TWI325000B - (pyrido/thieno)-[f]-oxazepin-5-one derivatives - Google Patents

Description

1325000 Ministry of Economic Affairs Zhizhi Property Bureau Completion Consumption Cooperatives Printing A7 B7 V. Inventive Note () The present invention relates to (pyrido/thieno)-[f]monooxazepine-5-one derivatives, including The use of the pharmaceutical composition and these (pyrido/thieno)-[f]-oxazepine-5-one derivatives for the treatment of neurological and psychiatric disorders. In the mammalian central nervous system (CNS), the conduction of nerve impulses is controlled by the interaction between the neurotransmitters > which are released by the sending neurons, and receive surface receptors on the neurons, which cause the nerves to receive The stimulation of the yuan. L-glutamate is the most abundant neurotransmitter in C N S. It regulates the major stimulation pathway in mammals and is called stimulating amino acid (EAA). These excitatory amino acids are physiologically important and play a variety of physiological processes such as learning and memory, the development of synaptic plasticity, motor control, respiration, cardiac vascular regulation and sensory perception. The receptor for the reaction glutamate is called the excitatory amino acid receptor (E A A receptor). These receptors are classified into two general types: (1) "ionotropic" receptors that directly bind to the opening of the cation conduit in the cell membrane of the neuron, and (2) G-protein linked "metabolism Metabotropic receptors that bind to a variety of secondary messenger systems leading to increased hydrolysis of phosphoinositide, activation of phospholipase D, increase or decrease in c-AMP formation, and changes in ion channel function. The receptor can be subdivided into three subtypes pharmacologically with a selective activator N_methyl_D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl Definition of Depolarization of Azoyl-4-propionic Acid (A Μ PA ) and Kainic Acid (KA) Synaptic A Μ Activation of PA Receptor Regulates Voltage Independently Fast (~ (Please read the back note first) Fill in this page again) i The standard paper size applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm) -4- 1325000 A7 B7 V. Invention Description (Ministry of Economics M-Property Bureau Xiaogong Consumer Cooperative Print 3⁄4 1 Ms reached high point response) excitability Post-synaptic currents (rapid EP s C ), while activation of synaptic NMDA receptors produces voltage-dependent, slow (~20 ms to high-point response) excitation currents. Regional distribution of AMP A receptors in the brain suggests The AMP A receptor regulates synaptic transmission in such a region that responds to cognitive and memory. A Μ PA receptor is thought to be the receptor responsible for the rapid opening and closing of the ion channel by activation of the activator. Configuration changes. The extent and duration of tube activation can be reduced by drugs, which act as negative allosteric modulators (eg, GYKI 52466), or they can be enhanced by drugs, which act as positive allosteric modulators. The structural class of the positive regulator of AMP A receptors in aniracetam (eg CX 5 16) is called Ampakines. The positive regulator of AMP A receptors can therefore bind to the glutamate receptor and, later, The binding of the agonist to the bundle allows for increased passage of ions through the receptor. The disadvantages of gluten-induced neurotransmission may be associated with many human neurological and psychiatric disorders. Positive A Μ PA receptor modulator In the treatment of neurological and psychiatric disorders The efficacy has been achieved by Yamada, K. A. (Exp. Opin. Invest · Drugs, 2000, 9, 765-777), Lees, G. J. (drugs, 2000, 59, 33-78) and Grove S · J. A. · et al. (Exp · Opin. Ther patent, 2000, 10, 1 539-1 548) commented. Various compounds that increase the function of the A Μ P A receptor have been recognized and recently reviewed by Grove S. J. A. et al. (supra). N-Fenyl fluorenyl-2-oxoridone (Anracacetam; 1^0£; 1^) is considered to be a ^11^31^6^ prototype (please read the notes on the back and fill out this page) The standard paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -5- 1325000 A7 B7 V. Description of invention (^ (Ito, I. et al., J. Physiol. 1990, 424, 533-543), after Some sulfonamides (such as cyclothiazepine, Eli Lilly & Co) were soon discovered as AMPA regulators (Yamada, K. A. and R〇thman, S. Μ., J. Physiol., 1992, 45 8,385). -407). Based on the structure of aniracetam, its derivatives with improved efficacy and stability have been developed by Lynch, G.S. and Rogers G. A., as in international patent application W〇94/02475 (The Regent of the University of California) The additional ampakines in the form of benzamidine and pyrrolidines were later disclosed in W096/38414 (Rogers, G. A. and Nilsson L.,; Cortec a pharmaceutical compound, followed by a compound in which the indoleamine functional conformation is restricted to the morphine morphine ring system, such as WO 97/36907 (Rogers G. A. and Lynch. G., The Regent) Compounds disclosed in the University of California; Cortec Pharmaceuticals, or restricted to the thiol benzoxanthene ring system, such as WO 99/5 1 240 (Rogers G · A · and Johnsti. om, P., The Regent Revised in the University of California. Structurally related to the structural derivatization of benzoindole derivatives and especially 1,2,4-benzothiazepine-1,2-dioxide, cyclothiazepineTM It has been shown to be a positive regulator of AMPA receptors in WO 99/42456 (NEUROSEARCH A/S). Positive AMP A receptor modulators have many useful applications in humans. For example, increasing the intensity of excitatory synapses can compensate Loss of synapses or receptors associated with aging and brain diseases (Aizheimer's disease, for example). Increased A Μ PA receptor-modulating activity can be more rapidly processed by multiple synaptic circuits found in higher brain regions And therefore it can produce an increase in perceptual movement and intelligence. A mpakines is further recommended to be effective as a memory enhancer. This paper scale applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) ------- -_%1_ (Please read the back first In addition, please fill out this page.) Department of Economic Affairs, Intellectual Property Office, Poverty Alleviation Cooperative, Printed -6 - 1325000 A7 __B7_ V. Description of Invention (4) To improve individuals with perceptual-motion problems and rely on the use of A Μ PA receptors The cognitive work of the brain network is compromised, treating individuals with stagnation, alcoholism and schizophrenia, and improving the effectiveness of the recovery of injured individuals. On the other hand, sustained AMP A receptor activation has been observed in experimental animals (for example, at high doses of some A Μ PA modulators, especially effective inhibitors of such receptor sensitization), which can cause bursts and It may also cause other anterior side effects (Yamada, K. A., Exp. Opin. Invest - Drugs, 2000, 9, 765-7 7 7). From the standpoint of the efficacy of A Μ P A receptor activation (especially by the thiadipine class of regulators) in terms of excitotoxicity, there is still a need to develop positive regulators with therapeutic indices. For this purpose the invention provides (pyrido/thieno)-[f]-oxazepine-5-one derivatives of the formula I, 0

