MX2008005336A - Tricyclic compounds useful as oxytocin receptor agonists - Google Patents

Abstract

Methods for treating and preventing anxiety, anxiety-related disorders, schizophrenia and schizophrenia-related disorders are described herein wherein said methods comprise the administration of oxytocin receptor agonists. of formula 1 , or a pharmaceutically acceptable salt thereof:1 wherein:G1 is (I) of formula 1 , or a pharmaceutically acceptable salt thereof:2 wherein:G2 is (II)

Description

TRICYCLIC COMPOUNDS USEFUL AS AGENTS OF OXYTOCIN RECEPTORS FIELD OF THE INVENTION The present invention relates to the use of non-peptide oxytocin receptor agonists for the treatment of schizophrenia, disorders related to schizophrenia, anxiety and anxiety-related disorders.

BACKGROUND OF THE INVENTION Oxytocin (OT) is a nonapeptide, which differs in two amino acids from its neurohypophyseal sister peptide, vasopressin arginine (AVP). OT is synthesized mainly in two divisions of hypothalamic neurons, the magnocellular cells of the supraoptic (SON) and paraventricular nuclei (PVN), and the parvocellular cells of the PVN. The oxytosynergic neurons of the SON project for the posterior pituitary where OT is released in the peripheral circulation of axon terminals in the capillary bed. This peripheral release is mainly and familiarly associated with OT effects in women during the peripartum period; when the OT participates in the stimulation of uterine smooth muscle contraction during labor, and the activation of the milk ejection reflex in mammary epithelial cells during lactation. Although Sir Henry Dale first described the uterotonic effects of oxytocin again in 1909, it was not until the 1980s that modern obstetricians began to exploit their tocogenic activity to help optimize supply without disastrous side effects. However, intricate studies with OT transgenic mice have shown that OT is not essential for normal delivery that helps to illustrate the teleological importance of its other, perhaps less appreciated, role in regulating central nervous system (CNS) functions. (Young, W. S., 3rd et al., Targeted reduction of oxytocin expression provides insights into its physiological roles, Adv Exp Med Biol 449, 231-40 (1998)).

Only recently (since the early 1990s) has the distinction between the peripheral and central oxytosynergic systems been appreciated. After cloning the oxytocin receptor (OTR) and numerous radioligand binding studies Immunolocalization, many were surprised to find the extent to which the oxytosergic efferents, particularly those emanating from the PVN, innervate extrahypothalamic sites through the CNS. Collectively, this network of connections forms what is termed as the central oxytosynergic system, whose OT positions exert influence on key neuroanatomical substrates behind social recognition (olfactory vulvo), aggression / shunned (MPOA), motivation (NA / DA, core of the brainstem), and fear / anxiety behavior (amygdala, hypothalamus, BNST). Although the emerging evidence has extended the roles for oxytocin that includes involvement in nociception and memory, most CNS research has focused on OT involvement in socio-sexual / reproductive behaviors (eg sexual behavior, behavior parental, formation of union pairs). A unifying principle of oxitosynergic action in the CNS begins to emerge: social interaction facilitates OT by reducing the anxiety associated with such encounters. (McCarthy, M. M. Estrogen modulation of oxytocin and its relation to behavior, Adv Exp Med Biol 395, 235-45 (1995)).

A commonly observed sequence of friendly social contact is the induction of a psychophysiological pattern that involves sedation, relaxation, reduced sympathoadrenal activity, and increased vague tone that is in contrast to fear / anxiety that leads to general mental activation, locomotor activity, and catabolic activity . (Uvnas-Moberg, K. Oxitocin linked antistress effects-relaxation and growth response, Acta Physiol Scand Suppl 640, 38-42 (1997)). The evidence consistently implies the central oxytosynergic system as a key axis in which these opposite effects are mediated.

The effects of peptide oxytocin on itself in models of CNS activity have been noted. For example: 1. OT (1-4 ug / kg), administered subcutaneously (s.c), produces a reduction in peripheral locomotor activity in the Open Field Anxiety model, indicating an effect similar to anxiolytic. (Uvnas-Moberg, K., Ahlenius, S., Hillegaart, V. &Alster, P. High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats Pharmacol Biochem Behav 49, 101-6 (1994)). 2. OT (3 mg / kg), administered intraperitoneally (i.p.), produces activity similar to the elevated anxiolytic plus labyrinth. (McCarthy, M.M., McDonald, C.H., Brooks, P.J. &Goldman, D. An anxiolytic action of oxytocin is enhanced by estrogen in the mouse, Physiol Behav 60, 1209-15 (1996)). 3. OT (10-100 ng), administered intracerebroventricularly (i.c.v.), produces increases in open-arm entries and time spent in the open arms of the higher labyrinth, suggesting that OT exerts a centrally mediated effect similar to anxiolytic. (Windle, R.J., Shanks, N., Lightman, S.L. &Ingram, C.D. Central oxytocin administration reduces stress-induced corticosterone relase and anxiety behavior in rats Endocrinology 138, 2829-34 (1997)). 4. OT anxiolytic activity in higher labyrinth of pregnant or lactating rats, but not virgin rats, suggesting a role of estrogen in OT control. (Neumann, I.D., Tomer, L. &Wigger, A. Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behavior in virgin, pregnant and lactating rats Neuroscience 95, 567-75 (2000)).

. Improved anxiety behavior in higher labyrinth is observed in OT female transgenic mice. (Mantella, R.C., Vollmer, R.R., Li, X. &Amico, J. A.

Female oxytocin-deficient mice display enhanced anxiety-related behavior. Endocrinology 144, 2291-6 (2003). 6. OT is known to inhibit the release of CRF, and cause a sub-regulation of the hypothalamic adeno pituitary axis (HPA). (Neumann, I.D., Wigger, A., Tomer, L., Holsboer, F. & Landgraf, R. Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J Neuroendocrinal 12, 235-43 (2000)). Hyperactivity of the HPA axis, frequently linked to the increased corticotrophin release factor (CRF) -mediated by the release of ACTH, is commonly observed in depressed human patients. 7. In humans, reduced levels of anxiety and the incidence of anxiety-related disorders are observed in humans during lactation, a process physiological mediated by increased OT levels (Altemus, Neuropeptides in anxiety disorders, Effects of lactation, Ann N and Acad Se / 771: 697-707 (1995). 8. Chronic and acute treatment of adult male rats with citalopram SSRI (20 mg / kg) leads to an increase in plasma oxytocin levels, suggesting that the release of oxytocin may be an important aspect of the pharmacological actions of the anti-depressants. (Uvnas-Moberg, K., Bjokstrand, E., Hillegaart, V. &Ahlenius, S. Oxytocin as a possible mediator of SSRI-induced antidepressant effects, Psychopharmacology (Berl) 142, 95-101 (1999)).

