MX2008010252A - 4-acylaminopyridine derivative mediated neurogenesis - Google Patents

Abstract

The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The invention includes methods based on use of a 4-acylaminopyridine derivative to stimulate or activate the formation of new nerve cells.

Description

MEDIATED NEUROGENESIS BY DERIVATIVE 4-ACILAMINOPIRLDIN INTERREFERENCE WITH RELATED REQUEST The present application claims the benefit of the provisional application of EE. UU No. 60/771, 090, filed on February 7, 2006, which is incorporated herein in its entirety as a reference.

FIELD OF THE INVENTION The present invention relates to methods for the treatment of diseases and conditions of the central and peripheral nervous system, by stimulating or increasing neurogenesis by means of a 4-acylaminopyridine derivative. The invention includes methods based on the application of a 4-acylaminopyridine derivative to stimulate or activate the formation of new nerve cells.

BACKGROUND OF THE INVENTION Neurogenesis is a vital process in the brain of animals and humans, through which new nerve cells are continuously generated throughout the life of the organism. Newborn cells are capable of transforming into functional cells of the central nervous system which are integrated into the neural circuits in the brain. It is known that neurogenesis persists throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and produce new and functional neurons and glial cells (for a review see Gage, 2000). It has been shown that a variety of factors can stimulate neurogenesis in the adult hippocampus, for example, adrenalectomy, voluntary exercise, enriched environment, hippocampal dependent learning and antidepressants (Yehuda, 1989; van Praag, 1999; Brown J, 2003; Gould, 1999; Malberg, 2000; Santarelli, 2003). Other factors, such as adrenal hormones, stress, age and drugs of abuse, negatively affect neurogenesis (Cameron, 1994, McEwen, 1999, Kuhn, 1996, Eisch 2004). The US patent UU No. 5,397,785, describes various 4-acylaminopyridine derivatives and compositions comprising them, and also their use in the treatment of senile dementia and Alzheimer's disease. The US patent UU No. 6,884,805, discloses polymorphic crystals of a 4-acylaminopyridine derivative and its use to activate a dysfunctional cholinergic neuron that is associated with disturbances of memory loss. None of these patents refers to the use of a 4-acylaminopyridine derivative with respect to neurogenesis. The reference of the previous documents is not considered as an admission that any of them is relevant prior art. All statements regarding the date or representation as to the content of these documents are based on the information available to the applicant and do not constitute an admission of the validity of the dates or content of these documents.

BRIEF DESCRIPTION OF THE INVENTION Methods for the prophylaxis and treatment of diseases, conditions and lesions of the central and peripheral nervous system, stimulating or increasing neurogenesis, are described herein. Aspects of the invention include increasing neurogenesis in cases of a disease, disorder or condition of the nervous system. The embodiments of the invention include methods of treating a neurodegenerative disorder, neurological trauma that includes trauma to the brain or central nervous system, or recovery thereof, depression, anxiety, psychosis, memory and learning disorders, and central nervous system ischemia or peripheral. In one aspect, the invention includes methods for stimulating or enhancing neurogenesis. Neurogenesis can be in a cell or tissue. The cell or tissue may be present in an animal subject or a human being, or alternatively it may be in an in vitro or ex vivo environment. In some embodiments, neurogenesis is stimulated or increased in a neural cell or tissue, such as the central or peripheral nervous system of an animal or animal. human. In case of an animal or human, the methods can be practiced with respect to one or more diseases, disorders or conditions of the nervous system, present in the animal or human subject. In this manner, embodiments of the invention include methods of treating a disease, disorder, or condition, by administering a neurogenic agent such as the one described herein. In another aspect, the invention includes methods of using chemical entities as neurogenic agents to increase neurogenesis. In some embodiments, a chemical entity is a 4-acylaminopyridine derivative such as those described in U.S. Pat. UU No. 5,397,785, which is hereby expressly incorporated by reference. In a non-limiting embodiment, the derivative is 2- (2-oxypyrrolidin-1-yl) -N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro (2,3-b) quinolin-4- il) acetoamide. In other embodiments, the derivative is in a polymorphic crystal form as described in U.S. Pat. UU No. 6,884,805, which is hereby expressly incorporated by reference. Of course, the invention includes the use of more than one derivative. In additional embodiments, the invention provides the use of one or more derivatives in combination with another neurogenic agent. In another aspect, the methods include identifying a patient suffering from one or more diseases, disorders or conditions, or a symptom thereof, and administering to the patient at least one neurogenic agent as described herein. As a non-limiting example, the agent is a 4-acylaminopyridine derivative such as 2- (2-oxypyrrolidin-1-yl) -N- (2,3-dimethyl- ,617,8-tetrahydrofuro (2,3-b) quinolin-4-yl) acetoamide, as a non-limiting example. In some embodiments, the invention provides a method that includes identifying a subject in need of an increase in neurogenesis, and administering to the subject one or more neurogenic agents such as those described herein. In other modalities, the subject is a patient, such as a human patient. In addition, the invention provides a method that includes administering one or more neurogenic agents to a subject exhibiting the effects of insufficiency or inadequate degree of neurogenesis. In some embodiments, the subject may be one that has been subjected to an agent that decreases or inhibits neurogenesis. Non-limiting examples of a neurogenesis inhibitor include opioid receptor agonists, such as a mu receptor subtype agonist such as morphine. In a related manner, the invention provides for the administration of one or more neurogenic agents to a subject or person that will be subjected to an agent that decreases or inhibits neurogenesis. In some embodiments, the subject or person may be one who is close to receiving morphine or another opioid receptor agonist, such as another opiate, and thus is close to a decrease or inhibition of neurogenesis. Non-limiting examples include administering a neurogenic agent to a subject before, simultaneously, or after administering to the subject morphine or other opiate for a surgical procedure. Also described are methods for preparing a population of neural stem cells suitable for transplantation, comprising culturing a population of neural stem cells (NSC's) in vitro, and contacting the cultured neural stem cells with at least one neurogenic agent of the invention. In some embodiments, the stem cells are prepared and then transferred to an animal or human host host. Non-limiting examples of the preparation include 1) contacting the cells with a neurogenic agent until the cells have undergone neurogenesis, for example that is detectable by visual inspection or cell counting; or 2) contact the cells with a neurogenic agent until the cells have been stimulated or sufficiently induced to neurogenesis. The cells are prepared in a non-limiting manner so that they can be transplanted to a subject, optionally with simultaneous administration, semi-simultaneous or subsequent of a neurogenic agent to the subject. Although the neural stem cells may be in the form of a culture or cell line in vitro, in other embodiments the cells may be part of a tissue that is subsequently transplanted to a subject. In another aspect, the invention includes methods for stimulating or enhancing neurogenesis in a subject by administering a 4-acylaminopyridine derivative and one or more additional neurogenic agents. In some modalities, neurogenesis occurs in combination with the stimulation of angiogenesis, which provides new cells with access to the circulatory system. The details of further embodiments of the invention are set forth in the accompanying drawings and the following description. Other features, objectives and advantages of the invention will be apparent from the drawings and the detailed description, and of the claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a dose-response curve showing the effect of the neurogenic agent MKC-231 on neuronal differentiation. The data are presented as the Percentage of the neuronal positive control minus the mean baseline value. The EC50 was observed at a concentration of MKC-231 of 5.1 μ? in the test cells, compared to 4.7 μ? in positive control cells. Figure 2 is a dose-response curve showing the effect of the neurogenic agent MKC-231 on the differentiation of astrocytes. The data are presented as the percentage of positive Control of astrocytes minus the baseline mean value. The EC50 was not determinable for MKC-231 (greater than the tested concentrations), compared to 19.9 μ? in positive control cells. Figure 3 is a dose-response curve that measures the toxicity / trophic effect of the neurogenic agent MKC-231 on a population of cultured neural stem cells. The data is presented as the Percentage of the mean basal cell count. Figure 4 is a dose-response curve showing the increase in the effects of the agent MKC-231 on neuronal differentiation by combination with an AMPA agonist (AMPA). The data is present as the Percentage of neuronal positive control minus the mean baseline value. The EC50 was observed at a concentration of MKC-231 of 0.99 μ? in combination with AMPA, compared to 5.1 pM with MKC-231 alone. Figure 5 is a series of immunofluorescent microscopic images of monolayers of human neural stem cells (hNSC) after immunohistochemical staining with the neuronal marker TUJ-1 (green), the astrocyte marker GFAP (red), and a nuclear cell marker (Hoechst 33342 in blue). The upper left image is a negative control (basal medium), the upper image in the middle is a positive neuronal control (basal medium plus a known promoter of neuronal differentiation), and the upper right image is a positive Control of astrocytes (basal medium more a known inducer of astrocyte differentiation). The lower left image shows the effect of 31.6 μ? of MKC-231 on the differentiation of hNSC, and the lower right image shows the effect of 31.6 pM of MKC-231 in combination with 0.3161 μ? of AMPA on neuronal differentiation. Figure 6 is the average dose-response curve of multiple experiments (N = 6) showing the increase in the effects of agent BCI-540 on neuronal differentiation by combination with a fixed concentration of AMPA agonist (0.32 pM AMPA ). The concentration of AMPA used does not promote neuronal differentiation on its own (gray dashed line). The data are presented as the Percentage of the neuronal positive control minus the mean baseline value. The EC50 was observed at a concentration of BCI- 540 of 0.22 μ ?, when in the presence of a fixed concentration of AMPA (black dashed line), compared to 3.7 μ? with BCI-540 only (solid black line). Figure 7 is a dose-response curve showing the inhibition of the effects of the agent MKC-231 on neuronal differentiation by combination with an AMPA antagonist (NBQX). The data are presented as the Percentage of the neuronal positive control minus the mean baseline value. The EC50 was observed at a concentration of MKC-231 of > 31.6 μ? in combination with AMPA, compared to 5.1 μ? with MKC-231 alone. Figure 8 is a bar graph depicting the change of neurogenesis in the hippocampus (increase of new neurons) compared to vehicle control (± SEM). The Y axis represents the percentage of change with respect to the control. Daily administration of 1.0 and 4.0 mg / kg of BCI-540 for 28 days produced an increase of 22% and 20%, respectively, of new neurons within the granular cell layer of the dentate gyrus. Figure 9 is a bar graph representing the latency change for eating in the suppressed novelty-feeding test (an animal model of depression), as compared to vehicle control (± SEM). The Y axis represents the percent change compared to the control. Daily administration of 1.0 mg / kg of BCI-540 and 10.0 mg / kg of fluoxetine for 21 days produced a decrease of 35% and 38%, respectively, of the latency to eat. Figure 10 is a bar graph representing the average percentage of time spent in the open arms of a high T-maze (an animal model of anxiety), as compared to vehicle control (± SEM). Daily administration of 1.0 mg / kg of BCI-540 for 21 days produced a 20% increase in time spent in the open arms. A single administration of the classic diazepam anxiolytic resulted in a 12% increase in time spent in the open arms.

