairment , memory deterioration caused by age, memory loss caused by age, natural aging, vascular dementia, dementia with Lewis bodies and Parkinson's disease. In a further embodiment, the invention is a method of treating memory impairment in an individual. The method includes administering to the individual a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase which is used to treat the deterioration of memory in the individual. The carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent that also treats the impairment of memory in the individual. Additional treatment of the memory may be a treatment similar to the carbamoyl ester or in a manner different from the carbamoyl ester which is characteristic of the pharmacologically active agent. Memory deterioration can be a memory impairment selected from the group consisting of a deterioration of memory consolidation, a deterioration of long-term memory and a deterioration of short-term memory. Any person skilled in the art would be able to identify an individual with memory impairment and assess deterioration. In a particular embodiment, a human individual suffers from memory impairment related to a condition selected from the group consisting of Alzheimer's disease, Parkinson's disease, memory loss caused by age, mild cognitive impairment and multiple sclerosis. In another embodiment, the human individual treated with the carbamoyl esters of the invention undergoes cognitive decline caused by age. Yet another embodiment of the invention is a method of delivering a pharmacologically active agent to a tissue. The method includes administering a carbamoyl ester to the tissue. The carbamoyl ester inhibits a cholinesterase and includes an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to at least one component of a pharmacologically active agent, whereby the pharmacologically active agent is supplied to the tissue. The tissue may be a tissue sample in vitro or it may be a tissue in vivo (in an individual). The tissue can be muscle tissue, nerve tissue or any combination of muscle, nervous, connective or epithelial tissue. The carbamoyl ester can be used to deliver a pharmacologically active agent to a tissue that is proximal or distal to a tissue having a cholinesterase that is inhibited by the carbamoyl ester. For example, a carbamoyl ester can be used to deliver a pharmacologically active agent, such as a cholinergic agent, to a muscle tissue. The carbamoyl ester can be linked to a cholinesterase (acetylcholinesterase, butyrylcholinesterase) so that it inhibits cholinesterase activity and, after hydrolysis (for example, with a cholinesterase), becomes a cholinergic agent. The pharmacologically active agent can be delivered to a muscle cell near the binding site of the carbamoyl ester to the cholinesterase or to a muscle cell distal to the binding site. Similarly, the carbamoyl ester can be linked to a cholinesterase in a neuron of the nervous system and deliver a cholinergic agent proximal or distal to the binding site. The carbamoyl ester can be linked to a cholinesterase and, after hydrolysis, for example, by reaction with cholinesterase, supplying, for example, a dopaminergic agent, serotonergic agent, adrenergic agent, noradrenergic agent, glutamatergic agent, GABAergic agent, histaminergic agent, inhibitor of mono-amino-oxidase, inhibitor of COMT, beta-secretase inhibitor, gamma-secretase inhibitor, potassium channel blocker, calcium channel blocker, adenosine receptor modulator, cannabinoid receptor modulator, nootropic, modulator of the neuropeptide pathway, neurotrophic, inhibitor of PDE IV, phosphatase / calcineurin inhibitor, receptor traffic regulator or tracer amino receptor modulator to a neuron proximal or distal to the binding site of the carbamoyl ester. Accordingly, the carbamoyl esters of the invention provide a method of administering a pharmacologically active agent to the central nervous system. The pharmacologically active agents can diffuse to variable regions of the brain and mediate their effects. In a particular embodiment, the invention is a method of administering an amphetamine compound or a methamphetamine compound to an individual by administering a carbamoyl ester to the individual. The carbamoyl ester inhibits a cholinesterase and comprises an amino group which, after hydrolysis, for example, by reaction with the cholinesterase, is converted to the amphetamine compound, whereby the amphetamine compound is delivered to the tissue. In a further embodiment, the invention is a method of treating glaucoma in an individual, comprising the step of administering to the individual a carbamoyl ester. The carbamoyl ester inhibits a cholinesterase, whereby glaucoma is treated in the individual, and includes an amino group which, after hydrolysis, for example, by reaction with cholinesterase, becomes at least a component of a pharmacologically active agent active that also treats glaucoma in the individual. In yet another embodiment, the invention includes pharmaceutical compositions comprising the carbamoyl esters described herein. The pharmaceutical composition comprises a carbamoyl ester which inhibits a cholinesterase, wherein the carbamoyl ester includes an amino group which, after hydrolysis, for example, by reaction with cholinesterase, is converted to at least one component of a pharmacologically active agent . In a particular embodiment, the carbamoyl ester of the pharmaceutical composition has the following structure: wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and each of Ri and R2, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl. In another embodiment, the carbamoyl ester of the pharmaceutical composition is not (3aS-cis) -1, 2, 3, 3a, 8, 8a-hexahydro-1,3a, 8-trimethyl-pyrrolo [2, 3-b] -indo-5-ol, 4-pyridinyl carbamate ester, carbamate ester of (3aS-cis) -1,2,3, 3a, 8, 8a, -hexahydro-1, 3a, 8-trimethyl-pyrrolo [ 2, 3-b] -indol-5-ol- (2-phenyl) ethyl, carbamate ester of (3aS-cis) -1,2,3, 3a, 8, 8a-hexahydro-l, 3, 8- trimethyl-pyrrolo [2, 3-b] indol-5-ol [1- (1-naphthyl) ethyl], carbamate ester of 7-bromo- (3aS-cis) -1,2,3, 3a, 8, 8a-hexahydro-l, 3a, 8-trimethyl-pyrrolo [2,3-b] -indol-5-ol-heptyl, or a tetrahydroisoquinolinyl carbamate ester. The carbamoyl esters of the invention can be used in the methods, pharmaceutical compositions, equipment and tests of the invention in a single dose or in multiple doses. Multiple doses may be administered as multiple doses in a single day, as a single daily dose administered for more than one day, as multiple doses administered daily for more than one day, or as a single dose on any given day, followed or preceded by multiple doses in the days of treatment. Multiple doses can be administered for a day, several days, a week, several weeks, a month, several months, a year or several years. The carbamoyl esters of the invention can be administered in the methods of the invention to an individual rapidly (briefly or in the short term) or chronically (prolonged or long term). For example, the carbamoyl esters of the invention can be used in methods for treating an individual by administering the carbamoyl ester to the individual once a day, several times (e.g., 2, 3, 4) in one day, for a day, several days, a week, several weeks, a month, several months or years. In one embodiment, the dose of the carbamoyl ester can be about 0.1 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, approximately 75 mg, approximately 90 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 500 mg, approximately 750 mg or approximately 1000 mg. In another embodiment, the dose of the carbamoyl ester may be between about 1 mg and about 100 mg; between about 2 mg and about 50 mg; or between about 5 mg and about 25 mg. In yet another embodiment, each dose of a multiple dose may be about 0.1 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about mg or about 1000 mg. In yet another embodiment, each dose of a multiple dose may be between about 1 mg and about 100 mg; between about 2 mg and about 50 mg; or between about 5 mg and about 25 mg. The carbamoyl ester and the pharmacologically active agent are administered in the methods of the invention or used in the tests and equipment of the invention in an effective amount. The term "effective amount", "effective amount", or "therapeutically effective amount", when referring to the amount of the carbamoyl ester or pharmacologically active agent, is defined as that amount, or dose, of the carbamoyl ester or pharmacologically active agent that is sufficient for the therapeutic efficacy (for example, an amount sufficient to treat a condition of the nervous system in an individual; increase ACh in an in vitro sample, in a tissue or in an individual; increase the transmission between two or more neurons; treat a cholinergic deficiency; treat a deterioration of memory; treat a deterioration of cognition; providing a pharmacologically active agent to a tissue or an individual). The carbamoyl ester optionally can be used in the methods, equipment and tests of the invention with an acceptable vehicle. The selection of an acceptable vehicle will depend on the method, equipment or test. For example, an acceptable vehicle in an in vitro method, test or equipment may be saline solution, a buffer or suitable cell culture medium. The carbamoyl esters of the invention can be administered alone or as mixtures with conventional excipients, for example, carrier substances, organic or inorganic, pharmaceutically or physiologically acceptable for enteral or parenteral application, which do not react in a harmful manner with the compound used in the method. Pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to modify the osmotic pressure, buffers, coloring substances, and / or aromatics that do not react in a harmful manner with the compounds used in the methods of the invention. The preparations can also be combined, when desired, with other active substances to reduce metabolic degradation. The preferred methods of administration of carbamoyl esters are oral administration (such as a tablet or capsule). The carbamoyl ester alone, or when combined with a mixture, can be administered in a single dose or in more than one dose at a certain time to confer the desired effect (for example, to improve a nervous system condition, increase acetylcholine , increase the transmission between two or more neurons, treat a cholinergic deficiency, treat a deterioration of the memory, treat a cognitive deterioration, supply a pharmacologically active agent). Carbamoyl esters can be administered to a target site in an individual. The selected target site may depend on the condition that is going to be treated. For example, a local injection into a skeletal muscle (the target site) can be used to treat a condition of the peripheral nervous system, or local injection into the cerebral spinal fluid, sinuses or ventricles of the brain (target sites) can be used to treat a condition of the central nervous system. In another example, eye drops, an ointment, a gel or an eye injection, containing the carbamoyl ester to treat glaucoma in an individual may be employed. When parenteral application is needed or desired, mixtures particularly suitable for carbamoyl esters are sterile, injectable solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. • In particular, vehicles for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. The ampoules are convenient unit dosages. The carbamoyl esters used in the methods, tests or equipment of the invention can also be incorporated into liposomes or can be administered by transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the present invention are well known to those skilled in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the entire disclosure of which is hereby incorporated by reference. The dosage and frequency (single or multiple doses) of administration to an individual can vary depending on various factors, including, for example, the condition of the nervous system to be treated, the type of cholinergic deficiency in the individual, the duration of nervous system involvement, degree of memory impairment (eg, deterioration in memory consolidation, impairment of short-term memory), degree of cognitive impairment (eg, attention, alertness, function executive, insomnia, excitement, lack of sleep, reaction time), the pharmacologically active agent that is going to be administered or cognition; the size, age, sex, health, body weight, body mass index and diet of the individual; the nature and degree of the symptoms of the condition or deterioration of memory or cognition, the type of concurrent treatment, the complications of the condition or deterioration, or other problems related to the health of the human being treated. Other regimens or therapeutic agents may be used in conjunction with the carbamoyl methods and esters employed in the methods of the invention. The adjustment and manipulation of the established dosages (eg, frequency and duration) are within the ability of those skilled in the art. The present invention is further illustrated by the following examples, which are not intended to be limitations in any way.