The biological activity of OT is mediated by a family of four receptors including, in addition to the specific oxytocin receptor, OTR, all known vasopressin receptors (V1a (WR), V2 (V2R), V1b (V3R)). OTR is a G-class protein G (GPCR) coupled receptor that exhibits its highest sequence similarity to V3R. Consistent with the sequence similarities of this family; there is only one greater selectivity 10 times for the OT compared to AVP in the OTR. (Chini, B. et al Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin FEBS Lett 397, 201-6 (1996); Postina, R., Kojro, E. & Fahrenholz, F. Sepárate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J Biol Chem 271, 31593-601 (1996)). The expression of the oxytocin receptor (OTR) is observed through the CNS with notable differences in distribution patterns between species. (Tribollet, E., Dubois-Dauphin, M., Dreifuss, JJ, Barberis, C. &Jard, S. Oxitocin receptors in the central nervous system, Distribution, development, and species differences.) Ann NY Acad Sci 652, 29 -38 (1992)). A common feature of OTR expression across species is the robust expression in the limbic system. In rodents, the OT binding sites are found in the bed nucleus of the striated terminals (BSNT), central amygdaloid nucleus, ventromedial hypothalamic nucleus, and ventral subiculum. The pattern of OT union is quite different in humans, but consistent with a proposed role in the regulation of social behaviors, with strong union observed in the lateral septal nucleus and the basal nucleus of Meynert that provides direct cholinergic entry to the basolateral amygdaloid nucleus . (Loup, F., Tribollet, E., Dubois-Dauphin, M. &Dreifuss, JJ Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain, An autoradiographic study, Brain Res 555, 220-32 ( 1991)).

In addition to the significant amount of evidence of oxytocin signaling binding with anxiolytic effects in mammals, there is also at least one evidence of oxytocin signaling linkage with schizophrenia. For example, there have been numerous studies that have indicated that perturbations in the concentration of oxytocin have been found in schizophrenic patients and that the treatment of schizophrenics with neuroleptics can further increase oxytocin concentrations. (Beckmann, H., Lang, R.E., Gattaz, W. F. Vasopressin-oxytocin in cerebrospinal fluid of schizophrenic patients and normal controls, Psychoneuroendocrinology 10: 187-191). In a rat model of prepulse inhibition (inhibition of the startle reflex immediately preceding intense stimulation with lower intensity stimulation), it has been shown that subcutaneous administration of oxytocin can restore dose-induced inhibition of prepulse. by dizocilpine (a non-competitive NMDA antagonist) and amphetamine. The inhibition of reduced prepulse has been demonstrated by patients with schizophrenia and it has been hypothesized that the action of oxytozine in this parameter is an indicator of the antipsychotic action, since such prepulse inhibition activity correlates strongly with the activity of the antipsychotic drug. (Feifel, D., and Reza, T. Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating, Psychopharmacology 141: 93-98 (1999)).

The discovery of new methods for the treatment and prevention of anxiety and schizophrenia are of paramount importance given the severe implications that each of these disorders can represent as well as the large number of people who are not currently being treated in a way satisfactory. Since oxytocin has been implicated in the treatment of anxiety and schizophrenia, there is a strong need for the discovery of new methods to treat anxiety and schizophrenia where these new methods would not employ oxytocin per se, but unlike agonists. peptides for the oxytocin receptor. Such compounds may present opportunities for the varied modulation of the oxytocin receptor, thus increasing the possibility of clinical success. Additionally, such compounds may have the additional advantage of improved pharmaceutical properties, for example, by being themselves available after oral administration and / or having increased mediated central effects. The current invention describes, Here for the first time, methods to treat and prevent anxiety and schizophrenia using certain non-peptide oxytocin receptor agonists.

BRIEF DESCRIPTION OF THE INVENTION The present invention describes methods for treating schizophrenia and disorders related to schizophrenia, anxiety and anxiety-related disorders which comprises administering to a mammal a compound of Formula 1 or a pharmaceutical salt. 1.

The present invention also describes methods for treating schizophrenia, disorders related to schizophrenia, anxiety, and anxiety-related disorders which comprises administering to a mammal a compound of Formula 2 or a pharmaceutically acceptable salt thereof: In some embodiments, this invention describes a method for the treatment of schizophrenia or a disorder related to schizophrenia, anxiety and disorders. related to anxiety comprising administering to a mammal a compound of Formula 1, or a pharmaceutically acceptable salt thereof; where G1, R1, R2, R3, R4, X1, a, and b are as defined in WO03 / 016316 (page 63-65; claim 1) which is incorporated herein by reference in its entirety.

In some embodiments, for the compound of Formula 1, G1 is (I) where A3 is S; NH; N-C 1-3 alkyl; -CH = CH- or CH = N; A4 is CH; A5 is CH; A6 is NH; A7 is C; A8 is N- (CH2) d-R7; A9, is N; A10 is CH and An is C; where d is 1, 2 or 3; and R is selected from hydrogen; C1-3 alkyl; optionally substituted phenyl; OH; O-alkyl; O-acyl; S-alkyl; NH2; NH-alkyl; N (alkyl) 2; NH-acyl; N (alkyl) -acetyl; CO2H; CO2- alkyl; CONH2; CONH-alkyl; CON (alkyl) 2; CN; and CF3.

In some embodiments, for the compound of Formula 1, G1 is In some embodiments, for the compound of Formula 1, R1, R2 and R3 are each independently selected from hydrogen; I rent; Fl; or Cl.