DETAILED DESCRIPTION OF THE MODALITIES OF THE INVENTION "Neurogenesis" is defined herein as the proliferation, differentiation, migration or survival of a neural cell in vivo or in vitro. In several embodiments, the neural cells are a neural, adult, fetal or embryonic stem cell, or a population thereof. The cells can be located in the central nervous system or anywhere in an animal or human being. The cells can also be in a tissue, such as neural tissue. In some embodiments, the neural cell is an adult, fetal or embryonic progenitor cell, or a population thereof, or a population of cells comprising a mixture of stem cells and progenitor cells. Neural cells include all brain stem cells, all progenitor cells in the brain, and all precursor cells in the brain. Neurogenesis includes the neurogenesis that occurs during normal development, as well as neural regeneration that occurs after a disease, damage or therapeutic intervention, for example by the treatment described herein. A "neurogenic agent" is defined as a chemical agent or reagent that can promote, stimulate or otherwise increase the amount or degree of neurogenesis in vivo or ex vivo or in vitro, with respect to the amount or degree of neurogenesis in the absence of the agent or reagent. In some embodiments, it is said that treatment with a neurogenic agent increases neurogenesis if it promotes neurogenesis by at least about 5%, at least about 10%, at least about 25%, at least about 50%, so less about 100%, at least about 500%, or more, compared to the amount or degree of neurogenesis in the absence of the agent, under the conditions of the method used to detect or determine neurogenesis. As non-limiting examples, the agent can be a small organic molecule that is a 4-acylaminopyridine derivative. The term "stem cell" (or neural stem cell (NSC)), as used herein, refers to an undifferentiated cell that is capable of self-renewal and transform into neuron, astrocyte, or oligodendrocyte. The term "progenitor cell" (e.g., neural progenitor cell), as used herein, refers to a cell derived from a stem cell that is not itself a stem cell. Some progenitor cells can produce progeny capable of transforming into more than one type of cell. The present invention includes methods for increasing neurogenesis by contacting the cells with a 4-acylaminopyridine derivative as a neurogenic agent. The cells may be in vitro or in vivo, and include cells that are present in a tissue or organ of an animal subject or human. The 4-acylaminopyridine derivative can be any that stimulates or increases neurogenesis. In a non-limiting example, the derivative is 2- (2-oxypyrrolidin-1-yl) -N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro (2,3-b) quinolin-4-) il) acetoamide (also known as MKC-231, or coluracetam, and identified with CAS Registry No. 135463-81-9). The cells are those susceptible to neurogenesis, in order to transform, by direct differentiation or by proliferation and differentiation, in differentiated neuronal or glial cells. Examples representative and non-limiting of other 4-acylaminopyridine derivative compounds for use in the present invention are given in the examples section given below. Without wishing to be limited by theory, and although some 4-acylaminopyridine derivatives have been contemplated with respect to the inhibition of acetylcholinesterase activity (AChE), it is believed that the present invention is not related to the inhibition of AChE because MKC-231 has no such inhibitory activity. Similarly, it is believed that the invention is not related to the binding of the derivative to muscarinic or nicotinic receptors. However, it is believed that the neurogenic action of MKC-231 can be by enhancing or sensitizing AMPA. These Beliefs are offered to improve the understanding of the invention and do not necessarily limit the invention. In applications for an animal or a human being, the invention relates to a method for contacting cells with a neurogenic agent, or an effective amount of the agent, in a manner that results in an increase in neurogenesis as compared to the absence of the agent. . A non-limiting example is the administration of the agent to the animal or human being. The neurogenic agent can be considered as supplied exogenously to a cell or tissue. In some embodiments, the term "animal" or "animal subject" refers to a non-human mammal, such as a primate, canine or feline. In other embodiments, the terms refer to a domestic animal (eg, livestock), or otherwise subject to human care or maintenance (eg, zoo animals and other animals for display). In other non-limiting examples, the terms refer to ruminants or carnivores, such as dogs, cats, birds, horses, cattle, sheep, goats, marine animals and mammals, penguins, deer, elk and foxes. The present invention also relates to methods of treating diseases, disorders and conditions of the central and peripheral nervous system (CNS and SNP, respectively), by administering one or more neurogenic agents. As used herein, "treatment" refers to the prevention, amelioration, alleviation or elimination of the disease, disorder or treated condition, or one or more symptoms of the disease, disorder or condition treated, as well as improvement of the general well-being of a patient, measured by objective or subjective criteria. In some embodiments, the treatment is used to reverse, attenuate, minimize, suppress or prevent the undesirable or noxious effects, or the effects of advancing a disease, disorder, or condition of the central or peripheral nervous system. In other embodiments, the method of treatment can be used advantageously in cases where additional neurogenesis would replace, replenish or increase the number of cells lost due to injury or disease, as non-limiting examples. Non-limiting examples of symptoms that can be treated with the methods described here include abnormal behavior, abnormal movement, hyperactivity, hallucinations, acute delirium, combativeness, hostility, negativism, withdrawal, isolation, memory defects, sensory defects, cognitive defects and tension. Non-limiting examples of abnormal behavior include irritability, poor impulse control, distraction, and aggression. In some embodiments, the methods of the invention comprise using a 4-acylaminopyridine derivative as a neurogenic agent. The invention, in this manner, includes methods for contacting a cell with a 4-acylaminopyridine derivative, or administering said derivative to a subject to produce neurogenesis. Some embodiments comprise the use of a derivative, such as MKC-231, or a combination of two or more derivatives, such as MKC-231 and another derivative, as a neurogenic agent. In some embodiments, the neurogenic agents used in the methods described herein are substantially inactive with respect to other receptors, such as muscarinic receptors, nicotinic receptors, dopamine receptors, and opioid receptors, as non-limiting examples. In some embodiments, a 4-acylaminopyridine derivative is administered to an animal or human subject to produce neurogenesis. In this manner, a 4-acylaminopyridine derivative can be used to treat a disease, disorder or condition such as the one described herein. In other embodiments, the 4-acylaminopyridine derivative can be used to increase neurogenesis in vitro. Neurogenic agents to be used in embodiments of the invention include MKC-231 as described above. It is represented by the following structure: In some embodiments, the 4-acylaminopyridine derivative is described in U.S. Pat. UU No. 5,536,728, or a crystal form polymorphic as described in US Pat. UU No. 6,884,805. Structures, biological activity data, methods for obtaining biological activity data, synthesis methods, modes of administration and pharmaceutical formulations of said compounds are described herein. Methods to determine the nature or degree of neurogenesis in vivo and in vitro, to detect changes in the nature or degree of neurogenesis, to identify neurogenesis modulating agents, to isolate and culture neural stem cells, and to prepare neural stem cells for transplantation or other purposes, for example the provisional application of EE is described. UU No. 60 / 697,905, and US publications. UU Nos. 2005/0009742, 2005/0009847, 20050032702, 2005/0031538, 2005/0004046, 2004/0254152, 2004/0229291, and 2004/0185429, all of which are hereby incorporated by reference in their entirety. Neurogenesis includes the transformation of neural cells into different potential lineages. In some embodiments of the invention, the transformation of the neural stem or progenitor cells is in a lineage of neuronal or glial cells, optionally excluding transformation into an astrocyte lineage. The neurogenic agents described herein include pharmaceutically acceptable salts, derivatives, prodrugs and metabolites of the agents. The methods for preparing and administering the salts, derivatives, prodrugs and metabolites of various agents are well known.