Wherein R1, R2 and R3 are respectively hydrazine or (Ci-4)alkyl; A r represents a fused thiophene or pyridine ring, and one or more selected from (C i - 4 ) alkyl, (C ! - 4) Alkoxy, (C 1 - 4 ) alkoxy (Ci-4), CF3, halogen, nitro, cyano, NR4R5 This paper scale applies to Chinese National Standard (CNS) A4 (210X 297) ()) (Please read the note on the back and then fill out this page) Order the Ministry of Economic Affairs Zhizhi Property Bureau, the consumer and consumer cooperatives printed 1325000 A7 B7 V. Invention description (j fused 咐 D or thiophene ring. The acridine ring can be fused to provide D-pyridyl and [3,2-f]-, pyrido[4,3 _f]_, pyridin [3,4-f]- or pyridine. [2,3—f]—Possible bond of a fused ring. The porphin ring condensation can occur by providing three thieno[2,3—ί]-, thieno[3,4—f]- or thiophene, respectively. [3,2 -f] - possible bond of a fused ring. The term (Ci-4)alkyl is used as a branched or unbranched alkyl group having 1 to 4 carbon atoms as defined in the formula. Butyl, isobutyl, tert-butyl propyl , isopropyl, ethyl and methyl. In the term (C i - 4 ) alkoxy, (C i - 4 )alkyl has the meaning defined above. S (Cl-4) Cl-4) A (Ci-4)alkyl group which is not substituted by a (Cl-4) alkoxy group, both of which have the meanings defined above. The term halogen means F, C 1 , B r or I. In the definition of I, R 4 and R 5 may form a 5- or 6-membered saturated heterocyclic ring together with the nitrogen atom to which they are bonded, and optionally comprise a further hetero atom selected from 0, S or NR 6. These heterocyclic substituents Examples are N-piperidinyl, N-pyrrolidinyl, morpholinyl, N-methyl-piperidinyl, N-ethyl-piperage and the like. In the definition of formula I, A represents 4 - The residue of a 7-membered saturated heterocyclic ring optionally contains an oxygen atom, meaning that A is a divalent group containing 2 to 5 carbon atoms, such as an extended ethyl group, a 1,3 ~ stretching propyl group, and a 1,4- butyl group. Base, 1,

5 _ pentyl group, one of which carbon atoms can be replaced by oxygen. Residues A and A This paper size applies to the Chinese National Standard (CNS) A4 specification (2丨0X297 mm) ---------— (Please read the notes on the back and fill out this page) Ministry of Finance, M Finance, 1 Bureau, S-Bone, Co-Bone Co-operative, Printing - 9-1325000 A7 _____B7 V. Description of Invention () The example of the 4-7-membered heterocyclic ring formed by the bonded nitrogen and carbon atoms is 吖丁定定, Pyrrolidine, piperidine, oxazolidine, isoxazole, morphine, and azepane. Preferred is a (pyrido/thieno)-[f]-oxazepine-5-one derivative of the formula I, wherein R1, R2 and R3 are Η» more preferably of the formula I (pyridyl/thiophene - [f] a oxazepine _5-ketone derivative, wherein Ar is a fused thiophene ring in which [3,2-f] is fused with D or a pyridine ring or [2,3 - f]. The (pyrido/thieno)-[f]monooxazepine-5-one derivative of the present invention can be produced by a method generally known in the art of organic chemistry. More specifically, such compounds can be prepared by using the procedures reviewed by A. G. Schultz et al. (J. Org. Chem. 1986, 5 1, 838-841) or by modification of such routes. (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Zhisheng Property Bureau, Xiaogong Consumer Cooperative, India