In some embodiments, for the compound of Formula 1, R4 is selected from In certain aspects, for the compound of Formula 1; two of R1, R2 and R3 are hydrogen and the other is not hydrogen.

In some embodiments, for the compound of Formula 1, R and R3 are each hydrogen, and R2 is methyl.

In some embodiments, for the compound of Formula 1; R4 is In certain aspects, the compound of Formula 1 is: 2-methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9 -carbonyl) -4- (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid benzylamide; 2,6-dimethyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9- 4, - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide; 3-Chloro-4- (3-methyl-4, 10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of 4, - (3) acid , 5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; 2-Fluoro-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide acid 4, - (3 , 5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; 2-Methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide acid 4, - (3 -Dimethylcarbamoyl-benzyl) -piperazine-1-carboxylic acid; and 2-methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-azabenzo [f] azulene-9-carbonyl) -benzylamide of 4, - ( 3-Dimethylthiocarbamoyl-benzyl) -piperazine-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula 1 is administered with at least one pharmaceutically acceptable excipient.

In some embodiments, the compound of Formula 1 is administered to a human.

In some embodiments, this invention is directed to the treatment of schizophrenia, the treatment of disorders related to schizophrenia, and the treatment of anxiety and anxiety-related disorders, using compounds of Formula 2, and pharmaceutically acceptable salts thereof; wherein d, Ri, R2, R3, Xi, R, R5, Y, and G2 are all as described in WO 03/000692 (page 61-65, claim 1), which is incorporated herein by reference in its entirety .

In certain embodiments, for the compound of Formula 2: G2 is (II) where A3 is S; NH; N-alkyl d.3; -CH = CH- or CH = N; A4 is CH; A5 is CH; A6 is NH; A7 is C; A8 is N- (CH2) d-R7; A9 is N; A10 is CH and An is C; where d is 1, 2 or 3; and R7 is selected from hydrogen; alkyl d-3; optionally substituted phenyl; OH; O-alkyl; O-acyl; S-alkyl; NH2; NH-alkyl; N (alkyl) 2; NH-acyl; N (alkyl) -acetyl; CO2H; CO2- alkyl; CONH2; CONH-alkyl; CON (alkyl) 2; CN; and CF3; R1, R2, and R3 are each independently selected from the group consisting of hydrogen; I rent; O-alkyl; Fl; Cl; or Br; X, is NH or O; R4 and R are each independently selected from the group consisting of hydrogen; O-alkyl; O-benzyl; and F; or R4 and R5 both are = O; -O (CH2) aO-; or -S (CH2) aS-; a is 2 or 3; And it is O or S; Y GT is (III) where h is 1 or 2; I is 1, 2 or 3; and X2 is N-alkyl.

In some embodiments, for the compound of Formula 2, G2 is: In some embodiments, for the compound of Formula 2, two of R1, R2 and R3 are hydrogen and the other is not hydrogen.

In some embodiments, for the compound of Formula 2, XT is NH.

In some embodiments, for the compound of Formula 2, R and R5 are each independently selected from hydrogen and O-alkyl.

In some embodiments, for the compound of Formula 2, d is 1-methyl- [1,4] diazepam.

In certain embodiments, the compound of Formula 2 is: 4-methyl-1- (N- (2-methyl-4- (2,3,4,5-tetrahydro-1,5-benzodiazepin-4-on-1 -yl-carbonyl) benzylcarbamoyl) -L-thioprolyl) perhydro-1,4-diazepine; 4-Methyl-1- (N- (2-methyl-4- (1-methyl-4,10-dihydropyrazolo [5,4-ib] [1, 5] -benzodiazepin-5-ylcarbonyl) benzylcarbamoyl) -L- thioprolyl) perhydro-1,4-diazepine; 4,4-dimethyl-1- (N- (2-methyl-4- (1-methyl-4,10-dihydropyrazolo [5,4-b] [1,5] -benzodiazepin-5-ylcarbonyl) benzylcarbamoyl) - L-tiprolil) perhydro-1,4-diazepine; 4-methyl-1 - (N- (2-methyl-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-4-ylcarbonyl) -benzylcarbamoyl) -L-thioprolyl) perhydro-1 , 4-diazepine; 4-methyl-1 - (N- (2-methyl-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-ylcarbonyl) -benzyloxycarbonyl) -L-prolyl) perhydro-1, 4 -diazepine; (4R) -Na- (2-chloro-4- (5,6,7,8-tetrahydrothieno [32-b] azepin-4-ylcarbonyl) benzyl-carbamoyl) -4-methoxy-L-proline-N-methyl -N- (2-piccolyl) amide; or 1 - ((4R) -Ns- (2-chloro-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-4- ilcarbonyl) benzyl-carbamoyl) -4-methoxy-L-prolyl) -4- (1-pyrrolidinyl) piperidine; or a pharmaceutically acceptable salt thereof.

It is appreciated that the structural modalities described herein can be combined together. Thus, for example, a modality described for Formula 1 can also be applied in conjunction with any of the other possible combinable structural modalities described for Formula 1. Accordingly, this invention contemplates both individual modalities as well as combinations of the modalities.

As used herein, the term "alkyl" is defined as lower alkyl radicals, having 1 to 6 carbons. The alkyl radicals can be straight chain, branched chain or C3-C6 cyclic. Some non-limiting examples of alkyl as defined herein include methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, sec-butyl, pentyl, hexyl, cyclopentyl, and the like. The alkyl groups as defined herein can also be substituted with 1 to 3 substituents selected from the group consisting of C 1-3 alkyl (unsubstituted), fluorine, chlorine, hydroxyl or phenyl.

The term "acyl" as defined herein refers to a radical (C = O) -R, wherein R is hydrogen, alkyl as previously defined, phenyl, naphthyl, pyridyl or thienyl, wherein said phenyl, naphthyl, pyridyl or thienyl they are optionally substituted with 1-3 groups selected from Alkyl d.3, halogen, O-C1-3 alkyl, or OH. Some non-limiting examples of acyl are formyl, acetyl, benzoyl and the like.