EXEMPLIFICATION EXAMPLE 1. SCHEME I. SYNTHESIS OF AN ESTER OF CARBAMOÍLO: Seventy-three milligrams (73 mg) of NaH (60% dispersion in mineral oil) were added to a solution of 0.3 g (1.82 mmol) of (-) -3 '-hydroxyphenylethyldimethylamine (1) in 15 ml of toluene. The solution was stirred at room temperature for 30 minutes and then added in a portion of 0.33 g of carbonyldiimidazole (CDl) (2.0 mmol), and heated at 80 ° C for 2 hours. Then dl-amphetamine sulfate (2) (0.335 g, 1.82 mmol) was added and the mixture was stirred at room temperature for 2 days. Distilled water (20 ml) and 15 ml of 1 M HCl solution were added to the reaction mixture and the aqueous and organic layers were separated. The aqueous layer was washed with chloroform, made basic with 1M NaOH to pH ~ 11 and extracted with ether. The ether layer was dried over sodium sulfate, evaporated and purified with a column of silica gel (eluted with 3% methanol and 1% triethylamine in ethyl acetate) to yield 0.27 g of the carbamoyl ester (3). ) (0.83 mmol, 46% yield). The carbamoyl ester (3) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.146 (d, 3H, J = 6.6 Hz, CH3), 1.312 (d, 3H, J = 6.7 Hz, CH3), 2.153 (s, 6H, 2 x CH3), 2,721 (dd, 1H, J = 13.4 and 7.2 Hz, CHE), 2866 (dd, 1H, J = 13.4 and 5.9 Hz, CEH), 3.218 (q, 1H, J = 6.6 Hz, CH), 3,960-4,936 ( m, 1H, CH), 4,870 (broad d, 1H, J = 7.7 Hz, NH), 6,943 (broad d, 1H, J = 7.2 Hz, CH arom.), 6,993 (broad s, 1H, CH arom.) , 7.078 (broad d, 1H, J = 7.7 Hz, CH arom.) 7.156-7.291 (m, 6H, CH arom.) Scheme I EXAMPLE 2. SCHEME II. SYNTHESIS OF A CARBAMOID ESTER The (S) - (-) - 3'-hydroxyphenylethyldimethylamine (96 mg, 0.58 mmol) (1) was dissolved in 4 ml of anhydrous ethyl acetate. N, N'-carbonyldiimidazole powder (283 mg, 1.74 mmol) was added and the mixture was stirred at room temperature for 20 hours. Acetic acid (313 mg, 5.22 mmol) was added to the mixture, followed by the addition of 162 mg of (-) - atomoxetine (4, 0.63 mmol). The resulting mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the mixture and the aqueous and organic layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over NaHCO 3, evaporated and purified with a column of silica gel (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 101 mg of the carbamoyl ester (5%). ) (0.23 mmol, 39.0% yield). The free base 5 was converted to the hydrochloride salt according to the procedure described in Example 14. The carbamoyl ester (5) was confirmed by NMR.