The (pyrido/thieno)-[f]-oxaza-5-one derivative of formula I can be prepared, for example, by cyclization according to a compound of formula II, wherein AI·, A and Ri-R3 have The meaning of the foregoing definition, any functional group having an acid hydrogen protected by a suitable protecting group, and wherein Q represents a hydroxyl group, a halogen or a (Ci-4) alkoxy group, and then removing any protecting groups (when the paper size is applicable to the Chinese country) Standard (CNS) A4 size (210X 297 mm) -10 - 1325000 A 7 B7 _5. Description of invention (where present). Cyclization of compounds in which Q is halogen or (C 1-4) alkoxy It can be carried out in a solvent such as dimethylformamidine and at a temperature of from 0 to 200 ° C, preferably from 25 to 150 ° C in the presence of a base such as sodium hydride or carbonic acid. a compound of formula II wherein Q is hydroxy, cyclization can be carried out under Mitsunobu conditions (Mitsunobu, 0., synthesis 198,1) using triarylphosphines (such as, for example, triphenylphosphine) and azodicarboxylic acid A dialkyl ester such as diisopropyl azodicarboxylate is produced in a solvent such as tetrahydrofuran. Suitable protecting groups for temporarily protected functional groups are known in the art, for example from Wuts, P. G. Μ and Greene, T. W.: Protective Groups in Organic Synthesis, Third Edition, Weiss , New York, 1999. (Please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Office, Negotiation for Poverty Alleviation, Printed Formula III, Formula IV, Compounds of Formula II, which can be derived from compounds of Formula III (wherein Ar and Q have the meanings defined above and oxime represents a carboxylic acid or a derivative thereof, such as a carboxylic acid The ester or carboxylic acid halide, preferably chloride or bromide, is prepared by the condensation of a compound of formula IV wherein R1-!^3 and hydrazine have the meanings defined above. When hydrazine represents a carboxylic acid, the condensation reaction (ie, deuteration) can be carried out by means of a coupling agent (for example, carbonyldiimidazole, dicyclohexylcarbodiimide and the like) in a solvent (for example, dimethyl group). Produced in guanamine or dichloromethane). When hydrazine represents a carboxylic acid halide, the amine scale with the amine derivative is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) -11 - 1325000 A7 B7 5. Inventive Note (The condensation of IV can be in the base (for example The presence of triethylamine) is carried out in a solvent such as dichloromethane. When hydrazine represents a carboxylic acid ester derivative, direct condensation with the amine derivative of formula IV can be carried out at elevated temperatures (for example, at about 50 to 20) This condensation can also be carried out using a Lewis acid (for example aluminum trichloride) such as D. R. Barm et al. (Biorg. Med. Chem. Lett., 1 999, 9, 1329-34). The preparation of the compound of the formula I can be carried out by using the above-mentioned method by using a one-pot two-stage step of the compound of the formula II, which is obtained from the condensation reaction between the compound of the formula III and the compound of the formula IV, without isolation from the reaction mixture. Further treatment with a base to produce a compound of formula I. ------------ (Please read the notes on the back and fill out this page) 0

The compound of formula II can also be obtained from a compound of formula V (wherein Ar, R3 and A are as defined above and T represents hydrogen, C(1-4)alkyl or alkoxy) and C^-4)alkyl metal reagent ( For example, a Grignard reagent is prepared in a solvent such as tetrahydrofuran. Compounds of formula II (wherein R 1 represents hydrogen and alkyl) can be prepared from a compound of formula V wherein T represents C(i-4)alkyl as a reduction (e.g., sodium borohydride) in a solvent such as ethanol. The compound of formula V (T represents alkoxy) can be derived from a compound of formula III as described in DE. Thurston et al. (Soc. Chem. Commun., 1990, 874-876) (wherein Μ represents a carboxylic acid chloride and a derivative) The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) f by the IK Ministry of Intelligence Assets Bureau a X Feihe Printing System

R 2 represents C -12- 1325000 A7 B7 V. Description of invention ()

TO is prepared from an alkanolamine imine of an alkyl glycolate. Compounds of formula V may be prepared by coupling a compound of formula III and IV, wherein a compound of formula III wherein Ar, M and Q are as defined above, and a compound of formula VI (wherein R3, A and T have the meanings as defined above) )preparation.