The term "optionally substituted phenyl" as defined herein, refers to a phenyl radical wherein said phenyl radical can be substituted with 1 to 3 substituents selected from the group consisting of Alkyl d.31 halogen, OH, and OAIkyl C ?. 3.

This invention relates to methods for treating mammals, preferably humans, for schizophrenia and disorders related to schizophrenia, which comprises the administration of a compound of Formula 1 or 2. This invention also discloses methods for treating mammals, preferably humans, for anxiety and anxiety-related disorders whose methods include administration of a compound of Formula 1 or 2. This invention also describes methods for treating schizophrenia and disorders related to schizophrenia comprising the administration of pharmaceutical compositions containing the compounds of formula 1 or 2, wherein such compositions are administered to a mammal (preferably human). This invention also discloses methods for treating mammals, preferably humans, for anxiety and anxiety-related disorders comprising the administration of pharmaceutical compositions containing the compounds of formula 1 or 2, or any of their structural modalities described herein, or any of its structural modalities described in any of the references that have been presented here This invention also discloses the use of a compound of Formula 1 or 2 in the manufacture of medicaments for the treatment of schizophrenia or symptoms related to schizophrenia.

This invention also discloses the use of a compound of Formula 1 or 2 in the manufacture of a medicament for the treatment of anxiety and anxiety-related disorders.

Schizophrenia is typically diagnosed through the application of any of a number of commonly accepted criteria for the disease. Such definitions are provided by, for example, the international statistical classification of diseases and health-related problems of the World Health Organization or the statistical manual and diagnosis of mental illnesses of the American Psychiatric Association (DSM), both of which are incorporated herein by reference. In its whole. In summary, schizophrenia is a disease that appears to have genetic and environmental triggers, and is typically defined by its overt symptoms or behaviors that include positive symptoms (behavior in addition to typical normal behaviors) and negative symptoms (behavior pretreatment behaviors). normal). Positive symptoms of schizophrenia include illusions, hallucinations, disorganization, frequent and excessive repetitive talk patterns, and disturbances or other inappropriate behaviors. Negative symptoms are usually typified by such behaviors as social abandonment, lack of affection, dullness of tonic talk, and reduced communication. Despite the symptoms associated with schizophrenia, people suffering from schizophrenia are they frequently divide into more general categories of behavior such as catatonic category (immobile, non-sensitive, rigid), disorganized schizophrenia (behavior and disorderly chat, inappropriate and flat affect) or paranoid (suffering from delusions, often related to threats of persecution falsely perceived ). For purposes of this invention, disorders related to schizophrenia refer to disorders in which at least some of the symptoms of schizophrenia are present, although a classification of schizophrenia may not be appropriate. For example, brief psychotic disorders, schizophreniform disorder, schizoaffective disorders, and delusional disorder are all considered as disorders related to schizophrenia for purposes of this invention. Anxiety can be described generally as a state of uneasiness or of apprehension. Anxiety may show variations in cause, duration, etiology, convenience, etc., and it is generally accepted that all individuals probably suffer from anxiety from one moment to the next.

Anxiety in its most serious forms can often paralyze an individual who suffers from it, and untreated, acute or chronic anxiety can often lead to many severe physical and psychological disorders. While anxiety can be considered an appropriate response to threatening or dangerous situations, it also occurs when the threat or perceived danger or threat is exaggerated or unfounded. Anxiety-related disorders include panic disorder, agoraphobia, phobias (including social phobia), obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder, and generalized anxiety disorder.

As used herein, the term "non-peptidergic" means that the compounds are characterized as not containing two or more amino acids coupled together. Thus, for example, a non-peptidergic compound can contain one or more amino acid residues, but will not contain two amino acid residues coupled via an amide bond that is linked to the C-terminus of one amino acid with the N-terminus of another amino acid. The amino acid as referred to herein refers to amino acids of natural occurrence.

As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural reference unless the context indicates I clearly control it. A) Yes, for example, a reference to "an oxytocin receptor agonist" includes a plurality of oxytocin receptor agonists, and a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art. , already so on. Additionally, an oxytoxin agonist refers to a molecule as described herein and is useful for the methods of this invention, wherein said molecule is capable of combining with, or otherwise modulating, the oxytocin receptor and initiating an activity in a cell that is of the same qualitative type of activity as oxytocin itself could initiate, wherein said qualitative type of activity needs to be characterized only by one or more measurable parameters. The type of response can only be qualitatively similar but does not have to meet a particular power criterion. Thus, an agonist of this invention can behave like oxytocin in one or more parameters in one or more cells or tissues, but not necessarily for all parameters in all cells or tissues.

The abbreviations in the specification correspond to units of measurement, techniques, properties, or compounds as follows: "min" means minutes, "h" means hours, "μl" means microliters, "mL" means milliliters, "mM" means millimolar, "M" means molar, "mmol" means millimoles, "cm" means centimeters, "SEM" means Standard error of the mean and "IU" means International unit.

In the context of this of this description, a number of terms should be used. The term "treatment" as used herein includes curative or preventive palliative treatment (eg, prophylactic) and "treating" as used herein also includes preventive, curative and palliative treatment.

The term "effective amount", as used herein, refers to an effective amount, in dosage, and for periods of time necessary, to achieve the desired result with respect to the treatment of schizophrenia, disorders related to schizophrenia, anxiety, and disorders related to anxiety.

It will be appreciated that the effective amount of the components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability to the components (alone or in combination with one or more combination drugs) to elicit a desired response in the individual, but also with factors such as the state of disease or severity of the condition to be relieved, hormone levels, age, sex, the weight of the individual, the state of the patient, and the severity of the pathological condition being treated, the concurrent medication or special diets that are followed by the patient in particular, and the other factors that those skilled in the art will recognize, with the dosage appropriate that is finally at the discretion of the attending physician. Dosage regimens can be adjusted to provide the improved therapeutic response. An effective amount is also one in which any detrimental or toxic effect of the components is compensated by the therapeutically beneficial effects. Preferably, the compounds of the present invention are administered in a dosage and for a time such that the number and symptoms of the disease are reduced.