RMN-1 !! of the HCl salt (CDC13, 400 MHz): d 1.808 and 1.825 (d, 3H, J = 6.8 Hz, CH3), 2.090-2.320 (m, 2H), 2.262 (ma) and 2.325 (mi) (s, 3H, CH3), 2.506-2.541 (m, 3H, CH3), 2.658-2.698 (m, 3H, CH3), 3,002 (ma) and 3,082 (mi) (s, 3H, CH3), 3,520-3,575 (m, 1H, CH), 3,662-3,700 and 3,892-3,961 (m, 1H, CH), 4,048-4,123 (m, 1H, CH), 5,180-5,252 (m, 1H, CH), 6,535-6,582 (m , 1H, CH arom.), 6.729-6.787 and 6.902-6.957 (m, 3H, 3 x CH arom.), 7.007-7.086 (m, 2H, 2 x CH arom.), 7.224-7.428 (m, 7H, 7 x CH arom.), 12,620 (broad s, 1H, HCl).

Scheme II EXAMPLE 3. SCHEME III. SYNTHESIS OF A CARBAMOID ESTER: 4-Nitrophenylchloroformate powder (0.179 g, 0.86 mmol) was added to a solution of 0.12 g (0.72 mmol) of (-) - 3'-hydroxyphenylethyldimethylamine (1) and 0.22 g (2.17 mmol) triethylamine in 10 ml of anhydrous dichloromethane (0.86 mmol) a 0 ° C. The solution was stirred at 0 ° C for 5 minutes followed by stirring at room temperature for an additional 30 minutes. Then a solution of 0.107 g of 1-methamphetamine (6) in 2 ml of anhydrous dichloromethane was added, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was applied to a column of silica gel. The carbamoyl ester (7) was eluted with 3% acetone in ethyl acetate containing 1% triethylamine. The fractions containing the carbamoyl ester (7) were combined and concentrated to yield 0.15 g of the carbamoyl ester (7) (0.44 mmol, 61% yield). The carbamoyl ester (7) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.192 (mi) and 1.275 (ma) (d, 3H, J = 6.8 Hz, CH3), 1305 and 1.326 (d, 3H, J = 3.0 Hz, CH3), 2.162 and 2.167 (s, 6H, 2 x CH3), 2746 (dd, 1H, J = 13.7 and 6.8 Hz, CHE), 2850 (dd, 1H, J = 13.7 and 6.8 Hz, CEH), 2868 and 2886 (s, 3H, CH3), 3.165-3.217 (m, 1H, CH), 4.558-4.633 (m, 1H, CH), 6.665 and 6.855 (broad d, 1H, J = 7.9 Hz, CH arom.), 6.723 and 6.928 (broad s, 1H, CH arom.), 7. 065 (broad d, 1H, J = 7 .2 Hz, CH arom. ), 7,176-7 .305 (m, 6H, CH arom.).

Scheme III EXAMPLE 4. SCHEME IV. SYNTHESIS OF CARBAMOIL ESTER At room temperature, diisopropylethylamine (5.16 g, 40 mmol) and CDI powder (6.48 g, 40 mmol) were added to a suspension of 7.34 g of 1-amphetamine sulfate (8) (40 mmol) in 140 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1 hour. (-) - a-3 'hydroxyphenylethyldimethylamine (1) (3.3 g, 20 mmol), which had been mixed with 0.8 g of sodium hydride (60% dispersion in mineral oil) in anhydrous toluene (120 ml) for 30 minutes , it was added to the mixture and the dichloromethane was removed under reduced pressure. The resulting suspension was heated to 85 ° C overnight with stirring. The reaction mixture was extracted with 0.5 M HCl (200 ml). The aqueous layer was washed with ethyl acetate, made alkaline at 0 ° C to pH ~ 11 with sodium bicarbonate and 0.5 N NaOH and extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified with a column of silica gel. Elution with a mixture of 20-30% ethyl acetate with 1% triethylamine in hexane yielded 1.53 g of the carbamoyl ester (9) (4.7 mmol, 23.5% yield). The carbamoyl ester (9) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.179 (d, 3H, J = 6.6 Hz, CH3), 1331 (d, 3H, J = 6.7 Hz, CH3), 2.174 (s, 6H, 2 x CH3), 2.789 (dd, 1H, J = 13.4 and 7.2 Hz, CfZH), 2.832 (dd, 1H, J = 13.4 and 5.9 Hz, CHtf), 3.228 (q, 1H, J = 6.7 Hz, CH), 3,980-4,062 ( m, 1H, CH), 4,856 (broad d, 1H, J = 7.2 Hz, NH), 6,955 (broad d, 1H, J = 7.4 Hz, CH arom.), 7,018 (broad s, 1H, CH arom.) , 7.095 (broad d, 1H, J = 7.7 Hz, CH arom.) 7.186-7.303 (m, 6H, CH arom.).

EXAMPLE 5: SCHEME V. SYNTHESIS OF A CARBAMOID ESTER The (S) - (-) - 3'-hydroxyphenylethyldimethylamine (1) (1.2 g, 7.3 mmol) was dissolved in 20 ml of anhydrous ethyl acetate. N, N'-carbonyldiimidazole powder (2.37 g, 14.6 mmol) was added and the mixture was stirred at 85 ° C overnight. After cooling to 0 ° C, 3.3 g of acetic acid (55.0 mmol) was added, followed by the addition of 2.8 g of 1-amphetamine (8) (20.7 mmol). The mixture was stirred at room temperature for 36 hours. Water (20 ml) and 1 M HCl (20 ml) were added and the aqueous and organic layers separated. The organic layer was extracted with 0.5 M HCl. The aqueous layers were combined and washed with ether twice, basified with NaHCO 3 and 0.5 N NaOH to pH -11 and extracted with ether. The ether layer was dried over NaHCO 3, evaporated and purified by chromatography on silica gel. Elution with a mixture of 25% ethyl acetate with 1% triethylamine in hexane yielded 0.93 g of the carbamoyl ester (9) (2.85 mmol, 39% yield).

Scheme V EXAMPLE 6. SCHEME VI. SYNTHESIS OF A CARBAMOID ESTER: Triphosgene (85.5 mg, 0.28 mmol) was dissolved in 2 ml of anhydrous dichloromethane. To this solution, a mixture of 145 mg of desmethylselegelin (10) (0.84 mmol) and 110 mg of diisopropylethylamine (DIEA) (0.85 mol) in 1 ml of anhydrous dichloromethane at 0 ° C was added and allowed to react for 10 minutes. The mixture was stirred at room temperature for 60 hours, and then added to a suspension of (-) -a-3 '-hydroxyphenylethyldimethylamine (1) (92 mg, 0.55 mmol) and sodium hydride (68 mg, 60% strength). dispersion in mineral oil) in anhydrous acetonitrile, which had been stirred at room temperature for 1 hour. The resulting mixture was stirred at room temperature overnight. The solvents of the above mixture were removed under reduced pressure. The residue was dissolved in 0.5 M HCl and washed with ether. The aqueous layer was basified with sodium bicarbonate and extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with 0.5 N NaOH (200 ml), dried over sodium sulfate and evaporated. The residue was purified with a column of silica gel (eluted with 30-60% ethyl acetate in hexane with 1% triethylamine) to yield 185 mg of the carbamoyl ester (11) (0.508 mmol, 92.3% yield) . The carbamoyl ester (11) was confirmed by NMR.