The compounds described herein that contain a chiral center include all possible stereoisomers of the compound, including compositions comprising the racemic mixture of the two enantiomers, as well as also compositions comprising each enantiomer individually, substantially free in another enantiomer. Thus, for example, a composition comprising the S-enantiomer of a compound substantially free of the R-enantiomer, or the R-enantiomer substantially free of the S-enantiomer is contemplated. If the named compound comprises more than one chiral center, the scope of the present description also includes compositions comprising mixtures of varying proportions of diastereomers, as well as also compositions comprising one or more diastereomers substantially free of one or more of the other diastereomers. By "substantially free" is meant that the composition comprises less than 25%, 15%, 10%, 8%, 5%, 2%, or less than 1% of the minor enantiomer or diastereomer. The methods for synthesizing, isolating, preparing and administering various stereoisomers are known. Methods for use in the treatment of any disease or condition for which it is beneficial to promote or stimulate, or otherwise augment, neurogenesis are described herein. One approach of the methods described here is to achieve a therapeutic result by increasing neurogenesis, as opposed to treating senile dementia, Alzheimer's disease, or memory disturbances / memory loss. This Thus, some methods written here can be used to treat any disease or condition susceptible to treatment by increasing neurogenesis. For example, in some embodiments, the methods described herein are used to treat diseases or conditions that are not associated with significant dementia or memory problems, such as Parkinson's disease, which is characterized by the degeneration of dopaminergic neurons. Thus, in one aspect, the present invention relates to the discovery of novel therapeutic indications for a 4-acylaminopyridine derivative. In some embodiments, the disease or condition treated is associated with pain or addiction, but unlike the known methods, the treatments of the invention are substantially mediated by an increase in neurogenesis. For example, in some embodiments, the methods described herein include enhancing ex vivo neurogenesis, such that a composition containing neural stem cells, neural progenitor cells, or differentiated neural cells, may subsequently be delivered to an individual to treat a disease or condition . In some modalities, the methods described herein allow the treatment of diseases characterized by pain, addiction or depression, by replenishment, replacement or direct complement of neurons or glial cells. In additional embodiments, the methods described herein increase the growth or survival of existing neural cells, or retard or reverse the loss of said cells in a neurodegenerative condition.

Examples of diseases and conditions treatable by the methods described herein include, without limitation, neurodegenerative disorders such as Parkinson's disease, Parkinson's disease, Huntington's disease (Huntington's chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease. , Parkinson's dementia syndrome, progressive subcortical gliosis, progressive supranuclear palsy, thalamic degeneration syndrome, hereditary aphasia, amyotrophic lateral sclerosis, Shy-Drager syndrome, and Lewy body disease. The invention also provides for the treatment of a nervous system disorder related to cellular degeneration, a psychiatric condition, trauma or cell injury, or other related neurological conditions. In practice, the invention can be applied to a subject or patient affected or diagnosed with one or more disorders of the central or peripheral nervous system in any combination. The diagnosis can be made by an expert in the applicable fields using known and routine methods that identify or distinguish these nervous system disorders from other conditions. Non-limiting examples of nervous system disorders related to cellular degeneration include neurodegenerative disorders, neural stem cell disorders, neural progenitor cell disorders, degenerative diseases of the retina and ischemic disorders. In some embodiments, an ischemic disorder comprises an insufficiency or lack of oxygen or angiogenesis, and a non-limiting example includes spinal ischemia, ischemic stroke, cerebral infarction, multi-infarct dementia. Although these conditions may be present individually in a subject or patient, the invention also provides for the treatment of a subject or patient affected or diagnosed with more than one of these conditions in any combination. Non-limiting modalities of nervous system disorders related to a psychiatric condition include neuropsychiatric disorders and affective disorders. As used herein, an affective disorder refers to a mood disorder, such as, for example, without limitation, depression, post-traumatic stress disorder (PTSD), hypomania, panic attacks, excessive elation, bipolar depression, bipolar disorder. (Manic depression), and seasonal mood (or affective) disorder. Other non-limiting modalities include schizophrenia and other psychosis, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes, cognitive function disorders, aggression, substance and alcohol abuse, obsessive-compulsive behavior syndromes, of personality limit, non-senile dementia, post-pain depression, postpartum depression, and cerebral palsy. Examples of nervous system disorders related to trauma or injury to cells or tissue include, without limitation, neurological traumas and injuries, trauma or injury related to surgery, retinal trauma and injury, epilepsy-related injury, spinal cord injury, injury of the brain, brain surgery, trauma related to brain injury brain, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to an infection, brain injury related to inflammation, injury of the spinal cord related to an infection, spinal cord injury related to an inflammation, brain injury related to an environmental toxin, and spinal cord injury related to an environmental toxin. Non-limiting examples of nervous system disorders related to other neurological related conditions include learning disorders, memory disorders, memory impairment associated with age (AAMI) or memory loss related to age, autism, attention deficit disorders, narcolepsy, sleep disorders, cognitive disorders, epilepsy and temporal lobe epilepsy. Additionally, the invention provides the use of a neurogenic agent to treat a subject or patient of a condition due to the anti-neurogenic effects of an opioid or opioid analgesic. In some embodiments of the invention, administration to a subject or patient of an opioid or opioid analgesic, such as a morphine-type opiate or other opioid receptor agonist, results in the decrease or inhibition of neurogenesis. The administration of a neurogenic agent of the invention in combination with opioid or opioid analgesic would reduce the anti-neurogenic effect. A non-limiting example is the administration of an agent Neurogenic of the invention in combination with an opioid receptor agonist after surgery (for example, for the treatment of postoperative pain). Thus, the invention includes a method of treating postoperative pain in a subject or patient, combining the administration of an opioid or opioid analgesic with a neurogenic agent of the invention. The analgesic can be administered before, simultaneously or after a 4-acylaminopyridine derivative. In some cases, the painkiller or opioid receptor agonist is morphine or another opiate. In other embodiments of the invention, the invention provides a method for treating or preventing the decrease or inhibition of neurogenesis in other cases that include the use of an opioid receptor agonist. Non-limiting examples include cases involving an opioid receptor agonist that decreases or inhibits neurogenesis, and substance addiction, substance addiction rehabilitation or relapse prevention of addiction. In some embodiments, the opioid receptor agonist is morphine, opium or another opiate. The compounds identified by the methods of the invention can also be used to treat diseases of the peripheral nervous system (SNP), which include without limitation neuropathies of the SNP (eg vascular neuropathies, diabetic neuropathies, amyloid neuropathies, etc.), neuralgia, neoplasms, diseases related to myelin, etc.