For example, for an afflicted patient, the compounds of formula 1 or 2 can be administered, in a dosage of about 0.1 mg / day to about 1000 mg / day, or about 1 mg / day to about 500 mg / day or about 10 mg / day at 500 mg / day for a sufficient time to reduce and / or substantially eliminate the number and / or severity of schizophrenic symptoms or symptoms related to anxiety.

The terms "component," "composition of compounds," "compound," "drug," or "pharmacologically active agent" or "active agent" or "medicament" are used interchangeably herein to refer to a compound or compounds or composition of the This material, when administered to a subject (human or animal), induces a desired pharmacological and / or physiological effect through systemic and / or local action.

The term "modulation" refers to the ability to improve or inhibit a functional property or a biological activity or process, for example, signaling or receptor binding activity. Such improvement or inhibition may be contingent upon the occurrence of a specific event, such as activation of a signal transduction path and / or may be manifest only in particular cell types.

"Administration," as used herein, means directly administering a compound or composition of the present invention, or administering a derivative or prodrug or analog that will form an equivalent amount of the active compound or substance within the body.

The term "subject" or "patient" refers to an animal that includes the human species that can be treated with the compositions, and / or methods of the present invention. The term "subject" or "subjects" is intended to refer to the masculine gender as feminine unless a gender is specifically indicated. According to the above the term "patient" includes any mammal that can benefit from the treatment of schizophrenia, disorders related to schizophrenia, anxiety and anxiety-related disorders. When a patient to be treated is a female of childbearing age, it should be taken into account that the oxytocin receptor agonist activity is associated with the induction of labor in pregnant women and, according to the above, this possible effect must be taken into account when It's about this population.

Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (ie, enantiomers). The present invention includes all such stereoisomers and any mixture thereof including racemic mixtures. Racemic mixtures of stereoisomers as well as substantially pure stereoisomers are within the scope of the invention. The term "substantially pure" as used herein, refers to at least about 90 mol%, more preferably at least about 95 mol%, and more preferably at least about 98 mol% of the desired stereoisomer is present in relation to other possible stereoisomers. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by the methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron, 33: 2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

The present invention includes prodrugs of the compounds of formula 1 or 2. "Prodrug," as used herein, means a compound that can be converted in vivo by metabolic means (eg, by hydrolysis) to a compound of formula 1 or 2. Various forms of prodigies are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, ef al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Laren, et al., (Ed). "Design and Application of Prodrugs," Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992, 8: 1-38, Bundgaard, J. Pharmaceutical Sciences, 1988, 77: 285 et seq .; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).

Additionally, the compounds of formula 1 or 2 can exist in solvated as well as non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purpose of the present invention.

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art. For example, the compounds of this invention can be prepared by the methods described in WO03 / 000692 and WO03 / 016316, both are hereby incorporated by reference in their entirety.

In other embodiments, the invention is directed to pharmaceutical compositions, comprising: to. at least compound of the formula 1 O 2, or pharmaceutically acceptable salts thereof; Y b. at least one pharmaceutically acceptable carrier.

Generally, the compound of Formula 1 or 2, or the pharmaceutically acceptable salt thereof, will be present at a level between about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 1%, by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 5%, by weight, based on the total weight of the pharmaceutical composition. In still other embodiments, the compound or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10%, by weight, based on the total weight of the pharmaceutical composition. In still other embodiments, the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 25%, by weight, based on the total weight of the pharmaceutical composition.

Such compositions are prepared according to acceptable pharmaceutical methods, as described. in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). The pharmaceutically acceptable carriers are those that are compatible with other ingredients in the formulation and biologically acceptable.

The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, binders, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid that is mixed with a finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and is compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other pharmaceutically suitable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as noted above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example , glycols) and their derivatives, and oils (for example, fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid form for parenteral administration.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can be administered intravenously. The oral administration can be in the form of liquid or solid composition.

In some embodiments, the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such forms, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example packaged powders, flasks, ampoules, prefilled syringes or bags containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or this may be the appropriate number of any such compositions in the package.

In another embodiment of the present invention, the compounds useful in the present invention can be administered to a mammal with one or more pharmaceutically active agents such as those agents that are used to treat any medical condition present in the mammal. Examples of such pharmaceutically active agents include tranquilizers, anti-psychotic agents, antidepressants and the like.

One or more pharmaceutical active agents can be administered in a therapeutically effective amount simultaneously (such as individually at the same time, or together in a pharmaceutical composition), and / or successively with one or more compounds of the present invention.

The route of administration can be any route, which effectively transports the active compound of formula 1 or 2 to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or ontofatic, or parenteral delivery. , for example rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment. Additionally, administration of the compound of formula 1 with other active ingredients may be concurrent or simultaneous.

EXAMPLES Oxytocin Receptor Agonists as anxiolytic-like Agents: METHODS AND MATERIALS Animals: Swiss-Webster male rats weighing 18-24 g are housed in groups 15 in wire cages, allowed access to food and water ad libitum, and maintained in a 12-hour light-dark cycle. All behavioral tests are developed during the light cycle. All studies are previously tested by the Institutional Animal Use and Care Committee, and are developed in accordance with the Laboratory Animals Use and Care Guide as adopted and promulgated by the National Institute of Health.