Y-NMR (CDC13, 300 MHz): d 1.339 (d, 3H, J = 6.6 Hz, CH3), 1327-1.415 (m, 3H, CH3), 2.187 (s, 6H, 2 x CH3), 2.215-2.258 (m, 1H, CH), 2843-2870 (m, 1H, CH), 3063 (dd, 1H, J = 13.5 and 7.5 Hz, CEH), 3.230 (q, 1H, J = 6.6 Hz, CH), 4.043 -4.118 (m, 2H, 2 x CH), 4.372-4.411 (m, 1H, CH), 6.846-7.024 (m, 2H, 2 x CH arom.), 7.108 (broad d, 1H, J = 7.7 Hz, CH arom.), 7.202-7.313 (m, 6H, CH arom.). 1 Scheme VI EXAMPLE 7. SCHEME VII. SYNTHESIS OF A CARBAMOYL ESTER: Triphosgene (140 mg, 0.47 mmol) was dissolved in 6 ml of anhydrous dichloromethane. To this solution, a mixture of 204.5 mg of 1-methamphetamine (6, 1.37 mmol) and 177 mg of diisopropylethylamine (DIEA) (1.37 mol) in 2 ml of anhydrous dichloromethane at 0 ° C was added and allowed to react for 10 minutes. . The mixture was stirred at room temperature during 2 days, and subsequently it was added to a solution of eseroline (12) (153 mg, 0.70 mmol) and 4-dimethylaminopyridine (268 mg) in 5 ml of anhydrous acetonitrile. The resulting mixture was stirred at room temperature overnight. The solvents of the above mixture were removed under reduced pressure. The residue was dissolved in sodium bicarbonate solution and extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over sodium sulfate and evaporated. The residue was purified with a column of silica gel (eluted with 30-60% ethyl acetate in hexane with 1% triethylamine) to yield 40 mg of the carbamoyl ester (13) (0.10 mmol, 14% yield) . The carbamoyl ester (13) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.177 (mi) and 1.261 (ma) (d, 3H, J = 6.7 Hz, CH3), 1386 (ma) and 1397 (mi) (s, 3H, CH3), 1,866- 1,932 (m, 2H), 2,505 (s, 3H, CH3), 2,542-2,767 (m, 3H), 2,803-2,870 (m, 1H), 2,860 (s, 6H, 2 x CH3), 4,078 (s) , 1H), 4,050-4,610 (m, 1H, CH), 6,254 (ma) and 6,285 (mi) (d, 1H, J = 8.4 Hz, CH arom.), 6,359 (ma) and 6,591 (mi) (d) , 1H, J = 2.2 Hz, CH arom.), 6,460 (ma) and 6,666 (mi) (dd, 1H, J = 8.4 and 2.2 Hz, CH arom.), 7,170-7,300 (m, 5H, CH arom. ). 12 Scheme VII EXAMPLE 8. SCHEME VIII. SYNTHESIS OF CARBAMOID ESTER: Esteroline (12) (57 mg, 0.26 mmol) was dissolved in 4 ml of anhydrous ethyl acetate. CDI (106 mg, 0.65 mmol) was added and the mixture was stirred at room temperature for 2 hours. Acetic acid (117 mg, 1.95 mmol) was added followed by 85 mg (0.57 mmol) of 1-methamphetamine (6). The resulting mixture was stirred at room temperature for 24 hours under an argon atmosphere. The reddish reaction mixture was washed with water. The aqueous solution was extracted with ethyl acetate, neutralized with 0.5 N NaOH to pH ~ 8 and extracted with ethyl acetate (3 x 50 ml). All organic layers were combined, dried over sodium sulfate, concentrated and purified with a column of silica gel (eluted with 30% ethyl acetate and 1% triethylamine in hexane) to yield 38.4 mg of the ethyl ester. carbamoyl (13) (0.1 mmol, 38.5% yield). The product was identical to the carbamoyl ester (13) obtained in Example 7.

Scheme VIII EXAMPLE 9: SCHEME IX. SYNTHESIS OF A CARBAMOID ESTER: Eseroline (12) (1.14 g, 5.2 mmol) was dissolved in 30 ml of anhydrous ethyl acetate. CDI (1.7 g, 10.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. Acetic acid (1.26 g, 21 mmol) was added followed by 1.46 g (7.5 mmol) of 1-amphetamine acetate salt (8). The mixture was stirred at room temperature for 24 hours under an argon atmosphere. The reaction mixture was basified with 0.5 N NaOH to pH ~ 8, and extracted with ethyl acetate (3 x 100 mL). All organic layers were combined, dried over sodium sulfate, concentrated and purified with a column of silica gel (eluted with 30% ethyl acetate and 1% triethylamine in hexane) to yield 1.0 g of ethyl ester. Carbamoyl (14) (2.64 mmol, 50.6% yield). The resulting carbamoyl ester (14) was confirmed by NMR. X-NMR (CDC13, 300 MHz): d 1.156 (d, 3H, J = 6.5 Hz, CH3), 1400 (s, 3H, CH3), 1892-1.939 (m, 2H), 2.513 (s, 3H, CH3) ), 2,568-2,767 (m, 3H), 2,853-2,890 (m, 1H), 2,885 (s, 3H, CH3), 3,990-4,064 (m, 1H, CH), 4,085 (s, 1H), 4,847 (d) broad, 1H, J = 7.4 Hz, NH), 6,298 (d, 1H, J = 8.3 Hz, CH arom.), 6,699 (broad s, 1H, CH arom.), 6,740 (broad d, 1H, J = 8.3 Hz, CH arom.), 7.178-7.317 (m, 5H, CH arom.).

Scheme IX EXAMPLE 10. SCHEME X. SYNTHESIS OF A CARBAMOYL ESTER: The (R) - (+) - 3'-hydroxyphenylethyldimethylamine (15) (95 mg, 0.57 mmol) was dissolved in 4 ml of anhydrous ethyl acetate. N, N'-carbonyldiimidazole powder (250 mg, 1.54 mmol) was added and the mixture was stirred at 85 ° C overnight. After cooling to 0 ° C, 250 mg of acetic acid (4.17 mmol) was added, followed by the addition of 158 mg of 1-methamphetamine (6) (1.06 mmol). The mixture was stirred at room temperature for 36 hours. Water (20 ml) and 1 M HCl (20 ml) were added and the layers separated. The organic layer was extracted with 0.5 M HCl. The aqueous layers were combined, washed twice with ether and made alkaline with NaHCO 3 and 0.5 N NaOH to pH ~ 11, followed by extraction with ether. The ether layer was dried over NaHCO 3, evaporated and purified by chromatography on silica gel (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 80 mg of carbamoyl ester (16) (0.23). mmol, 41.2% yield). The carbamoyl ester (16) was confirmed by NMR. Y-NMR (CDC13, 400 MHz): d 1.197 and 1.276 (d, 3H, J = 6.8 Hz, CH3), 1,314 and 1,328 (d, 3H, J = 3.0 Hz, CH3), 2,162 and 2,167 (s, 6H, 2 x CH3), 2,752 (dd, 1H, J = 13.6 and 6.4 Hz, CHH), 2 . 845 (dd, 1H, J = 13.6 and 8.8 Hz, CHH), 2. 869 and 2. 887 (s, 3H, CH3), 3. 170-3. 240 (m, 1H, CH), 4. 562-4. 626 (m, 1H, CH), 6,671 and 6,854 (broad d, 1H, J = 7.8 Hz, CH arom.), 6,751 and 6,932 (broad s, 1H, CH arom.), 7,068 (broad d, 1H, J 7.2 Hz, CH arom.), 7.184-7.301 (m, 6H, CH arom.).