Other conditions that can be beneficially treated by increasing neurogenesis are known in the art (see, for example, US publications Nos. 20020106731, 2005/0009742, 2005/0009847, 20050032702, 2005/0031538, 2005/0004046, 2004 / 0254152, 2004/0229291, and 2004/0185429, which are hereby incorporated by reference in their entirety). In some embodiments, the neurogenic agents used in the methods described herein comprise pharmaceutical compositions that include at least one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" includes any excipient known in the art to be suitable for pharmaceutical application. Suitable excipients and pharmaceutical formulations are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (19th ed.) (Genaro, ed. (1995) Mack Publishing Co., Easton, Pa.). Preferably, the pharmaceutical excipients are chosen based on the desired mode of administration of the neurogenic agent. The pharmaceutically acceptable carrier can include, for example, disintegrants, binders, lubricants, glidants, emollients, humectants, thickeners, silicones, flavoring agents and water. The neurogenic agent can be incorporated with excipients and administered in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or any other form known in the pharmaceutical art. The pharmaceutical compositions of invention can also be formulated in sustained release form. Sustained release compositions, enteric coatings, etc., are known in the art. Alternatively, the compositions may be a rapid release formulation. In some embodiments, the methods of treatment according to the invention comprise the step of administering to a mammal a neurogenic agent as defined herein, for a time and at a concentration sufficient to treat the objective condition of the treatment. The methods of the invention can be applied to individuals who have or are in a position to develop disorders related to neural degeneration, neural damage or neural demyelination. In some embodiments, the methods described herein comprise a step of selecting a population or subpopulation of patients, or selecting an individual patient, one that is more amenable to treatment or less susceptible to side effects than other patients having the same disease or condition. For example, in some embodiments, a subpopulation of patients is identified as more susceptible to neurogenesis with a neurogenic agent by taking a cell or tissue sample from prospective patients, isolating and culturing neural cells from the sample, and determining the effect of one or more agents Neurogenic on the degree or nature of neurogenesis, thus allowing the selection of patients for whom the therapeutic agent has a substantial effect on neurogenesis. Advantageously, the selection steps result in a more effective treatment for the disease or condition than known methods using the same or similar compounds. In other embodiments, the method of treatment comprises identifying, generating or propagating neural cells ex vivo using one or more neurogenic agents, and transplanting the cells in a subject. In another embodiment, the method of treatment comprises the steps of contacting a stem cell or neural progenitor cell with one or more neurogenic agents to stimulate neurogenesis, and transplanting the cells to a patient in need of treatment. Also described are methods for preparing a population of neural stem cells suitable for transplantation, comprising culturing a population of neural stem cells (NSC's) in vitro, and contacting the cultured neural stem cells with at least one neurogenic agent of the invention. In addition, the invention includes methods of treating the diseases, disorders and conditions described herein, by transplanting said cells to a subject or patient. The methods described herein may comprise administering to the subject an effective amount of a compound or pharmaceutical composition. In general, an effective amount of a compound according to the invention is an amount sufficient to stimulate or increase neurogenesis in the subject treatment object, as compared to the absence of the compound. An effective amount of a composition may vary depending on several factors including, without limitation, the activity of the active compounds, the physiological characteristics of the subject, the nature of the treated condition, and the route or method of administration. The methods of the invention typically include administration of an agent of the invention on a dose scale of 0.001 ng / kg / day to 500 ng / kg / day, preferably on a dose scale of 0.05 ng / kg / day to 200 ng / kg / day. Advantageously, the methods described herein allow the treatment of the indications with reductions in side effects, dose, frequency of dosage, duration of treatment, tolerability, or other factors. In some embodiments of the methods described herein, the use of neurogenic agents having selective activity can allow effective treatment substantially with fewer, or less severe, side effects compared to existing treatments. For example, neurogenic agents with selectivity in the CNS can reduce side effects associated with activity in opioid receptors outside the desired tissue / target organ. It is known that established methods for treating various CNS and SNP conditions with compounds having activity against opioid receptors cause side effects including, without limitation, sweating, diarrhea, hot flashes, hypotension, bradycardia, bronchoconstriction, contraction of the urinary bladder, nausea, vomiting, parkinsonism, and an increased risk of mortality. In some embodiments, the methods described herein allow the treatment of certain conditions with doses that minimize these side effects. Depending on the desired clinical result, the compositions Pharmaceuticals of the invention are administered by any suitable means to achieve a desired effect. Various methods of delivery are known and can be used to deliver a test agent to a subject or to NSC's, or progenitor cells in a tissue of interest. The method of delivery will depend on factors such as the tissue of interest, the nature of the compound (for example its stability and ability to cross the blood-brain barrier), and the duration of the experiment, among other factors. For example, an osmotic minipump can be implanted in a neurogenic region such as the lateral ventricle. Alternatively, the compounds can be administered by direct injection into the cerebrospinal fluid or spinal column, or into the eye. The compounds can also be administered in the periphery (for example by intravenous or subcutaneous injection)., or oral supply), and subsequently cross the blood-brain barrier. In various embodiments, the pharmaceutical compositions of the invention are administered in a manner that allows them to make contact with the subventricular zone (SVZ) of the lateral ventricles or the dentate gyrus of the hippocampus. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Intranasal administration generally includes, without limitation, inhalation of aerosol suspensions to deliver the compositions to the nasal mucosa, trachea and bronchioles. In some embodiments, the compounds of the invention are administer to cross or to dodge the blood-brain barrier. Methods that allow traversing the blood-brain barrier are known and include minimizing factor size, providing hydrophobic factors that facilitate passage, and conjugating the neurogenic agent or other agent with a vehicle molecule that has substantial permeability through the barrier hematoencephalic In some cases, the neurogenic agent can be administered by means of a surgical procedure by implanting a catheter coupled to a pump device. The pump device can also be implanted or can be placed extracorporeally. The administration of the neurogenic agent may be in intermittent pulses or as a continuous infusion. Devices for injection into areas other than the brain are known. In a preferred embodiment, the neurogenic agent is administered locally to the ventricle of the brain, substantia nigra, striatum, locus ceruleus, Meynert basal nucleus, pedunculopontine nucleus, cerebral cortex or spinal cord, for example by injection. Methods, compositions and devices for delivering therapeutic agents, including therapeutic agents for the treatment of diseases and conditions of the CNS and SNP, are known in the art. In some embodiments, the delivery or targeting of neurogenic agents to a neurogenic region, such as the dentate gyrus or the subventricular zone, increases efficacy and reduces side effects as compared to known methods including administration with the same compound or a similar compound.

In embodiments of the invention for treating subjects and patients, methods include identifying a patient suffering from one or more diseases, disorders or conditions, or a symptom thereof, and administering to the subject or patient at least one neurogenic agent as described here. The identification of a subject or patient who has one or more diseases, disorders or conditions, or a symptom thereof, can be made by the professional using any appropriate means known in the field. In additional embodiments of the invention, the methods can be used to treat a cell, tissue, or subject that is exhibiting decreased neurogenesis or increased neurodegeneration. In some cases, the cell, tissue or subject has been subjected to, or has been in contact with, an agent that decreases or inhibits neurogenesis. A non-limiting example is a human subject who has been given morphine or another agent that decreases or inhibits neurogenesis. Non-limiting examples of other agents include opioids and opioid receptor agonists, such as mu receptor subtype agonists, which inhibit or diminish neurogenesis. Thus, in additional embodiments of the invention, the methods can be used to treat subjects suffering from, or diagnosed with, depression or other withdrawal symptoms of morphine or other agents that decrease or inhibit neurogenesis. This is different from the treatment of subjects who suffer, have been diagnosed, depression independent of an opiate, for example of a psychiatric nature, as described herein. In additional embodiments, the methods can be used to treat a subject with one or more addictions or chemical dependencies, such as morphine or other opiates, wherein the addiction or dependence decreases or is alleviated by increasing neurogenesis. In embodiments that comprise the treatment of depression, the methods may also comprise the use of one or more antidepressant agents. Thus, in the treatment of depression in a subject or patient, the method may comprise a neurogenic agent as described herein with one or more antidepressant agents known to the person skilled in the art. Non-limiting examples of antidepressant agents for use with a neurogenic agent of the invention include an SSRI, such as fluoxetine (Prozac®), citalopram, escitalopram, fluvoxamine, paroxetine (Paxil®), and sertraiine (Zoloft®), as well as the active ingredients of known medications that include Luvox® and Serozone®; selective reuptake inhibitors of norepinephrine (SNRI) such as reboxetine (Edronax®) and atomoxetine (Strattera®); selective inhibitors of the reuptake of serotonin and norepinephrine (SSNRI) such as venlafaxine (Effexor) and duloxetine (Cymbalta); and agents such as baclofen, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS). In some embodiments, an opioid receptor agonist of the kappa subtype and an SSRI, or baclofen, is used in the practice of the invention. The combination therapy can be used advantageously to improve the condition of the subject or patient.