Test Compounds: Oxytocin (American Peptide Company, Sunnyvale, CA) is dissolved in a saline vehicle. 2-Methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-azabenzo [f] azulene-9-carbonyl) -benzylamide of 4, - ( 3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic oxytocin agonist (hereinafter "cpd A") and bis- (2-hydroxy-ethyl) -amide 10 - [(2-methyl-2 ' -trifluoromethyl- [1, 1'-biphenyl] -4-yl) carbonyl] -10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine-3-carboxylic acid (hereinafter " cpd B ") (Patent W / O 02/083680) are prepared and dissolved in a 1% Tween-80/1% DMSO / saline vehicle. 2-Methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide hydrochloride is prepared , - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid by dissolution of 2-methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza 4 - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid (4,9-azulene-9-carbonyl) -benzylamide (4.2 g) in EtOH (100 mL) and the solution is cooled with a ice bath. Hydrochloric acid is bubbled into the solution for 10 min. Ether is added and the resulting white precipitate is collected by filtration to give 2.4 g of the title compound. MS (ES) m / z [M-H] 580.3 ICV injections: mice are slightly anesthetized with halothane. Oxytocin is administered in the left or right ventricle by visual location. A 26-gauge Hamilton syringe with a 3-mm needle is used for injections and the injection site is visualized by locating the middle of the invisible line running diagonally from the left eye to the right ear. The compounds are injected in a total volume of 2 μl. 4-plate test (FPT :) The four-plate apparatus consists of a Plexiglas chamber (18 x 25 x 16 cm) with a floor with four identical rectangular metal plates (8 x 11 cm), which are separated from each other the other by a space of 4 mm and are connected to a computerized device that can supply electrical shocks (0.8 mA, 0.5 sec) (Aran et al., Evaluation of a rapid technique for detecting minor tranquilizers, Neuropharmacology 10: 459-69 (1971 )). In this test, the mice are placed in the chamber and after a brief conditioning period (18 seconds), the innate motivation of the animal to explore the new environment is suppressed by administering a gentle shock to the legs each time the animal crosses any of the boundaries (spaces) while moving from one plate to the other (referred to as crossing punished). After any crossing punished, there is a second time where the mouse can cross the electric plates without receiving another shock. A blinded experimenter for dosing conditions that administer shocks, and a computer records the total number of punishments an animal makes during a 1-minute test period. Clinically effective classes of anxiolytic compounds such as benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), or 5-HT1A agonists produce increases in the punishment crosses in this paradigm, which is an indicator of activity similar to activity. Anxiolytic (Aron et al., Evaluation of a rapid technique for detecting minor tranquilizers.) Neuropharmacology 10: 459-69 (1971); Bourin et al. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models. J Psychiatry Neurosci 17: 72-7 (1992); Hascoet et al. Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice. Pharmacol Biochem Behav 65: 339-44 (2000)). In all experiments, the test procedure consists of a single injection or two injections followed by a test session 30 minutes later.

Statistical analysis: a one-way analysis of variance (ANOVA) is developed to determine the effects of the test compound treatments, followed by Less Significant Difference Tests for a post hoc analysis. All figures are shown with mean ± standard error of the mean.

RESULTS Oxytocin produces effects similar to anxiolytics in FPT mice.

The FTP mouse is a preclinical model frequently used to detect the anxiolytic activity of the test compounds. The central administration of oxytocin (1-10 mg, icv) produces a dose-dependent increase in crosses punished (F (3.36) = 8.99, p <0.0001, Fig.1). The Post hoc analysis reveals significant increases in the crosses punished in the two highest doses (30% and 51% increase of the vehicle and 3 and 10 μg respectively, p <0.05). These data suggest an effect similar to the anxiolytic of centrally administered oxytocin.

The oxytocin agonist produces similar effects to the anxiolytics in the FTP mouse Peripheral administration of cpd A (3-100 mg / kg, ip), produces a significant overall effect in crosses punished (F (4,45) = 4,11, p <0.01, Fig. 2). The significant post hoc analysis increases in crosses punished in the group of 10 and 30 mg / kg (32% and 25% increase of the vehicle for 10 and 30 mg / kg respectively, p <0.05).). These data suggest an effect similar to the anxiolytic Cpd A administered peripherally.

Blocking of the effects similar to the anxiolytics of cpd A by an oxytocin receptor agonist penetrating the brain.

To determine whether the effects similar to the anxiolytics of CPDA are mediated by the oxytocin receptor (OTR), cpd B, a penetrating OTR antagonist of the brain, is administered in combination with cpd A. Cpd A (10 mg / kg , ip) increases the crosses punished compared to the vehicle (p <0.05, Fig. 3). Coadministration of cpd B (10-30mg / kg, ip) blocks the anxiolytic-like effect of cpd A in a dose-dependent manner (63% and 100% inverse for 10 and 30 mg / kg respectively), which attains importance in the dose 30 mg / kg p < 0.05). Cpd B ho has had an effect on crosses punished when administered alone. These data indicate that the OTR antagonist cpd B blocks the anxiolytic effect of cpd A in the four-plate model.

Veh 10 Fig. 1. Effects similar to oxytocin (ug, ív) of four mouse plates. The central administration of oxytocin (1-10 μg, 30 minutes before testing) produces a dose-dependent increase in crosses punished, suggesting an effect similar to the anxiolytic. * p < 0.05 compared to vehicle group (Veh), n = 10 per group.

Veh 3 10 30 100 Fig. 2. Effects similar to the anxiolytics of the Cpd A non-peptide oxytocin receptor agonist in the model of four of four mouse plates. Peripheral administration of Cpd A (3-100 mg / kg, 30 minutes before testing) increases the number of crosses punished. Which suggests an effect similar to the anxiolytic. * p < 0.05 compared to vehicle group (Veh), n = 10 per group.

Cpd A (10 mg / kg, i.p.) Cpd B (10-30 mg / kg, i.p) Fig. 3. The Cpd B dose-dependent non-peptide oxytocin receptor antagonist blocks the anxiolytic effect of Cpd A in the four-plate model. The Cpda A 10 mg / kg, ip, 30 minutes before the test) increases the crosses punished, which is blocked by the coadministration of Cpd B (10-30 mg / kg, 30 minutes before the test). * p < 0.05 compared to vehicle (Veh) ** p < 0.05 compared to cpd A, n = 10 per group.

Oxytocin Receptor Agonists as antipsychotics: METHODS AND MATERIALS The inhibition of acoustic startle reflex (PPI) prepulse is an operational measurement of sensorimotor blockade that can be measured across many species. Deficits in PPI have been reported in patients with schizophrenia, which leads to its use as a preclinical model of the disease. In rats, the PPI is reduced in a way that is similar to that seen in schizophrenia after the administration of certain psychotomimetic drugs (for example MK801, amphetamine). In our study we use MK801, a non-competitive NMDA antagonist and d-Amfetamine, a non-selective dopamine agonist. The MK801 (0.1 mg / kg se, 10 min before testing) and d-Amfetamine (4 mg.kg se, before testing) produced significant interruption through three prepulse intensities (5db, 10db and 15db).