Scheme X EXAMPLE 11. SCHEME XI. SYNTHESIS OF A CARBAMOID ESTER: The (S) - (-) - 3'-hydroxyphenylethyldimethylamine (1) (145 mg, 0.88 mmol) was dissolved in 4 ml of anhydrous ethyl acetate. N, N'-carbonyldiimidazole powder (356 mg, 2.20 mmol) was added and the mixture was stirred at room temperature for 20 hours. Acetic acid (395 mg, 6.58 mmol) was added, followed by the addition of 283 mg of 2-phenylethylamine (17, 2.34 mmol). The mixture was stirred at room temperature overnight. Water (10 ml) and 1 M HCl (10 ml) were added and the layers separated. The organic layer was extracted with 0.5 M HCl. The aqueous layers were combined, washed with ether twice and basified with 0.5 N NaHCO 3 until pH 11, followed by extraction with ether. The ether layer was dried over NaHCO 3, evaporated and purified with a column of silica gel.

Elution with 25% ethyl acetate in hexane with 1% triethylamine yielded 90 mg of carbamoyl ester (18) (0.29 mmol, 32.7% yield). The carbamoyl ester (18) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.328 (d, 3H, J = 6.7 Hz, CH3), 2.169 (s, 6H, 2 x CH3), 2.860 (t, 2H, J = 6.8 Hz, CH2), 3.231 (q, 1H, J = 6.7 Hz, CH), 3.466-3.532 (m, 2H, CH2), 5.002 (broad s, 1H, NH), 6.966 (dd, 1H, J = 8.0 and 1.4 Hz, CH arom. .), 7,030 (broad s, 1H, CH arom.), 7,092 (broad d, 1H, J = 7.7 Hz, CH arom.) 7,183-7,334 (m, 6H, CH arom.).

Scheme XI EXAMPLE 12. SCHEME XII. SYNTHESIS OF A CARBAMOIS ESTER: The (S) - (-) - 3'-hydroxyphenylethyldimethylamine (1) (81 mg, 0.49 mmol) was dissolved in 4 mL of anhydrous ethyl acetate. N, N'-carbonyl.diimidazole powder (199 mg, 1.23 mmol) was added and the mixture was stirred at room temperature for 20 hours. Acetic acid (184 mg, 3.07 mmol) was added, followed by the addition of 186 mg of d-amphetamine acetate salt (19) (0.96 mmol). The mixture was stirred at room temperature overnight. Water (5 ml) and 1 M HCl (5 ml) were added and the aqueous and organic layers were separated. The organic layer was extracted with 0.5 M HCl. The aqueous layers were combined, washed with ether twice and basified with NaHCO 3 and 0.5 N NaOH to pH 11, followed by extraction with ether. The ether layer was dried over NaHCO 3, evaporated and purified with a column of silica gel (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 95 mg of carbamoyl ester (20) ( 0.29 mmol, 59.4% yield). The carbamoyl ester (20) was confirmed by NMR. Y-NMR (CDC13, 300 MHz): d 1.192 (d, 3H, J = 6.6 Hz, CH3), 1.367 (d, 3H, J = 6.7 Hz, CH3), 2.205 (s, 6H, 2 x CH3), 2.759 (dd, 1H , J = 13.4 and 7.2 Hz, CHH), 2896 (dd, 1H, J = 13.4 and 5.9 Hz, CEH), 3.295 (q, 1H, J = 6.6 Hz, CH), 3.990-4.044 (m, 1H, CH ), 4847 (broad d, 1H, J = 7.2 Hz, NH), 6,966 (broad d, 1H, J = 7.4 Hz, CH arom.), 6,976 (broad s, 1H, CH arom.), 7,114 (broad d , 1H, J = 7.7 Hz, CH arom.) 7.191-7.324 (, 6H, CH arom.).

Scheme XII EXAMPLE 13. SCHEME XIII. SYNTHESIS OF CARBAMOID ESTER: The (R) - (+) - 3'-hydroxyphenylethyldimethylamine (15) (195 mg, 1.18 mmol) was dissolved in 7 mL of anhydrous ethyl acetate. N, N'-carbonyldiimidazole powder (250 mg, 1.54 mmol) was added and the mixture was stirred at 85 ° C overnight. After cooling to 0 ° C, 177 mg of acetic acid (2.95 mmol) was added, followed by the addition of 276 mg of 1-amphetamine sulfate. (8) (1.50 mmol). The mixture was stirred at room temperature for 36 hours. Water (10 ml) and 1 M HCl (10 ml) were added and the aqueous and organic layers were separated. The organic layer was extracted with 0.5 M HCl. The aqueous layers were combined, washed with ether twice and basified with NaHCO 3 and 0.5 N NaOH to pH 11, followed by extraction with ether. The ether layer was dried over NaHCO 3, evaporated and purified with a column of silica gel (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 100 mg of carbamoyl ester (21) ( 0.31 mmol, 26.0% yield). The carbamoyl ester (21) was confirmed by NMR. Y-NMR (CDC13, 400 MHz): d 1.179 (d, 3H, J = 6.6 Hz, CH3), 1342 (d, 3H, J = 6.7 Hz, CH3), 2.183 (s, 6H, 2 x CH3), 2.755 (dd, 1H, J = 13.5 and 7.2 Hz, CHH), 2896 (dd, 1H, J = 13.5 and 5.6 Hz, CEH), 3.249 (q, 1H, J = 6.7 Hz, CH), 3.960-4.936 ( m, 1H, CH), 4890 (broad d, 1H, J = 7.9 Hz, NH), 6,974 (broad d, 1H, J = 7.9 Hz, CH arom.), 7,021 (broad s, 1H, CH arom.) , 7.102 (broad d, 1H, J = 7.7 Hz, CH arom.) 7.190-7.322 (m, 6H, CH arom.).