Non-limiting examples of combination therapy include the use of doses that reduce the side effects of an antidepressant agent when used alone. For example, an antidepressant agent such as fluoxetine or paroxetine or sertraline, may be administered at a reduced or limited dose, optionally also reduced in administration sequence, in combination with a neurogenic agent of the invention. The reduced dose with the neurogenic agent mediates a sufficient antidepressant effect so that the side effects of the antidepressant agent alone are reduced or eliminated. In embodiments for treating weight gain or inducing weight loss, a neurogenic agent of the invention may be used in combination with another agent to treat weight gain or induce weight loss. Non-limiting examples of another agent to treat weight gain or induce weight loss include various diet pills that are commercially available. In other embodiments comprising combination therapy, the methods of the invention comprise increasing neurogenesis in a subject or patient by administering a 4-acylaminopyridine derivative and one or more additional neurogenic agents or one or more neurogenesis modulating agents. Thus, although the neurogenic agents of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more additional active agents, such as another neurogenic agent, optionally one that works by a alternative mechanism. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The invention is not limited in terms of the administration sequence. Additional neurogenic agents may be an opioid or non-opioid agent (acts independently of an opioid receptor). In some embodiments, the additional neurogenic agent is one that antagonizes one or more opioid receptors or is an inverse agonist of at least one opioid receptor. An opioid receptor antagonist or reverse agonist of the invention may be specific or selective (or alternatively, non-specific or non-selective) for opioid receptor subtypes. Thus, an antagonist can be non-specific or non-selective in such a way that it antagonizes more than one of the three known opioid receptor subtypes, identified as OP1, OP2, and OP3 (also known as delta od, or kappa, or μ or mu , respectively). Thus, an opioid that antagonizes any of two or three of these subtypes, or an inverse agonist that is specific or selective for two or three of these subtypes, can be used in the practice of the invention. Alternatively, an antagonist or inverse agonist may be specific or selective for one of the three subtypes, such as the kappa subtype as a non-limiting example. In some embodiments, the additional neurogenic agents used in the methods described herein have "selective" activity (e.g. in the case of an antagonist or inverse agonist) under certain conditions, against one or more opioid receptor subtypes with respect to the degree or nature of activity against one or more other opioid receptor subtypes. For example, in some embodiments, the neurogenic agent has an antagonistic effect against one or more subtypes, and a much weaker or substantially no effect against other subtypes. As another example, an additional neurogenic agent used in the methods described herein can act as an agonist in one or more subtypes of the opioid receptor, and as an antagonist in one or more other opioid receptor subtypes. In some embodiments, a neurogenic agent has activity against the kappa opioid receptors, while having substantially less activity against one or both of the receptor subtypes: delta and mu. In other modalities, a neurogenic agent has activity against two subtypes of the opioid receptor, such as the kappa and delta subtypes. As non-limiting examples, the agents naloxone and naltrexone have non-selective antagonistic activity against more than one subtype of the opioid receptor. In some embodiments, the selective activity of one or more opioid antagonists results in greater efficacy, fewer side effects, lower effective doses, less frequent dosing, or other desired attributes. An opioid receptor antagonist is an agent capable of inhibiting one or more responses characteristic of an opioid receptor or receptor subtype. As a non-limiting example, an antagonist can be competitively or non-competitively linked to an opioid receptor, an agonist or partial agonist (or other ligand) of a receptor, or a final signaling molecule to inhibit the function of the receptor. An inverse agonist capable of blocking or inhibiting a constitutive activity of an opioid receptor can also be used. An inverse agonist can be competitively or non-competitively linked to an opioid receptor or a final signaling molecule to inhibit the function of a receptor. Non-limiting examples of inverse agonists for use in the practice of the invention include ICI-174864 (? /, / V-diallyl-Tyr-Aib-Aib-Phe-Leu), RTI-5989-1, RTI-5989-23 and RTI-5989-25 (see Zaki et al J. Pharmacol, Exp Therap 298 (3): 1015-1020, 2001). In other embodiments, the additional neurogenic agent can be a modulator of a muscarinic receptor. Non-limiting examples of such agents include the muscarinic agonist milamelin (CI-979) and xanomelin; the muscarinic agent alvamelina (LU 25-109), 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane (YM-796) or YM-954, cevimelína (AFI02B), sabcomelina (SB 202026), talsaclidin (WAL20 4 FU), CD-0102 (5- (3-ethyl-1, 2,4-oxadiazol-5-yl) -1, 4,5,6-tetrahydropyrimidin-trifluoroacetic acid) , derivative of 1-methylene-1, 2,5,6-tetrahydropyridyl-1, 2,5-thiazole, such as tetra (ethylene glycol) (4-methoxy-1, 2,5-thiadiazole-3) -yl) [3- (1-methyl-1, 2,5,6-tetrahydropyrid-3-yl) -1,5,5-thiadiazol-4-yl] ether, or a compound that is functionally related or structurally with a derivative of 1-methyl-1, 2,5,6-tetrahydro-dyril-1, 2,5-thiazole, besipyridine, SR-46559, L-689,660, S-9977-2, AF-102 , or tiopílocarpina, a clozapine analog or a diaryl [a, d] cycloheptene, such as an amino-substituted form thereof, a benzimidazolidinone derivative, and a spiroazacyclic compound such as 1-oxa-3,8-diaza-spiro [4.5] decan-2-one, a tetrahydroquinoline analogue; and a my muscarinic receptor agonist selected from 55-LH-3B, 55-LH-25A, 55-LH-30B, 55-LH-4-1A, 40-LH-67, 55-LH-15A, 55-LH -16B, 55-LH-1 1C, 55-LH-31A, 55-LH-46, 55-LH-47, 55-LH-4-3A. In additional embodiments, the additional agent may be one that increases the concentration of an endogenous muscarinic agonist such as acetylcholine. Non-limiting examples of such additional agents include the inhibitors of acetylcholinesterase tacrine, donepezil, itoprid, rivastigmine, and galantamine. In additional embodiments, the additional neurogenic agent can be a modulator of an androgen receptor. Non-limiting examples include the androgen receptor agonists dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Of course, a combination therapy may be that of a neurogenic agent of the invention with a therapy not based on a chemical agent. Non-limiting examples include the use of psychotherapy for the treatment of many conditions described herein, such as psychiatric conditions, as well as behavior modification therapy, as used in a weight loss program. Having generally described the invention, it will be more readily understood by reference to the following examples, which are provided by way of illustration and are not considered to be limiting of the present invention, unless so specified.

EXAMPLES EXAMPLE 1 Effect on neuronal differentiation of human neural stem cells Human neural stem cells (hNSCs) were isolated and grown in a monolayer culture; they were plated, treated with various concentrations of MKC-231 (test compound), and stained with TUJ-1 antibody, as described in the provisional US application. UU No. 60 / 697,905 (which is incorporated by reference). Mitogen-free test medium was used as a positive control for neuronal differentiation, together with basal medium without growth factors as a negative control. The results are shown in Figure 1, which shows dose-response curves of neuronal differentiation after subtracting the mean background values. The dose-response curve of the neuronal positive control is included as a reference. The data are presented as a percentage of the neuronal positive control. The data indicate that MKC-231 promoted neuronal differentiation above background values.

EXAMPLE 2 Effect on the differentiation of astrocytes from hNSC's Experiments were carried out as described in Example 1, except that the positive control for astrocyte differentiation contained a mitogen-free test medium with positive control for astrocyte differentiation, and the cells were stained with GFAP antibody. The results are shown in Figure 2, which show dose-response curves of astrocyte differentiation after subtracting background mean values. It was observed that MKC-231 does not significantly increase the differentiation of astrocytes above the values of the basal medium.

EXAMPLE 3 Toxic / trophic effect on human neural stem cells Experiments were performed as described in example 1, except that the cells were stained with a nuclear dye (Hoechst 33342). The results are shown in Figure 3. The data is shown as a percentage of the average basal cell count. Concentrations that are toxic are below 80% of the basal cell count. Trophic compounds show dose-dependent increases in cell counts. MKC-231 showed no toxicity to concentrations up to 31.6 μ ?.