T

Compounds of formula V I I I I , IV and VI are available from commercial sources and are prepared by modifications to the literature procedures or literature procedures known to those skilled in the art. It will be understood by those skilled in the art that various compounds of formula I can be obtained by appropriate conversion reactions of the functional groups corresponding to certain substituents on the aromatic ring. For example, (Ci-4) a base alcohol and a compound of formula I (wherein ar, A and R1 - R3 are as defined above, and one or more substituents on the Ar ring are, for example, but not limited to Reaction of a fluoro or chloro group in the presence of a base such as sodium hydride to give a compound of formula I wherein one or more substituents on the Ar ring are (Ci-4)alkoxy) one or more The compound of formula I wherein the substituent on the A r ring is C〇NR4R5 can be subjected to a carbonylation reaction catalyzed by palladium(II) (e.g., dichlorobis(triphenylphosphine)palladium) as described by A. Schoenberg et al. J. Org Chem. 1 974,39,3 3 1 8 ), converting one or more compounds of formula I having a substituent on the A r ring to a corresponding carboxylic acid ester to form a paper size for use in China Standard (CNS) Λ4 specification (2丨0><:297 mm) (Please read the note on the back and fill out this page)

*1T Ministry of Economic Affairs, Wisdom, Finance, 1st Bureau, Employees, Bone Cooperative, Printed -13- 1325000 A7 B7

V. Description of the invention (A (please read the precautions on the back and fill out this page). Preparation of ester to saponification of carboxylic acid 'Use sodium hydroxide such as in tetrahydrofuran-water, and carboxylic acid with amine of formula nhr4r5 Cooperating with 'using, for example, carbonyldiimidazole as a coupling agent' to produce a compound of formula 1 (wherein one or more substituents on the Ar ring is C〇NR4R5). To a compound of formula I (one or more of which is on the Ar ring) The carboxylic acid precursor having a substituent of C Ο NR 4 R 5 ) can be oxidized by using a compound of the formula I (in which one or more substituents on the Ar ring is a methyl group) using an oxidizing agent such as chromium trioxide. The preparation of the compound of formula I (wherein one or more substituents on the Ar ring is C〇NR4R5) can be carried out by using the method described by A. Schoenberg and R. F. Heck (J. Or g.

Chem. 1974, 39, 33 27 ), by a compound of formula I wherein one or more substituents on the A r ring are halo, palladium(II) in the presence of an amine of the formula NHR4R5 (eg dichlorobis ( Triphenylphosphine)palladium) catalyzed carbonylation preparation. Printed by the Ministry of Economic Affairs, Zhisheng Property Bureau, Completion Consumer Cooperative