Scheme XIII EXAMPLE 14: PREPARATION OF STERES CHLORHYDRATE SALTS OF CARBAMOÍLO: Carbamoyl ester dissolved in chloroform (3 ml per mmol). A solution of HCl 1 was added dropwise M in ether (1.5-2 molar equivalents) at 0 ° C. After the completion of the addition of hydrochloric acid, the mixture was allowed to warm to room temperature. The solvents were removed by evaporation and the residue dried in vacuo to yield the hydrocarbon salt of the carbamoyl ester visible as a white to off white solid.

EXAMPLE 15: CARBAMOÍLO STERES INHIBITING JN VITRO ACETILCOLINESTERASA: All the reagents used in these experiments were of analytical grade. Acetylthiocholine iodide and 5,5'-dithiobis- (2-nitro) benzoic acid (DT? B) and human recombinant acetylcholinesterase (C1682) were purchased from Sigma Chemical Co. (St. Louis, MO). The activity of acetylcholinesterase of carbamoyl esters at 25 ° C was determined by a modification of the colorimetric method Ellmann, et al. (Biochem. Pharmacol., 1: 88-95 (1961)). The enzyme, carbamoyl ester or stigmine and buffer were preincubated for 30 minutes. At the end of the pre-incubation period, the acetylthiocholine substrate was added. The final test mixture contained 10 mM Tris buffer (pH 8), 0.3 mM Acetylthiocholine and 0.33 mM DT? B and 0.08 U / ml enzyme. At least five (5) different concentrations of the carbamoyl ester or stigmine were tested by experiment IC50. The hydrolysis of acetylthiocholine was indirectly monitored by measuring the formation of the conjugate between thiocholine and DTNB. The optical density was recorded at 405 nm for 5 minutes using a microplate spectrophotometer (Polarstar, BMG Labtech) and plotted against time. The inverse of the initial proportions is plotted for a range of concentrations of inhibitor against concentration (Dixon Plot) to obtain the IC50 value (the concentration at which enzyme activity is inhibited by 50%) as the opposite value of intersection x ( Burlingham, et al., J. Chem. Ed., 80: 214-218 (2003)). The results are summarized below: Compound IC50 Rivas igmina 2,615 nM 5 460 nM 7 302 nM 9 404 nM 13 5,440 nM 14 253 nM 20 449 nM These data show that the carbamoyl esters of the invention inhibit acetylcholinesterase in vitro. The inhibition of acetylcholinesterase by carbamoyl esters may be greater than the inhibition of acetylcholinesterase by a stigmine, like rivastigmine. The carbamoyl esters synthesized from stigmines were found to have similar or increased activity compared to stigmine. For example, the carbamoyl ester (14) resulted in a 10-fold increase in enzyme activity compared to rivastigmine. Therefore, structural alterations in stigmines, carbamoyl esters with known enzymatic activity, do not diminish or inhibit the enzymatic activity of stigmine.

EXAMPLE 16: CARBAMOÍLO STERS INHIBIT CHOLINESTERASE IN BRAIN: Male Wistar rats were injected intraperitoneally (ip) with rivastigmine or with carbamoyl esters 7 and 9. The dose of rivastigmine or carbamoyl ester resulted in a cholinergic behavior effect with side effects minimum and was well tolerated by the animals. The animals were decapitated 3 hours after the injection and the brains were removed quickly. The brain tissue was cut into small pieces, placed on ice and immediately homogenized with a Polytron PT1200 (Kinematic AG) kit in 10 ml of ice-cold Tris with 0.1% Triton-X and protease inhibitors. The protease inhibitors in the extraction buffer were Antipain (10 μM) Aprotinin (5 UIT / mg protein), Bestatin (60 nm), Leupeptin (10 μM) and Pepstatin (1 μM). The final dilution of the homogenate in the final test mixture was 120 times.

The total cholinesterase activity was determined by a modification of the colorimetric method of Ellmann, et al. (Biochem Pharmacol., 7: 88-95 (1961)), as described above. Acetylthiocholine hydrolysis was monitored indirectly by measuring the formation of the conjugate between thiocholine and DTNB. The optical density was recorded at 405 nm for five (5) minutes using a microplate spectrophotometer (Polarstar, BMG Labtech), and plotted against time. The initial proportions were calculated from the inclination of the linear portion of the graph. The cholinesterase activity was normalized by the protein content of the homogenate. The relative cholinesterase activity was calculated as the ratio of normalized cholinesterase activity in a rat treated with a control compound or a carbamoyl ester to the normalized cholinesterase activity in rats treated with saline. These data are summarized below: Compound Dosage Actividac 1 Inhibition of relative ChE ChE Rivastigmine 2 mg / kg 85% 15% 7 2 mg / kg 62% 38% 9 8 mg / kg 59% 41% This data shows that the administ.

The systemic nature of the compounds of the invention results in the inhibition of total cholinesterase activity in the mammalian brain. The carbamoyl esters resulted in significant inhibition of cholinesterase activity in the brain, compared to rivastigmine with minimal side effects. Accordingly, the carbamoyl esters of the invention can be used in methods that inhibit cholinesterases with mild side effects compared to the cholinesterase inhibitors available so far.

EXAMPLE 17: ÉSTER DE CARBAMOÍLO RELIEVES AMNESIA INDUCED BY ESCOPOLAMINE IN MULTIPLE TEST PASSIVE AVOIDANCE TEST: Inhibitory avoidance was used as a selection of cognitive performance because the discrete nature of the task allows for precise pharmacological manipulation and the ability to selectively study the acquisition, consolidation, or recall of information learned This task has been widely used to evaluate the facilitating effects of centrally acting drugs in both normal and untreated animals, and in animals made amnesic by the use of scopolamine, a cholinergic muscarinic receptor antagonist that produces marked amnesia. The inhibitory avoidance apparatus used in these experiments consisted of a light chamber and a dark chamber, which were joined by means of a sliding guillotine door. The training involved placing a rat inside the light chamber with its head away from the door. Ten seconds later, the sliding door was opened, and the latency was recorded to enter the camera obscura (100 seconds maximum). When the rat entered the dark chamber, it received a continuous shock on the legs (0.4 mA) through the metal grid floor until it returned to the light chamber. This sequence of events continued until the rat remained in the light chamber for a period of 100 consecutive seconds or until it received a maximum of 5 continuous shocks on the legs. The retention test, or the ability of the rat to recall previous events in the inhibitory avoidance apparatus, was conducted 24 hours after the initial test. The rat was placed in the light chamber with its head away from the door. Ten seconds later, the door opened, allowing the rat access to the camera obscura. No shock was administered to the legs during retention test. Latency was recorded upon entering the darkroom (900 seconds maximum) and was used as a memory measurement. To evaluate the effects of carbamoyl esters on scopolamine-induced amnesia, the rats were injected with saline or scopolamine hydrochloride (0.75 mg / kg) 30 minutes before training on the Inhibitory Avoidance task. Immediately after the training test, the rats were injected with saline or the carbamoyl ester. Retention for the task in rats treated with scopolamine or saline was evaluated as described above, 24 hours later. No compound (drug) was administered to the rat prior to the retention trial and no shock was given during the retention trial. For the retention test, the rat was placed in the light chamber. Fifteen seconds later, the door opened automatically and latency was measured upon entering the dark compartment. The latency when entering the camera obscura is the primary memory measurement in this task. The carbamoyl esters were evaluated in this protocol. The esters of carbamoyl and rivastigmine were injected i.p. in the rats. The following table summarizes the most effective dose (the dose that increases the highest latency) for each compound, the performance relative to the control group without damage (saline) as well as the performance relative to the group without damage (scopolamine) at the most dose effective These results show that the systemic administration of the carbamoyl esters of the invention increases the performance in an animal model of amnesia.