Animals: Rats derived from Sprague-Dawley (SD) males weighing 200-250 g are grouped in standard bed cages. They are allowed access to water and food ad libitum, and are kept in a 12-hour dark light cycle. All behavioral tests are developed in the light cycle. All studies are previously approved by the Institutional Animal Use and Care Committee, and are developed in accordance with the Laboratory Animal Use and Care Guide as adopted and promulgated by the National Institute of Health.

Test Compounds: The oxytocin agonist Cpd A is dissolved in 1% Tween-80/1% DMSO / saline vehicle. The MK801 (Sigma, St Louis MO) is dissolved in 2% Tween-80 / saline. The d-Amafetamine (Sigma, St. Louis MO) is dissolved in saline.

Test equipment Each test chamber (SR-LAB System, San Diego Instruments) consists of a Plexiglas cylinder (8.8 cm in diameter) mounted on a frame and held in position by four metal pins to a base unit. The movement of the rat inside the cylinder is detected by a piezoelectric accelerometer attached below the frame. A 24 cm speaker mounted above the cylinder provides white and background noise, acoustic noise blasts and acoustic prepulses. The entire device is housed in a ventilated enclosure (39 x 38 x 56 cm). The presentation of the acoustic pulse and the prepulse stimulus are controlled by the SR-LAB software and the interface system, which also digitizes, rectifies and records the responses of the accelerometer. The average startle amplitude is determined by averaging 100.1 ms readings taken from the start of the pulse stimulus. For calibration purpose, sound levels they are measured with a Quest sound meter, the "A" scale with the microphone placed inside the Plexiglas cylinder.

Test Sessions The test sessions begin when the rats are placed in the startle chambers during a 5 min acclimatization period with 64db (A) of white noise background. After the acclimation period, the rats are exposed to four types of stimuli. The stimulus that elicits the startle is a 20-ms bandwidth at a sound pressure level of 120 dB (A). Three different intensities of auditory prepulse stimuli are used. These consist of 69.74 or 79 dB (A), an explosion of 20-ms bandwidth that presents 100-ms (start to start), before the startle pulse. These four test types are presented against a constant of 64 dB (A) of white noise background. A test session consists of an initial pulse stimulus, followed by 15 sequences of 4 types of stimulus, presented in pseudo-Alteat order, for a total of 61 trials. The intraassay intervals averaged 15 s.

Evaluation of results The startle amplitude is defined as the average value of the pulse-only tests. To evaluate the effect of drug treatment on the startle response, data from single-pulse trials are analyzed using one-way ANOVA with repeated measurements (one-way randomized block design), followed by a post hoc minus difference test significant (LSD) (the comparison is made with vehicle / interruption control agent). The prepulse inhibition is defined as 100 - [(startle amplitude tests in prepulse / pulse start only amplitude tests) x 100]. Although the data is generated to block the three different prepulse strengths, an average blocking rating is calculated across all the prepulse strengths, and this is analyzed by the ANOVA factor with repeated measurements (one-way randomized block design). . This is followed by a post hoc LSD. The criterion for the significance of alterations in the startle amplitude and the PPI is established in PO.05.

Results We observed that oxytocin (.04 - 1 mg / kg s.c.) reversed the deficits induced by MK801 in PPI in rats in a dose-dependent manner (data not shown). This observation is in agreement with the published observations (Feifel &Reza, Oxytocin modulates psychotomimetic-induced deficits in sensomotor gating, Psychopharmacology (Berl) 141 (1): 93-8 (1999)). Oxytocin has been implicated for playing an important role in the modulation of the gutamérgica and dopaminergic regulation of PPI and oxytocin can thus act as a novel endogenous antisychotic agent. We observed that MK801, a non-competitive NMDA antagonist (0.1 mg / kg sc 10 min before testing) produces significant interruption in PPI through three prepulse identities (XPPI treatment interaction, p <0.05, Fig. 4B) without effect alone in startle (p> 0.05, 4B). Cpd A (3-30 mg / kg, i.p.), a different peptide agonist of the reversed MK801 OTR induces deficits in PPI at levels 10dB and 15dB in the highest doses tested (30mg / kg, Fig. 4A). d-Amfetamine, a non-selective dopamine agonist, (4 mg / kg s.c., 10 min before testing) produces significant disruption across the three prepulse identities (XPPI treatment interaction, p <0.05, Fig. 5B). The Cpd A (HCl salt) (10 mg / kg i.p.) a non-peptide agonist of the interruption induced by reverse d-amphetamine OTR at 5 dB and 10dB; Cpd A (HCl salt) at 30 mg / kg, i.p. reverse the interruption induced by d-amphetamine at 10dB (Fig. 5a). Collectively, this evidence suggests the clinical utility of OTR agonists as antipsychotics.

* MK801 produces significant interruption through all three prepulse intensities • 30 mg / kg reversed in MK801 induces interruption in 10dB and 15dB Fig. 4. Effects of Cpd A on startle response and interrupted PPI MK801 in rats. The MK801 (0.1 mpk, 10 min pretreatment) produces significant interruption through all three prepulse strengths tested. The Cpd A (3, 10, 30, mg / kg i.p., 30 mins before test) reverses the deficit induced by MK801 at 10dB and 15dB.

G dB 10 dB 15 dB or o. Intensity percentage (dB above background noise) B VeftfVeh Veh / Amph 3íAmp ?? lO mpíi SaiAiap * d-Amphetamine produces significant interruption through all three prepulse intensities # 10 mg / kg reverse amphetamine-induced interruption at 10 dB and 15 dB Fig. 5. Effects of Cpd A (HCl salt) on startle response and interrupted PPI induced by d-amphetamine induced in rats. d-Amfetamine (4 mg / kg, it is 10 minutes pretreatment) produces significant interruption through all three pulse intensities tested. Cpd A (HCl salt) (10 mg / kg ip, 30 mins before test) deficit induced by d-amfetamine reversed in 5dB and 10 dB.

Cpd A (HCl salt) (30 mg / kg ip, 30 mins before test) interruption induced by d-amphetamine reversed by 10 dB.

When ranges are used here for physical properties such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of specific range modalities are intended to be included.

The description of each patent, patent application, and publication cited or described in this document are incorporated herein in their entirety; Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as long as they fall within the true spirit and scope of the invention.