The compound of the formula I in which one or more of the substituents on the A r ring is CN may be a C 0NH 2 substituent from one or more of the A r rings by dehydration using a dehydrating agent such as phosphorus oxychloride. Preparation of a compound of formula I. The compound of formula I wherein one or more of the substituents on the A r ring is CN may be subjected to an iE (0) catalyzed cyanation reaction as described in M. A11 e 1. ma η and A · H a 11 berg (J. Org. Chem. 2000, 65, 7984) is prepared from a compound of formula I wherein one or more substituents on the Ar ring are bromo or iodo. One or more of the compounds of formula I wherein NR4R5 has a substituent of NR4R5 may be substituted by halogen of the formula NHR4R5 from one of the paper scales or to the Chinese National Standard (CNS) Α4 grid (210Χ 297 mm) ) -14 - 1325000 A7 __B7_ V. INSTRUCTION DESCRIPTION (彳) 2 The above compound of the formula wherein the substituent on the A r ring is a fluorine group or a chlorine group is prepared. A compound of formula I wherein one or more substituents on the A r ring are NR4R5 can be as described by J. P. Wolfe et al. (J. Org. Chem. 2000, 65, 1158) by an amine of the formula NHR4R5. The palladium catalyzed amination reaction is prepared from a compound of formula I wherein one or more substituents on the Ar ring are a chloro, bromo or iodo group. A compound of formula I wherein one or more substituents on the A r ring are NR4RS and one of R4 or R5 is hydrogen may be bonded to the formula C(1-4)alkyl Y by a nitrogen atom (wherein Y is a leaving group, for example The alkylation of an alkylating agent of an alkyl or aryl sulfonate, a chloro group, a bromo group or an iodine group is carried out by using a substituent on one or more of the Ar ring as NR4R5 and R4 and R5 are both hydrogen. Preparation of a compound of formula I. One or more of the substituents on the A r ring are NR4R5 and the compounds of formula I wherein R4 and R5 are both ruthenium may be subjected to a reduction reaction such as a palladium-catalyzed reduction reaction with hydrogen from one or more of the A r rings. The preparation of a compound of formula I wherein the substituent is a nitro group. The compound of formula I wherein one or more substituents on the A r ring are NR4C OR6 may be a compound of formula I wherein one or more substituents on the A r ring are NHR4, such as C (i - 5) Preparing a compound of formula I (wherein A represents a residue of a 4- to 7-membered saturated heterocyclic ring substituted with 1 to 3 hydroxyl groups) by treatment with mercapto chloride or an anhydride such as acetic anhydride in a solvent such as pyridine Treatment of a base such as sodium hydride in a solvent such as tetrahydrofuran with an alkylating agent of formula C(i-4)alkyl Y (wherein Y is as defined above) wherein A represents selectivity by 1-3 A compound of formula I wherein the alkoxy group is substituted with a residue of a 4-7 membered saturated heterocyclic ring. In the compound of formula I, where A is substituted by 1-3 hydroxy groups, the paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (21〇Χ 297 mm) --------~^. - (Please read the notes on the back and fill out this page.) Order f Ministry of Economic Affairs Zhici Property Bureau Staff Dismantling Cooperatives India Purple-15- 1325000 Ministry of Economic Affairs Zhici Property Bureau Staff Consumer Cooperatives Printed Β7 Β7 V. Invention Description ( a residue of a 7-membered saturated heterocyclic ring which can be treated with a halogenating agent such as triethyl (diethylamino) sulfur (DAST) or a carbon tetrachloride-triphenylphosphine composition And substituted by halogen. Similarly, a compound of formula I wherein six of the residues representing a 4- to 7-membered saturated heterocyclic ring having the same carbon atom selectively substituted by two halo groups can be treated by a halogenating agent (for example, DAST). Prepared from the corresponding keto-derivatives. Compounds of formula I wherein A represents a residue of a 4-7 membered saturated heterocyclic ring which is optionally substituted by 1 to 3 hydroxy groups, with an oxidizing agent such as R.E. Ireland and Swern oxidation as described by D. W. Nor beck (J. Org. Chem. 1 985, 50, 2 1 98-2200) Wherein A represents a compound of formula I which is a residue of a 4- to 7-membered saturated heterocyclic ring which is optionally substituted with 1 to 3 keto groups. (Pyridino/thieno)-[f]monooxazepine-5 of formula I The ketone derivatives and their salts comprise at least one palmitic center, and thus stereoisomers, including enantiomers, and, if appropriate, diastereomers are present. The scope of the invention includes the above stereoisomers And the individual R and S enantiomers of the compounds of formula I and their salts, substantially free, that is, with less than 5%, preferably less than 2%, especially less than 1% of the other enantiomer, and any Mixtures of such enantiomers, including asymmetric mixtures of such races containing substantially equal amounts of the two enantiomers, to obtain pure stereoisomers in the art are Conventional, for example, the synthesis using a palmitic derivatization or the synthesis starting from a palmitic intermediate, the conversion of an enantioselective enzyme, using a stereoisomer or enantiomer of a chromatography assay on a palm medium Separation of structures. Such methods, for example, disclose that the paper size is appropriate China National Standard (CNS) A4 Specification (2丨OX297 吨t) 1 I n 1 I 1· n Ί. II nn (Please read the notes on the back and fill out this page) -16- Ministry of Economic Affairs. 3⁄4 Property Bureau S (Working Consumer Cooperatives Printed 1325000 A7 _______B; / __ V. Invention Description (in Chirality in Industry (edited by ANCollins, G. N. Sheldrake and J. Crosby, 1992; John Weiss)" can be applied to this A specific method for the stereoselective preparation of the inventive aryloxazepin-5-one derivatives is those described by Schultz, AG et al. (J. Org. Chem. 1 986, 5 1, 838-84 1 ). . The pharmaceutically acceptable salt can be obtained by using a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid or an organic acid such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, and anti-butyl Treatment with alkaloids, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like is obtained according to the free base of the compound of formula I. The compounds of the invention may exist in dissolved and undissolved form with pharmaceutically acceptable solvents such as water, ethanol and the like. Generally, for the purposes of the present invention, the dissolved form is considered to be equivalent to the undissolved form. The present invention further provides a pharmaceutical composition comprising a (pyrido/thieno)-[f]monooxazepine derivative of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt Additives, and other therapeutic agents are blended. The term "acceptable" means compatible with the other ingredients of the composition and not deleterious to the user thereof. Compositions include, for example, those suitable for oral, sublingual and subcutaneous, intravenous, intramuscular, topical or rectal administration, and the like, all unit dosage forms for administration. For oral administration, the active ingredient may be presented in discrete units such as the tablet 'capsules, powders, granules, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical compositions of the present invention may be present in unit or multi-volume containers, such as a predetermined amount of injectable liquid, such as sealed vials and ampoules, and the paper size applies to the Chinese National Standard (CNS) A4 specification. (2I0X297 mm) ---------------tT------ (Please read the notes on the back and fill out this page) 1325000 A7 B7 V. Invention Description (' Stored under lyophilized (lyophilized) conditions, it is only necessary to add a sterile liquid carrier, such as water, prior to use, in admixture with such pharmaceutically acceptable adjuvants, for example as standard reference, Gennaro, A. R. Remington: Pharmacy Science and Practice (20th Edition, Lippinc〇tt Williams & Wilkins, 2000, especially see Section 5: Pharmaceutical Manufacturing) 'The active agent can be compressed into solid dosage units, such as medicines. 9. A lozenge, or processed into a capsule or suppository. The active agent may be applied to a flowing composition via a pharmaceutically acceptable liquid, such as an injection preparation, in the form of a solution, suspension, emulsion, or by a spray, such as a nasal spray. In order to produce a solid dosage unit, it is intended to use conventional additives such as gargles, colorants, polymeric binders and the like. Generally, any pharmaceutically acceptable additive which does not interfere with the function of the active compound can be used. Suitable carriers for administration together as a solid composition include lactose, starch, cellulose derivatives and analogs, or mixtures thereof, for use in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterilization may be employed. An injectable solution comprising a pharmaceutically acceptable dispersing and/or wetting agent, such as propylene glycol or butylene glycol. The invention further comprises a pharmaceutical composition, as described above, in combination with a packaging material suitable for combination with the composition, The packaging material includes an indication that the composition is used for the aforementioned use. The (pyrido/thieno)-[f]-oxazapine-5-ketone of the present invention is a positive regulator of AMPA receptor, such as by When (pyrido/thieno)-[f]monooxazepin-5-one is present, it is applied in the conventional whole cell temporary circuit clamp method. Determination of the increase in steady state current induced by acid salt (see Example 10 and Table 1). Compounds can be used to treat Chinese paper standards (CNS) A4 specifications (210X297 mm) (please read the notes on the back) Fill in this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Negative Labor Consumer Cooperative Printed -18- 1325000 A7 B7 V. Invention Description (Please read the note on the back and fill out this page). The treatment needs to be increased by A Μ PA. Neurological and psychiatric disorders of the body-regulated synaptic response, such as neurodegenerative diseases, cognitive or dysfunctional dysfunctions, such as aging, attention to disease, 'trauma', stroke, epilepsy, Aizheimei's disease, depression Symptoms, schizophrenia, psychosis, anxiety, sexual dysfunction, a disease caused by autism, or a disease or disorder caused by neurological or substance abuse and alcoholism. The compound of the present invention can be administered to a human in a dose of 0. 00 to 50,000 mg per kg of body weight, preferably at a dose of 0.1 to 20 mg per kg of body weight. The invention is illustrated by the following examples. Example 1. (S) — 2 , 3 , 10 , l〇a-tetrahydro-1H, 5H-pyrrolo[2,lc]thieno[2,3_f][1,4]monooxazepine-5 —ketone oxime