EXAMPLE 4 Effect of MKC-231 in combination with an AMPA agonist on the differentiation of human neural stem cells Experiments were performed with various concentrations of MKC-231 alone or with 0.316 μ? of an AMPA agonist (AMPA), in general as described in example 1 for neuronal differentiation. The results are shown in Figure 4, which shows dose-response curves for neuronal differentiation after subtracting the mean background values. With 0.316 μ? of the AMPA agonist AMPA increases the stimulation of neuronal differentiation with the neurogenic agent MKC-231. These data show that the AMPA agonist acts as an enhancer or sensitizer of neuronal differentiation mediated by MKC-231. The data also indicate that MKC-231 apparently exerts part of its neurogenic effect as an AMPA enhancer or sensitizer. Also see figure 6 with respect to BCI-540 in combination with AMPA and neuronal differentiation.

EXAMPLE 5 Effect of MKC-231 in combination with an AMPA antagonist on the differentiation of human neural stem cells Experiments were performed with various concentrations of MKC-231 alone or with 1.0 mM and an AMPA antagonist (NBQX), in general as described in example 1 for neuronal differentiation. The results are shown in Figure 7, which shows dose-response curves for neuronal differentiation after subtracting the mean background values. With 1.0 mM of the AMPA antagonist NBQX, the stimulation of neuronal differentiation with the agent MKC-231 is inhibited. These data show that an AMPA antagonist acts as an inhibitor of neuronal differentiation mediated by MKC-231. The data also indicate that MKC-231 exerts part of its neurogenic effect through activation of the AMPA receptor.

EXAMPLE 6 Effect on neurogenesis in the rat hippocampus BCI-540 was administered to male F344 rats by means of daily oral forced feeding, once for 28 days (1.0 and 4.0 mg / kg / day, orally). BrdU was administered once a day for 5 days (days 9 to 14, 100 mg / kg / day, p.). The animals were sacrificed on day 28. The brains were They were excised and processed to examine neurogenesis. Figure 8 shows the change in neurogenesis compared to the vehicle control (± SEM). The Y axis represents the percent change compared to the control. The X axis indicates treatment with vehicle at 100% (black bar) and BCI-540 dosed at 1.0 and 4.0 mg / kg / day (black bars). The black line indicates 100% of vehicle control. Daily administration of 1.0 and 4.0 mg / kg of BCI-540 for 28 days resulted in a statistically significant increase in new neurons within the granular cell layer of the dentate gyrus.

EXAMPLE 7 Effect in the Novelty test-suppressed feeding in the rat BCI-540 was administered to male F344 rats by oral forced feeding once a day for 21 days (1.0 and 4.0 mg / kg / day, orally). Fluoxetine was administered by forced oral feeding once a day for 21 days (1.0 and 4.0 mg / kg / day, orally). They were administered BrdU once a day for 5 days (days 9 to 14, 100 mg / kg / day, ip.). The animals were examined after 21 days of drug administration. Figure 9 shows the change of latency to eat compared to vehicle control (± SEM). The V axis represents the percentage of change compared to the vehicle control. The X axis indicates treatment. The vehicle is set to 100%. The black line indicates 100% of vehicle control. The 21-day administration of BCI-540 and fluoxetine resulted in a statistically significant decrease in latency to eat the pelleted food, which is indicative of antidepressant activity.

EXAMPLE 8 Toxic / trophic effect on human neural stem cells BCI-540 was administered to male Sprague Dawley rats by forced oral feeding once a day for 21 days (1.0 mg / kg / day, orally). As a positive control, once the diazepam anxiolytic was administered (1.5 mg / kg, ip.), 30 minutes before the analysis. Figure 10 shows the percent change in time spent in the open arms for the groups treated with BCI-540 and diazepam (± SEM). The Y axis represents the percentage of time in the open arm. The X axis indicates treatment with vehicle (black bar), positive control of diazepam (gray bar) and treated animals BCI-540 (black bars) (n = 1 5 / group). Chronic administration of BCI-540 results in a significant increase in the time spent in the open arms, which is indicative of anxiolytic activity. BCI-540 showed anxiolytic efficacy comparable to diazepam administered acutely.

EXAMPLE 9 Immunohistochemistry with neuronal and astrocyte markers Immunohistochemistry was performed as described in the provisional EE application. UU No. 60 / 697,905 (incorporated by reference), using TUJ-1 as a neuronal cell marker and GFAP as an astrocyte marker. The results are shown in Figure 5, with control images included in the upper part for reference; the cells treated with 31.6 μ? of MKC-231 are only shown in the lower left, and the combination of 31.6 μ? of MKC-231 with 0.316 μ? of AMPA is shown in the lower right.

EXAMPLE 10 Exemplary neurogenic agents This example provides representative derivatives of 4-acylaminopyridine for use in various aspects and I modalities; invention as described above and below. A 4-acylaminopyridine derivative of the invention is represented by the following formula (1): wherein R1 represents a C2-C6 alkyl group or a group represented by the following formula (2): wherein each of R2 and R3 independently represents a hydrogen atom, a C6 alkyl group, a C3-C6 cycloalkyl group or a group represented by the following formula (3): COOR5 (3) wherein each of R4 and R5 independently represents a hydrogen atom or an alkyl group of CrC6, or R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent: wherein R6 represents a hydrogen atom or an alkyl group of Ci-C6, and n represents 0 or an integer from 1 to 3; Y wherein R7 represents a hydrogen atom, an alkyl group of C6 or a halogen atom, wherein each of R8 and R9 independently represent a hydrogen atom or an alkyl group of CrC4, wherein each of R 0 and R 11 independently represents a hydrogen atom or an alkyl group of C-i-C4, wherein each of R12 and R13 independently represent a hydrogen atom or an alkyl group of C ^ -C4, or R12 and R13 can be combined with each other to form an alkylene group of C2-C6, with the proviso that when R1 is a C2-C6 alkyl group or a group represented by the formula (2) wherein one of R2 and R3 is a hydrogen atom or an alkyl group of CrC6, and the other of R2 and R3 is a hydrogen atom or -CH2COOR5, wherein R5 is the same as defined above, or R2 and R3 together with the nitrogen atom to which both R2 are attached R3 represent: where R7 is the same as defined above, or is not wherein R9 is the same as defined above; Y It is not wherein R 2 represents a hydrogen atom or an alkyl group of Ci-C4) or is not In formula (1), non-limiting examples of a C2-C6 alkyl group (or an alkyl group having 2 to 6 carbon atoms) represented by R1, include the following: an ethyl group, a n-group propyl, an isopropyl group, an n-butyl, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. In some embodiments, a C2-C4 alkyl group is used in the methods and practice of the invention. Non-limiting examples of a C6 alkyl group represented by each of R2 to R7 include the following: a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec group -butyl a tert-butyl group, an n-pentyl group, and an n-hexyl group. In some embodiments an alkyl group of CrC4 is used in the methods and practice of the invention. Non-limiting examples of a C3-C6 cycloalkyl group represented by each of R2 and R3 include the following: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

A halogen atom represented by R7 is selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Non-limiting examples of a C 1 -C 4 alkyl group represented by each of R 8 and R 13 include the following: a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a group sec-butyl and a tert-butyl group. Among the compounds represented by the formula (1) and in some embodiments of the invention, a compound wherein R 1 represents a C 2 -C 6 alkyl group or a group represented by the formula (2) wherein R 2 represents a hydrogen atom or an alkyl group of CrC6) R3 represents a hydrogen atom, an alkyl group of CrC6, a cycloalkyl group of C3-C6 or a group represented by formula (3), wherein each of R4 and R5 independently represent an hydrogen or a C6 alkyl group, or R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent wherein R6 represents a hydrogen atom or an alkyl group of CrC6, and n represents 0 or an integer of 1 to 3; Y wherein R7 represents a hydrogen atom, a C1-C6 alkyl group or a halogen atom, wherein each of R8 and R9 independently represents a hydrogen atom or a C4 alkyl group, or wherein each of R 10 and R 1 independently represents a hydrogen atom or a C 1 -C 4 alkyl group; Y It represents wherein each of R12 and R13 independently represents a hydrogen atom or an alkyl group of C-1-C4, or R 2 and R 13 can be combined with each other to form an alkylene group of C 2 -C 6, or Very preferably, it is a compound where It represents wherein R7 to R1 are as defined above. In addition to the molecules shown above, the present invention also provides the pharmaceutically acceptable acid addition salts of the molecules. In some embodiments, the acid addition salts of a compound represented by the formula (1) are pharmaceutically and physiologically acceptable. As non-limiting examples are provided the inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and the organic acid addition salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and camphor sulfonate. The compound represented by the formula (1) and the acid addition salt thereof may be present in the form of a hydrate or solvate. The hydrate or solvate can also be used in the methods and practice of the present invention. The methods of preparation of the above compounds are provided in the US patent. UU No. 5,397,785, which is incorporated herein by reference. Example 25 relates to the preparation of MKC-231.