EQUIVALENTS Since this invention has been particularly shown and described with reference to its preferred embodiments, those skilled in the art will understand that various changes may be made in the form and details thereof without departing from the scope of the invention, encompassed by the claims. annexes.

Claims (53)

1. CLAIMS 1. A carbamoyl ester which inhibits a cholinesterase, comprising an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent.
2. 2. The carbamoyl ester according to claim 1, wherein the hydrolysis occurs by reaction with an enzyme.
3. 3. The carbamoyl ester according to claim 2, wherein the enzyme is a cholinesterase.
4. 4. The carbamoyl ester according to claim 3, wherein the cholinesterase is an acetylcholinesterase.
5. 5. The carbamoyl ester according to claim 3, wherein the cholinesterase is a butyrylcholinesterase.
6. 6. The carbamoyl ester according to claim 1, wherein the hydrolysis occurs by reaction with an acid.
7. 7. The carbamoyl ester according to claim 1, wherein the carbamoyl ester has the following structure: wherein: A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and each of R ± and R2, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl , an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl.
8. 8. The carbamoyl ester according to the claim 7, where the carbamoyl is not (3aS-cis) -1,2, 3,3a, 8, 8a-hexahydro-l, 3a, 8-trimethyl-pyrrolo [2,3-b] -indo-5-ol , 4-pyridinyl carbamate ester, (3aS-cis) -1,2,3,3a, 8,8a, -hexahydro-l, 3a, 8-trimethyl-pyrrolo carbamate ester [2, 3-b] -indol-5-ol- (2-phenyl) ethyl, carbamate ester of (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3,8-trimethyl-pyrrolo [2, 3-b] indol-5-ol [1- (1-naphthyl) ethyl], carbamate ester of 7-bromo- (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1, 3a, 8-trimethyl-pyrrolo [2, 3-b] -indol-5-ol-heptyl, or a tetrahydroisoquinolinium carbamate ester.
9. 9. The carbamoyl ester according to claim 8, wherein the carbamoyl ester is selected from the group consisting of: wherein each of R3, R4 and R5, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl.
10. 10. The carbamoyl ester according to claim 9, wherein the carbamoyl ester is selected from the group consisting of: 10
11. 11. The carbamoyl ester according to claim 10, wherein the carbamoyl ester is selected from the group consisting of:
12. 12. The carbamoyl ester according to claim 1, wherein the pharmacologically active agent is a pharmacologically active agent of the central nervous system type.
13. 13. The carbamoyl ester according to claim 12, wherein the central nervous system type pharmacologically active agent is selected from the group consisting of a memory facilitating agent and a cognition facilitating agent.
14. 14. The carbamoyl ester according to claim 1, wherein the pharmacologically active agent is an amphetamine compound.
15. 15. The carbamoyl ester according to claim 14, wherein the amphetamine compound is an amphetamine.
16. 16. The carbamoyl ester according to claim 14, wherein the amphetamine compound is a methamphetamine.
17. 17. The carbamoyl ester according to claim 1, wherein the pharmacologically active agent is at least one member selected from the group consisting of a cholinergic agent, an adrenergic agent, a noradrenergic agent, a dopaminergic agent, a serotonergic agent, a glutamatergic agent, a GABAergic agent, a histaminergic agent, an inhibitor of mono-amino-oxidase, a COMT inhibitor, a beta-secretase inhibitor, a gamma-secretase inhibitor, a potassium channel blocker, a calcium channel blocker, an adenosine receptor modulator, a cannabinoid receptor modulator, a nootropic, a modulator of the neuropeptide pathway, a neurotrophic, a PDE IV inhibitor, a phosphatase / calcineurin inhibitor, a regulator of the receptor traffic, a modulator of the amino receptor in traces, blocker of the sodium / calcium exchange, sigma receptor modulator, imidazoline receptor modulator, angiotensin-converting enzyme inhibitors, antioxidants and drug acos non-steroidal anti-inflammatory.
18. 18. The carbamoyl ester according to claim 17, wherein the cholinergic agent is selected from the group consisting of an acetylcholinesterase inhibitor, a butyrylcholinesterase inhibitor, a cholinergic antagonist, a cholinergic agonist, an allosteric modulator of a cholinergic receptor and a open channel blocker.
19. 19. The carbamoyl ester according to claim 17, wherein the adrenergic agent is selected from the group consisting of an alpha receptor agonist, a beta receptor agonist, an alpha receptor antagonist and a beta receptor antagonist.
20. 20. The carbamoyl ester according to claim 17, wherein the noradrenergic agent is selected from the group consisting of a norepinephrine reuptake inhibitor and a norepinephrine releasing agent.
21. 21. The carbamoyl ester according to the claim 17, wherein the serotonergic agent is selected from the group consisting of a serotonergic antagonist, a serotonergic agonist, a serotonergic reuptake inhibitor and a serotonin releasing agent.
22. 22. The carbamoyl ester according to claim 17, wherein the glutamatergic agent is selected from the group consisting of an NMDA receptor agonist, an NMDA receptor antagonist, an NMDA-glycine site agonist, an NMDA site antagonist. -glycine, AMPA receptor agonist and an AMPA receptor antagonist.
23. 23. The carbamoyl ester according to claim 17, wherein the GABAergic agent is selected from the group consisting of a GABA receptor antagonist, a GABA receptor agonist, a benzodiazepine site agonist, and a benzodiazepine site antagonist. .
24. 24. The carbamoyl ester according to claim 17, wherein the dopaminergic agent is selected from the group consisting of a dopaminergic antagonist, a dopaminergic agonist, a dopaminergic reuptake inhibitor, a dopaminergic releasing agent, dopamine and L-DOPA.
25. 25. A method of treating an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase and includes an amino group which, after hydrolysis, becomes at least one component of a pharmacologically active agent that treats the individual for a condition of the individual.
26. The method according to claim 25, wherein the pharmacologically active agent is at least one member selected from the group consisting of a cholinergic agent, an adrenergic agent, a noradrenergic agent, a dopaminergic agent, a serotonergic agent, a glutamatergic agent, a GABAergic agent, a histaminergic agent, a mono-amino-oxidase inhibitor, a COMT inhibitor, a beta-secretase inhibitor, a gamma-secretase inhibitor, a potassium channel blocker, a calcium channel blocker, an adenosine receptor modulator, a cannabinoid receptor modulator, a nootropic, a modulator of the neuropeptide pathway, a neurotrophic, a PDE IV inhibitor, a phosphatase / calcineurin inhibitor, a regulator of the receptor traffic and a modulator of the amino receptor in traces.