Add 3 to the solution of 3-chlorothiophene-2-carboxylic acid (0.5 g; 6. 325 mmol) in dimethylformamide (5 ml) from the Consumer Cooperative of the Zhici Property Bureau of the Ministry of Economic Affairs. 1, 1, carbonyldiimidazole (1.07 g; 6.4 milmol) and the solution was stirred at room temperature for 1 hour, followed by the addition of (3)-(+)-2~% ||| 0.6 5 5 ml; 6.64 pens). The reaction was stirred at room temperature overnight and carefully added to 60% sodium hydride in mineral oil (this paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) -19- 1325000 A7 B7 Ministry of Economic Affairs and your property bureau Xiaogong Consumer Cooperatives Printing Disaster V. Inventions (2) 4 HEPES buffer solution: 130 mM NaCl, 5.4 m Μ Κ C 1 > 1 Ο m Μ HEPES, l. mM MgCl2, 1.8CCl2, 2.5 mM glucose, Adjust to pH 7.4. Prepare. All brains were excised and placed on sterilized filter paper, soaked in Η B S and removed cerebellum. The brain was minced and added to the enzyme solution (0.5 mg/ml protease X and 〇5 mg/ml protease in HB S), followed by standing at room temperature for 40 minutes before milling to digest. The cells were resuspended and then counted to produce a final concentration of 1 · 5 X 1 0 6 ml. Cells were aliquoted on poly-D-lysine- and Matrigel®-treated cover glass and incubated for 1-2 hours at 37 Torr. When the incubation is complete, each of the covered glass is filled with 1 ml of growth medium and the cells are returned to the incubator. The mitotic inhibitor cytosine arabinoside (5 Μ) was added after 3 - 5 days and the cells were returned to the incubator until needed. Β : Temporary Clips Sweet Record Temporary Clamp Technology Full Cell Configuration (Hamill et al., Pflugers Arch. 198 1, 39, 85-10-00) to measure hippocampal neurons from 4-7 days after maintenance. Glutamine-induced current. The cover glass containing the culture was transferred to a recording chamber (Warner Instruments, Hamden, C T ) mounted on a reverse microscope (Nikon, Kingston UK). The recording chamber contains 1-2 ml extracellular solution (i45mM N a C 1 -5 4 m Μ Κ C 1 · 1 〇m Μ HEPES > 0.8 mM MgCl2, 1.8CaCi2, 10 mM Portuguese paper scale for Chinese national insertion ^ ( CNS ) A4 specification (2i〇X297 mm) (Please read the note on the back and fill out this page) Order -27- 1325000 Ministry of Economic Affairs Zhizhi Property Bureau Lending Workers Poverty Cooperatives Printing " A7 _B7__ V. Invention Description ('glucose and 30 mM sucrose, adjusted to pH 7.4 with 1 M NaOH) and fixed perfusion at a rate of 1 ml/min. Record at room temperature (2 〇 - 2 2 0) using an Axopatch 2 0 0 B amplifier ( Axon Instrument Co., Ltd., Foster City, CA) completed. Data acquisition and analysis using signal software (Cambridge, Cambridge, UK). Pipettes from GC1 20F-1 0 glass (Harvard Instruments, Edenbridge, UK) P — 8 7 electrode puller (Sutter Instruments' Nova Rfo, CA). Temporary circuit electrode when filled with extracellular solution (14 mM mM potassium gluconate, 2 mM HEPES' 1. ImM EGTA, 5 mM phosphoric acid ' 3mM ATP > 0 . 3 m M GTP'O.lmM C a C 1 2 * 5 m M MgCl2 with a typical resistance of 3 - 5 Μ Ω when adjusted to pH 7.4 with 1 M KOH. The cells are clamped at a fixed potential of -6 OmV and use a 12-pipe semi-rapid drug. Supply unit (DAD — 1 2 . Digitimer, Wei wy η Garden, UK) supplies glutamate (0.5 mM). Activator glutamate supplies 1 s every 30 s. Response using whole-cell configuration There is no “decrease” over time. Between supplies, brine flows to remove any dead volume in the system. For each application, steady state current is plotted from the difference between baseline and steady state current and averaged over 300 ms. Two solutions of the compound in the extracellular solution, one with guanamine and one without. The procedure is: supply compound for 10 seconds, supply compound + strontium salt for 1 second, then wash with saline for 10 seconds, then delay 1 0 seconds. When the compound is not dissolved, use 0.5% DMSO as the co-dissolved paper. The Chinese National Standard (CNS) A4 specification (2丨〇Χ: 297 mm)~ (Please read the notes on the back and fill in the following) This page) -28- 1325000 A7 B7 V. Invention Description (' The results are presented in Table I, the present compounds 1 0 # Μ concentration, the percentage increase in steady state current in the extracellular solution. (Please read the notes on the back and fill out this page.) Ordering · Ministry of Economic Affairs, your property bureau ia: Gongxiao f Cooperative printed this paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) - 29- 1325000 A7 B7 V. INSTRUCTIONS (\7 Table 1 Increase in steady state current of compound at 10/ζΜ (5)-2,3,11,113-tetrahydro-1's 5沁pyrrolo[2,1 -£;]pyridin[3,2-qiu,4]-oxazapine-5-one* 22 (5)-2,3,10,1〇3-tetram-1 to 51!