EXAMPLE 11 Exemplary compositions and dosages In addition to the description of the above compositions, the present invention also provides additional compositions comprising a neurogenic agent herein. Optionally, the The composition may include an additional neurogenic agent such as the one described above. In some embodiments, the composition comprises a pharmaceutically effective amount of a 4-acylaminopyridine derivative of formula (1), as described above, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable adjuvant. A neurogenic compound of the present invention can be used as a therapeutic agent or medicine by administering it individually or in a mixture with a pharmaceutically acceptable carrier. Optionally, the compound can be formulated with one or more additional neurogenic agents as described herein. The composition can be determined routinely by the person skilled in the art based on the solubility and properties of the compound used as the active ingredient, the route of administration and the dosage regimen. As a non-limiting example, the compound of the present invention can be administered orally in the form of granule, solubilized granule, powder, tablet, hard capsule, soft capsule, syrup, emulsion, suspension and solution. The compound of the present invention can also be administered intravenously, intramuscularly or subcutaneously by injection. The compound of the present invention can be prepared as an injectable powder which is injected after dissolving or suspending it in a suitable solvent when used. The compound can be used with an organic vehicle or diluent or inorganic, solid or liquid, which is suitable for oral, intestinal, parenteral or local administration. Non-limiting examples of a vehicle for a solid preparation are lactose, sucrose, starch, talcum, cellulose, dextrin, kaolin and calcium carbonate. A liquid preparation for oral administration, ie, emulsion, syrup, suspension, solution, etc., may contain a diluent such as water, vegetable oil, etc., as non-limiting examples. The liquid preparation may contain an auxiliary such as a humectant, suspending agent, sweetening agent, aromatic agent, coloring agent, preservative, etc., in addition to an inert diluent. In some embodiments, the liquid preparation can be encapsulated in an absorbable wall substance, such as gelatin. As the solvent or suspending agent for preparing a parenteral formulation, such as an injectable formulation, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate and lecithin can be used. Said compositions can be prepared using standard techniques known to the person skilled in the art. The daily clinical dose of the compound of the present invention in oral administration can be from about 1 mg to about 1000 mg, for example from about 10 mg to about 100 mg for an adult. The person skilled in the art can determine whether it is convenient to increase or decrease the dose depending on the age of the patient, his condition or disease, and if he is being administered another medicine or active agent. The daily dose of the compound of the present The invention can be administered in one, two, or three portions, with suitable time intervals between them. It can also be administered intermittently. The daily dose of the compound of the present invention in injection may be from about 0.1 mg to about 100 mg, for example from about 0.5 mg to about 50 mg, for an adult. In addition, the compounds of the invention are of very low toxicity and produce fewer side effects.

EXAMPLE 12 Exemplary crystal forms Pure or essentially pure crystal forms of a 4-acylaminopyridine derivative can also be used in the methods and practice of the invention. In some embodiments, a crystal form of N- (2, 3-dimethyl-5,6,7,8-tetrahydrofuro [2,3-b] quinolin-4-yl) -2- (2-oxopyrrolidin-1-l) acetamide (or MKC-231), as described in U.S. Pat. UU No. 6,884,805. The crystal may be of Form A or B. The patent also provides a description of the preparation that includes the preparation of physiologically acceptable solvates of the crystal forms. The crystal form A is characterized by one or more of the following: (i) a melting point obtained from a calorimetry curve of differential scan less than about 220 ° C, particularly a melting point obtained from a differential scanning calorimetry curve of about 217.6 ° C, (ii) a peak at the X-ray diffraction angle, 2T, of 9.8 ° (± 0.2 °), (iii) the absence of a peak at an X-ray diffraction angle, 2T, of 7.3 ° (± 0.2 °), (iv) a solubility in water of less than about 0.5 mg / mL, particularly a solubility in water of approximately 0.35 mg / mL, and (v) a storage solubility greater than the crystal form B. The crystal form B is characterized by one or more of the following: (i) a melting point obtained from a differential scanning calorimetry curve greater than about 220 ° C, in particular a melting point obtained from a differential scanning calorimetry curve of approximately 222.6 ° C, (ii) a peak in the X-ray diffraction angle, 2T, of 7.3 ° (± 0.2 °), (iii) the absence of a p ico in the X-ray diffraction angles, 2T, of 9.8 ° (± 0.2 °), (iv) a solubility in water greater than about 0.5 mg / mL, particularly a solubility in water of about 0.73 mg / mL, and ( v) a storage stability less than the crystal form A. The crystal form may be in the form of a crude pharmaceutical agent comprising the crystal of form A or form B. Further, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable vehicle and the crystal in form A or in form B. In greater detail, the crystal of form A is characterized by one or more than the following: a) a melting point (extrapolated onset) obtained from a differential scanning calorimetry curve of less than about 220 ° C, for example on the scale of 213-220 ° C, or on the scale of 215- 220 ° C, on the scale of approximately 216-218 ° C, on the scale of approximately 218 ° C, and on the scale of approximately 217.6 ° C, (b) at least one peak in the X-ray diffraction spectrum at a 2T diffraction angle of 8.7 °, 9.8 °, 11.4 °, 13.3 °, 15.5 °, 16.8 ° and 17.6 ° (± 0.2 °, respectively), for example at least one peak in the diffraction spectrum X-ray in the 2T diffraction angle of 9.8 ° (± 0.2 °), (c) the absence of a peak (taking into account baseline noise and variations between the instruments) at an X-ray diffraction angle 2T of 7.3 °, 9.3 °, 1 .9 °, or 14.8 ° (± 0.2 °, respectively), (d) a solubility in water (at 25 ° C) less than about 0.5 mg / mL, for example on the scale of ap approximately 0.1-0.5 mg / mL, on the scale of approximately 0.2-0.45 mg / mL, on the scale of approximately 0.3-0.4 mg / mL, and on the scale of approximately 0.35 mg / mL, (e) better stability at ambient temperature (approximately 25 ° C) and during storage (over time) than crystal form B. The crystal form B is characterized by one or more of the following: a) a melting point (extrapolated onset) obtained from a differential scanning calorimetry curve greater than about 220 ° C, for example on the scale of 220-225 ° C, on the scale of about 221-224 ° C, on the scale of about 222-223 ° C, on the scale of about 223 ° C, and on the scale of about 222.6 ° C, (b) at least one peak in the X-ray diffraction spectrum at a diffraction angle 2T of 7.3 °, 9.3 °, 1 1 .9 ° , 13.5 °, 14.8 °, 15.9 °, 17.5 °, or 18.6 ° (± 0.2 °, respectively), for example at least one peak in the X-ray diffraction spectrum at a 2T diffraction angle of 7.3 ° (± 0.2 °), (c) the absence of a peak (taking into account baseline noise and variations between instruments) at an X-ray diffraction angle, 2T, of 8.7 °, 9.8 °, or 16.8 ° (± 0.2) °, respectively), (d) a solubility in water (approximately 25 ° C) greater than approximately 0.5 mg / mL, for example in the range of approximately 0.5-1 mg / mL, in the range of approximately 0.6-0.9 mg / mL, on the scale of approximately 0.7-0.8 mg / mL, and in the scale of approximately 0.73 mg / mL, and (e) a stability at room temperature (approximately 25 ° C) and during storage (with time) lower than the crystal form A. The invention also provides the forms of stable A and B glass of MKC-231, pure or essentially pure. The crystal forms can be prepared with good reproducibility using a physiologically compatible solvent, such as ethanol, water, or a mixture thereof. The term "essentially pure" indicates that the shape of crystal A or the shape of crystal B contains less than about 10% by weight of the other polymorphic form, for example less than about 5% by weight of the other polymorphic form. Ideally, the aforementioned percentages refer to any other polymorphic form insofar as they may exist different polymorphic forms of Form A and Form B described herein. A crystal form can be used in a pharmaceutical composition comprising a pharmaceutically acceptable carrier (eg, physiologically acceptable or pharmacologically compatible) for the treatment of the diseases, disorders or conditions described herein. Therefore, the crystal forms of the invention (and pharmaceutical compositions thereof), are useful in a method of treating a mammal, particularly a human, with a disease. The route of administration for the crystal form A or B of the invention is not particularly limited. The crystal form can be administered orally or parenterally, optionally while in crystal form. Alternatively, it is administered as a pharmaceutical composition containing the active ingredient and the additives, which are pharmaceutically acceptable (for example pharmacologically compatible). The choice of the vehicle will be determined in part both by the particular composition and by the particular method used to administer the composition described above. Pharmaceutically acceptable additives can be used. Non-limiting examples include carriers, disintegrants, disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, dissolution agents, dissolution aids, isotonicity agents, pH regulators, stabilizers, propellants and adhesives. Non-limiting examples of preparations suitable for Oral administration include tablets, capsules, powders, fine granules, granules, solutions and syrups. Non-limiting examples of preparations suitable for parenteral administration include injections, drops, ointments, creams, percutaneous absorption agents, ophthalmic drops, ear drops, inhalers and suppositories. The formulations can be presented in sealed unit dose or multiple dose containers, such as ampoules and flasks, and can be stored in a freeze-dried (freeze-dried) condition, which only requires immediately before the addition of the sterile liquid vehicle, for injectable water example. The form of the pharmaceutical composition is not restricted to those mentioned herein. Additional vehicles can be added to preparations for oral administration. Suitable additive carriers include glucose, lactose, D-mannitol, starch and crystalline cellulose; disintegration aids or disintegrators such as carboxymethylcellulose, starch and cal salt of carboxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, poly (vinylpyrrolidone) and gelatin; lubricants such as magnesium stearate and talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol and titanium oxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, pure water and hard fat. Typical additives for injectable preparations or eye drops include dissolution agents or dissolution aids that can be injections aqueous or to dissolve before use, such as distilled water for injection, physiological salt solutions and propylene glycol; isotonicity agents such as glucose, sodium chloride, D-mannitol and glycerin; pH regulators such as inorganic acids, organic acids, inorganic salts and organic salts. The doses of the medicament of the invention can be increased or decreased appropriately depending on the disease, the purpose of the treatment (for example prevention or treatment) and the conditions of the patient, such as age, weight and symptoms. However, in general, the daily doses for an adult patient by oral administration are from about 0.05 mg to about 500 mg per day. In general, the aforementioned doses can be administered once or several times a day, or every several days. The crystal forms can be further understood by consulting the following references: Chaki et al., Bioorganic &; Medical Chemistry Letters, 5 (14), 1489-1494 (1995); Chaki et al., Bioorganic & Medical Chemistry Letters, 5 (14), 1495-1500 (1995); Bessho and others, Arznein. Forsh./Drug Res., 46 (1), 369-373 (1996); Murai and others, J. Neuron. Transm. [Sec. General], 98, 1-13 (1994); and Akaike and others, Jpn. J Pharmacol., 76, 219-222 (1998). All references cited herein, including patents, patent applications and publications, are hereby incorporated by reference in their entirety, whether previously incorporated or not specifically.