Claims (17)

1. A method for treating schizophrenia or a disorder related to schizophrenia, anxiety or an anxiety-related disorder comprising administering to a mammal a compound of Formula 1, or a pharmaceutically acceptable salt thereof: where: G1 is (I) where A3 is S; NH; N-alkyl d.3; -CH = CH- or CH = N; A4 is CH; A5 is CH; A6 is NH; A7 is C; A8 is N- (CH2) d-R7; A9 is N; A10 is CH and An is C; where d is 1, 2 or 3; and R7 is selected from hydrogen; Alkyl d.3; optionally substituted phenyl; OH; O-alkyl; O-acyl; S-alkyl; NH2; NH-alkyl; N (alkyl) 2; NH-acyl; N (alkyl) -acetyl; CO2H; CO2- alkyl; CONH2; CONH-alkyl; CON (alkyl) 2; CN; and CF3; R1, R2 and R3 are each independently selected from hydrogen; I rent; Fl or Cl; a is 1 or 2; b is 1, 2 or 3; X1 is O or NH; and R4 is selected from

2. The method of claim 1, wherein G1 is

3. The method of claim 1, wherein R2 is methyl.

4. The method of claim 1, wherein R 4 is

5. The method of claim 1, wherein X1 is NH.

6. The method of claim 1, wherein the compound of Formula 1 is: a) 2-Methyl-4- (3-methyl-4, 10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of 4, - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; b) 2,6-dimethyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzoClafzulene-9-carbonyl) -benzylamide of 4, - (3 , 5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; c) 3-Chloro-4- (3-methyl-4, 10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of 4, - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; d) 2-Fluoro-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of acid 4, - (3,5-Dihydroxy-benzyl) -piperazine-1-carboxylic acid; e) 2-methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of 4, - (3-Dimethylcarbamoyl-benzyl) -piperazine-1-carboxylic acid; Y f) 2-Methyl-4- (3-methyl-4,10-dihydro-3H-2,3,4,9-tetra-aza-benzo [f] azulene-9-carbonyl) -benzylamide of acid 4, - (3-Dimethyl-tiocarbamoyl-benzyl) -piperazine-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein the compound of Formula 1 is administered with at least one pharmaceutically acceptable excipient.

8. The method of claim 1, wherein the mammal is a human.

9. A method for treating schizophrenia or a disorder related to schizophrenia, anxiety, or an anxiety-related disorder, comprising administering to a mammal a compound of Formula 2, or a pharmaceutically acceptable salt thereof: where: (II) where A3 is S; NH; N-C 1-3 alkyl; -CH = CH- or CH = N; A4 is CH; A5 is CH; A6 is NH; A7 is C; A8 is N- (CH2) d-R7; A9 is N; A10 is CH and An is C; where d is 1, 2 or 3; and R7 is selected from hydrogen; C1-3 alkyl; optionally substituted phenyl; OH; O-alkyl; O-acyl; S-alkyl; NH2; NH-alkyl; N (alkyl) 2; NH-acyl; N (alkyl) -acetyl; CO2H; CO2- alkyl; CONH2; CONH-alkyl; CON (alkyl) 2; CN; and CF3; Ri, R2, and R3 are each independently selected from the group consisting of hydrogen; I rent; O-alkyl; Fl; Cl; or Br; XT is NH or O; R and R5 are each independently selected from the group consisting of hydrogen; O-alkyl; O-benzyl; and F; or R and R5 both are = O; -O (CH2) aO-; or -S (CH2) aS-; a is 2 or 3; And it is O or S; Y G- is (CH2) h \ > (CH2) ¡(III) where h is 1 or 2; I is 1, 2 or 3; and X2 is N-alkyl.

10. The method according to claim 9, wherein G2 is:

11. The method according to claim 9, wherein two of R1, R2 and R3 are hydrogen and the other is not hydrogen.

12. The method according to claim 9, wherein XT is NH.

13. The method according to claim 9, wherein R4 and R5 are each independently selected from hydrogen and O-alkyl.

14. The method according to claim 9, wherein G ^ is 1-Methyl- [1, 4] diazepam.

15. The method according to claim 8, wherein the compound of Formula 2 is: a) 4-Methyl-1- (N- (2-methyl-4- (2,3,4,5-tetrahydro-1,5-benzodiazepin-4-on-1-yl-carbonyl) benzylcarbamoyl) -L- thioprolyl) perhydro-1,4-diazepine; b) 4-Methyl-1- (N- (2-methyl-4- (1-methyl-4,10-dihydropyrazolo [5,4-b] [1,5] -benzodiazepin-5-ylcarbonyl) benzylcarbamoyl) - L-thioprolyl) perhydro-1,4-diazepine; c) 4,4-dimethyl-1- (N- (2-methyl-4- (1-methyl-4,10-dihydropyrazolo [5,4-b] [1,5] -benzodiazepin-5-ylcarbonyl) benzylcarbamoyl ) -L-tiprolil) perhydro-1, 4-diazepine; d) 4-Methyl-1- (N- (2-methyl-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-4-ylcarbonyl) -benzylcarbamoyl) -L-thioprolyl) perhydro -1, 4-diazepine; e) 4-Methyl-1- (N- (2-methyl-4- (5,6,7,8-tetrahydrothieno [3,2-Ib] azepin-4-ylcarbonyl) -benzyloxycarbonyl) -L-prolyl) perhydro -1, 4-diazepine; f) (4R) -Na- (2-chloro-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-4-ylcarbonyl) benzyl-carbamoyl) -4-methoxy-L-proline -N-methyl-N- (2-picolyl) amide; or g) 1 - ((4R) -Na- (2-chloro-4- (5,6,7,8-tetrahydrothieno [3,2-b] azepin-4-ylcarbonyl) benzyl-carbamoyl) -4-methoxy- L-prolyl) -4- (1-pyrrolidinyl) piperidine; or a pharmaceutically acceptable salt thereof.

16. The method of claim 9, wherein the compound of Formula 2 is administered with at least one pharmaceutically acceptable excipient.

17. The method of claim 9, wherein the mammal is a human.