-pyrrole [2,14 thieno[2,3-5][1,4]-oxazepine-5-one (Example 1) 32 Shame-2,3,10,Te-tetrahydro-111,5沁pyrrole And [2,1-£:]thieno[2,3-1][1,4]-oxazepin-5-one (Example 2A) 20 (S)-8-trifluoromethyl-2, 3,11,11 heart tetrahydro-1 511-11 pyrrolo[2,1-(:] 嗟 并 [3,2-, 4] oxazepine-5-one (example J 2B) 21 (R)-8-trifluoromethyl-2,3,11,1 la-tetrahydro-1H,5H-pyrrolo[2,lc]thieno[3,2-f][l,4]oxy Azapine-5-ketone (Example 2C) 19 (5)-8-Methyl-2,3,11,113-tetrahydro-111,511-pyrrolo[2,1-£:]pyridine[3,2 -!][1,4]-oxazepine-5-one hydrochloride (Example 3) 12 (5)-8-Chloro-2,3 , 11,113-tetrahydro-1 511-pyrolo[2,1<|pyrido[3,2-£][1,4]-oxazepine-5-one (Example 4A) 16 ( R)-8-Chloro-2,3,11,113-tetrahydro-inden 5沁pyrrolo[2,1-indenyl]pyridoindole, 2-£][1,4]-oxazepine-5 -13⁄4Example 4B) 29 (± )-6,6a,7,8,9,10-hexahydro-12H-Dpiro[2,lc]D is more than pyridine[3)2-f][l, 4]-oxaza-l2-ketone (Example 4D) 13 (5)-7-Chloro-2,3,10, t-tetrahydro-111,51{-pyrrolo[2,丨-(:]thiophene And [3,2-[][1,4]-oxazepine-5-one (Example 5) 16 (R)-7-chloro-2,3,10,-tetrahydro-111,5沁Pyrrolo[2,1-indole:]thienoindole, 2-!][1,4]-oxazepin-5-one (Example 6A) 20 (5)-8-methoxy-2,3,ll ,lla-four gas-1H,5H-卩比略和[2,lc]吼D and [3,2-f][l,4]oxazepine·5-ketone stains 7) 22 * : Prepared as described by Schultz, AG et al. (J. Org. Chem. 1986, 51, 83 8-84 1 ) using alternative designations: 1, 2, 3, 10, 11, 1 la(S)-hexahydrogen -5H.pyrrolo[2,buc]pyrido[3,2-f][l,4]oxazepin-5-one; Sleeve, MC et al. (J. Med. Chem. 1991, 34, 1 3 14- 1 328) The name 6a,7,8,9-tetrahydro-6H has been used, 11H-D is a compound of the compound [3,2-f]pyrrolo[2,buc][l,4]oxazepine-U-ketone. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the back note and fill out this page) Φ. -30- 1325000 A7 B7___ V. Invention Description (& Example 1 1. Differential enhancement of low-rate response, 72 seconds (DRL 7 2 ) Rats are pre-trained in a standard operating room to follow Andrew et al. (Andrew JS, Jansen JHM, Linders S, P rincen A. Drinkenburg WHIM. Coenders CJH And Vossen JHM (1994)). The effect of imipramine and mirtazapine on the performance of rats. Drug development study, 32: 58-66) Complete the DRL72 step. The test period lasted for 60 minutes without limiting the number of trials. Each test begins with an stimulating light on the activated liver. If the rod reaction has passed for 72 seconds, only small sphere delivery is produced. The response on the pole before 72 seconds has reset the timer and is not rewarded. The number of pellets obtained and the number of rod presses were recorded and used to calculate the efficiency rating. The test compound was administered via the intraperitoneal route for 30 minutes before the start of the test period. Antidepressants increase the number of resulting small spheres and reduce the number of rod presses. (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-(:]pyridinium[3,2-{][1,4]oxazepine- 5-ketones appear to be antidepressant curves. Example 1 2. Inhibition of amphetamine-induced hyperkinesis. The mice were injected with a drug or excipient control group. After 30 minutes, the mice were 1.5 mg/kg d. - Amphetamine sulfate or saline sc injection and immediate placement in an infrared motion box where motion activity (long-term beam breakage of two adjacent bundles) and foreign body behavior (repeated short-term beam breakage of the paper λ degree applies to Chinese national standards ( CNS ) A4 specification (2IOX297 mm) " -31 - (Please read the note on the back and fill in the purchase) Φ. Ministry of Economic Affairs Zhizhi Property Bureau employee consumption cooperative print 1325000 A7 ___ B7 V. Invention description ( ' ) The 60-minute cycle was measured. The experiment used a 3-NOW ANOVA analysis with an experimental period, an infrared motion box and treatment as a factor, and a 'Tukey (HSD) test to track the main effects in the treatment situation. (S) — 2 , 3 ' 11 , lla — four 1-Η,5Η-pyrrolo[2,lc]pyrido[3,2-f][1,4]oxazepine-5-one and (S)-2,3,11,lla-tetrahydro- 1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1.,4]'oxazepin-5-one (Example 1) inhibits amphetamine-induced overactivity. Read the notes on the back and fill in this page. Order Ψ. Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives print % This paper scale applies to China National Standard (CNS) A4 specifications (210X297 public t ) -32-