27. 27. The method according to claim 25, wherein the condition of the individual being treated by the pharmacologically active agent is at least one condition selected from the group consisting of a condition of the central nervous system, a condition of the peripheral nervous system and a condition of the system nervous self The method according to claim 27, wherein the central nervous system condition is at least one condition selected from the group consisting of Parkinson's disease, memory impairment and cognitive impairment. 29. The method according to claim 28, wherein memory impairment occurs in a human and is associated with at least one condition selected from the group consisting of Alzheimer's disease, memory loss caused by age, a deterioration of the Memory consolidation, a deterioration of short-term memory, mild cognitive impairment and multiple sclerosis. 30. A method of treating a condition of the nervous system in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase by means of which it treats the affection of the nervous system in the individual and wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent that also treats the affection of the nervous system in the individual. 31. A method of treating a condition of the central nervous system in an individual, comprising the step of administering to the individual a carbamoyl ester that inhibits acetylcholinesterase whereby the condition of the central nervous system in the individual is treated, wherein the carbamoyl ester includes an amino group which, after hydrolysis, becomes at least one component of a pharmacologically active agent, wherein the pharmacologically active agent is selected from the group consisting of an amphetamine compound and a methamphetamine compound, whereby the pharmacologically active agent also treats the condition of the central nervous system in the individual. 32. The method according to claim 31, wherein the amphetamine compound is an amphetamine. 33. The method according to claim 31, wherein the methamphetamine compound is a methamphetamine. 34. A method for increasing acetylcholine in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase, whereby acetylcholine is increased and includes an amino group which, after of hydrolysis, it becomes at least a component of a pharmacologically active agent that also increases acetylcholine in the individual. 35. A method for increasing acetylcholine in an individual, comprising the step of administering to the individual a carbamoyl ester that inhibits acetylcholinesterase, whereby the acetylcholine is increased in the individual, wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent, wherein the pharmacologically active agent is selected from the group consisting of an amphetamine compound and a methamphetamine compound. 36. A method of treating a cholinergic deficiency in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase whereby cholinergic deficiency is treated in the individual, and in wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent that also treats cholinergic deficiency in the individual. 37. The method according to claim 36, wherein the cholinergic deficiency in the individual is Alzheimer's disease. 38. A method of treating an impairment of memory in an individual, comprising the step of administering to the individual a carbamoyl ester, wherein the carbamoyl ester inhibits a cholinesterase whereby the deterioration of memory in the patient is treated. individual, and wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent that also treats memory impairment in the individual. 39. The method according to claim 38, wherein the deterioration of the memory in the individual is at least one member selected from the group consisting of a deterioration of the memory consolidation, a deterioration of the long-term memory and a deterioration of short-term memory. 40. The method according to claim 38, wherein the individual is a human. 41. The method according to claim 40, wherein the deterioration of the memory is associated with at least one condition selected from the group consisting of Alzheimer's disease, memory loss caused by age, mild cognitive impairment and multiple sclerosis. 42. The method according to claim 38, wherein the pharmacologically active agent is an amphetamine compound. 43. The method according to claim 42, wherein the amphetamine compound is an amphetamine. 44. The method according to claim 42 wherein the methamphetamine compound is a methamphetamine. 45. A method of delivering a pharmacologically active agent to a tissue, comprising the step of administering a carbamoyl ester to the tissue, wherein the carbamoyl ester inhibits a cholinesterase and includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent, whereby the pharmacologically active agent is delivered to the tissue. 46. The method accordto claim 45, wherein the tissue is found in a human. 47. The method accordto claim 45, wherein the pharmacologically active agent is an amphetamine compound. 48. The method accordto claim 45, wherein the pharmacologically active agent is a memory facilitatagent. 49. The method accordto claim 45, wherein the pharmacologically active agent is a cognition facilitatagent. 50. The method accordto claim 45, wherein the pharmacologically active agent is at least one member selected from the group consistof a cholinergic agent, an adrenergic agent, a noradrenergic agent, a dopaminergic agent, a serotonergic agent, a glutamatergic agent, a GABAergic agent, a histaminergic agent, a mono-amino-oxidase inhibitor, a COMT inhibitor, a beta-secretase inhibitor, a gamma-secretase inhibitor, a potassium channel blocker, a calcium channel blocker, an adenosine receptor modulator, a cannabinoid receptor modulator, a nootropic, a modulator of the neuropeptide pathway, a neurotrophic, a PDE IV inhibitor, a phosphatase / calcineurin inhibitor, a regulator of the receptor traffic and a modulator of the amine receptor in traces. 51. A pharmaceutical composition comprisa carbamoyl ester that inhibits a cholinesterase, wherein the carbamoyl ester includes an amino group which, after hydrolysis, is converted to at least one component of a pharmacologically active agent. 52. The pharmaceutical composition accordto claim 51, wherein the carbamoyl ester has the followstructure: wherein: A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and each of Ri and R2, independently or in combination, is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl, and a substituted heterocycloalkyl. 53. The pharmaceutical composition according to claim 52, wherein the carbamoyl is not (3aS-cis) -1,2,3, 3a, 8, 8a-hexahydro-l, 3a, 8-trimethyl-pyrrolo [2, 3- b] -indo-5-ol, 4-pyridinyl carbamate ester, (3aS-cis) -1, 2, 3, 3a, 8, 8a, -hexahydro-1, 3a, 8-trimethyl- carbamate ester pyrrolo [2, 3-b] -indol-5-ol- (2-phenyl) ethyl, carbamate ester of (3aS-cis) -1, 2, 3, 3a, 8, 8a-hexahydro-l, 3, 8-trimethyl-pyrrolo [2, 3-b] indol-5-ol [1- (1-naphthyl) ethyl], carbamate ester of 7-bromo- (3aS-cis) -1, 2, 3, 3a, 8, 8a-hexahydro-1,3a, 8-trimethyl-pyrrolo [2, 3-b] -indol-5-ol-heptyl, or a tetrahydroisoquinolinyl carbamate ester. SUMMARY OF THE INVENTION The invention relates to carbamoyl esters that inhibit cholinesterase activity and, after hydrolysis, release a pharmacologically active agent. In one embodiment, the carbamoyl ester has the following structure: Formula (I) wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl. Carbamoyl esters are used in methods to treat an individual. The pharmacologically active agent obtained by hydrolysis of carbamoyl esters can, for example, treat a condition of the nervous system, a cholinergic deficiency and conditions or diseases associated with a deficiency of a pharmacologically active agent, such as acetylcholine. 1/1 Slow hydrolysis