Having fully described this invention, those skilled in the art will appreciate that it can be performed within a wide range of parameters, concentrations and equivalent conditions without departing from the spirit and scope of the invention and without further experimentation. Although the invention has been described with respect to specific embodiments thereof, it will be understood that it is susceptible to further modifications. This application is intended to cover any variation, use or adaptation of the invention that generally follows the principles of the invention, and includes such deviations from the present disclosure within the knowledge or usual practice in the art to which the invention pertains, and as can apply to the essential characteristics previously established.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a 4-acylaminopyridine derivative to said subject or patient in the preparation of a medicament useful for the treatment of a nervous system disorder related to cellular degeneration, a psychiatric condition, trauma and / or cell injury, or other condition neurological related, in a subject or patient.

2. The use as claimed in claim 1, wherein said nervous system disorder related to cellular degeneration is selected from a neurodegenerative disorder, a neural stem cell disorder, a neural progenitor cell disorder, a degenerative disease of the retina, an ischemic disorder, and combinations thereof.

3. The use as claimed in claim 1, wherein said nervous system disorder related to a psychiatric condition is selected from a neuropsychiatric disorder, an affective disorder, depression, hypomania, panic attacks, anxiety, excessive jubilation, depression bipolar disorder, bipolar disorder (manic depression), seasonal mood (or affective) disorder, schizophrenia and other psychosis, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes, cognitive function disorders, aggression, abuse of substances and alcohol, syndromes of obsessive compulsive behavior, personality limit disorder, non-senile dementia, depression after a pain, postpartum depression, cerebral palsy, and combinations thereof.

4. The use as claimed in claim 3, wherein said nervous system disorder related to a psychiatric condition is selected from the group consisting of depression, bipolar depression, bipolar disorder (manic depression), depression following a pain and postpartum depression.

5. The use as claimed in claim 1, wherein said nervous system disorder related to trauma and / or cell injury is selected from neurological traumas and injuries, trauma and / or injury related to surgery, injury and retinal trauma, injury related to epilepsy, spinal cord injury, brain injury, brain surgery, brain injury related to a trauma, spinal cord injury related to a trauma, brain injury related to cancer treatment, injury to the brain spinal cord related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to an environmental toxin, spinal cord injury related to an environmental toxin, and combinations of the smos.

6. - The use as claimed in claim 1, wherein said related neurological condition is selected from learning disorders, memory disorders, autism, attention deficit disorders, narcolepsy, sleep disorders, cognitive disorders, epilepsy, temporal lobe epilepsy, and combinations thereof.

7. The use as claimed in claim 3, wherein said psychiatric condition comprises depression.

8. The use as claimed in claim 7, wherein the medicament is further adapted to be administrable with an antidepressant.

9. The use as claimed in claim 7, wherein said depression is due to the subject or patient using morphine.

10. The use as claimed in any of claims 1-9, wherein said 4-acylaminopyridine derivative is 2- (2-oxypyrrolidin-1-yl) -N- (2,3-dimethyl-5.6 , 7,8-tetrahydrofuro (2,3-b) quinolin-4-yl) -acetoamide.

11. The use as claimed in claim 10, wherein said 4-acylaminopyridine derivative is in the crystal form.

12. - A method of preparing cells or tissue for transplants to a subject or patient, comprising: stimulating or increasing neurogenesis in said cells or tissue by contacting said cells or tissue with a 4-acylaminopyridine derivative.

13. - A method of stimulation or increase of neurogenesis in a cell or tissue, comprising: contacting said cell or tissue with a 4-acylaminopyridine derivative.

14. - The method claimed in claim 12, wherein said cells or tissue are in an animal subject or a human patient.

15. The method claimed in claim 14, wherein said patient is in need of neurogenesis, or has been diagnosed with a disease, condition or injury of the central or peripheral nervous system.

16. - The method claimed in any of claims 13-15, wherein said method also comprises contacting said cells or tissue with an opioid or non-opioid neurogenic agent.

17. The method claimed in claim 16, wherein said non-opioid neurogenic agent is a muscarinic receptor ligand, such as sabcomelin.

18. - The method claimed in claim 13, wherein said neurogenesis comprises the transformation of neural stem cells (NSC's) in a neuronal lineage.

19. - The method claimed in claim 13, wherein said neurogenesis comprises the transformation of neural stem cells (NSC's) into a glial lineage.

20. The method claimed in any of claims 16-19, wherein said opioid is an antagonist of the kappa opioid receptor.

21. The method claimed in claim 20, wherein said opioid is a selective antagonist of the kappa opioid receptor.

22. The method claimed in claim 21, wherein said opioid is selected from JDTic, norbinaltorphimine and buprenorphine.

23. - The method claimed in claim 14 or 15, wherein said cells or tissue exhibit decreased neurogenesis, or are subject to an agent that decreases or inhibits neurogenesis.

24. The method claimed in claim 23, wherein said agent that decreases or inhibits neurogenesis is an opioid receptor agonist.

25. The method claimed in claim 24, wherein said agonist is morphine or another opiate.

26. The method claimed in claim 14 or 15, wherein said subject or patient has one or more addictions or dependencies of chemical substances.