Claims (1)

1325000 A8 B8 C8 D8 VI. Patent Application Scope Annex 3: Patent Application No. 91 1 1 1 754 Replacement of Chinese Patent Application Range; 1 · Treatment of Neurological Diseases or Spirits W^·;^·Cao Zibei Shouts 'h Disease Or the disorder is in response to an increase in the synaptic response regulated by the AMP A receptor in the central nervous system, the pharmaceutical composition comprising a therapeutically effective amount of (pyrido/thieno)-[f]-oxygen nitrogen of the following formula I Miscellaneous hood - 5-ketone derivative, II--.--, -Φ —— (please fill in the page on the back of Ht#) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in which R 1, R 2 and R 3 are Η; A r represents a fused thiophene or pyridine ring, optionally selected from a (Cl-4) alkyl group, (Ci-4 Alkoxy, CF3, halogen, and a substituent of NR4R5; R 4 and R 5 are respectively fluorenyl or (C i - 4 )alkyl; or R 4 and R 5 together with the nitrogen atom to which they are bonded form 5 — Or a 6-membered saturated heterocyclic ring; A represents a C 2 -5 stretching group in which one carbon atom may be replaced by an oxygen atom, and the ring-containing ring containing A is substituted by a hydroxy substituent; Applicable to Chinese national standards (CMS > A4 specification (210X297 mm) - ΙΓ. 1325000 A8 B8 C8 D8 VI. Application for patent-practical salt. 2 · For pharmaceutical composition of claim 1 Wherein A r is a [3,2_f] fused pyridine or a [2,3 - f] fused thiophene ring oxime 3. The pharmaceutical composition of claim 1 includes a compound (S)-2,3, 11 , 11a - tetrahydro - 1H, 5H - pirodi[2,1 - 〇] pyridine and [3,2-{] [1,4]-oxazole 5 — Ketone or its pharmaceutically acceptable salt. ----------^------1T------^ (Please read the notes on the back of the section and fill out this page. Printed by the Ministry of Consumer Affairs, the Intellectual Property Bureau, the Consumer Cooperatives, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -2-