JPH06505698A - new compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] new compound The present invention relates to compounds exhibiting pharmacological activity, methods for producing the same, compositions containing the same, and Concerning its use in the treatment of mammals.

EP-A-0327223 (Beacham Group BLC) relieves anxiety and/or tetrahydrobenzochenobiridines with antidepressant activity. It shows.

A group of compounds have now been developed that have been shown to improve CNS activity, particularly anxiety relief. and/or were found to have antidepressant activity.

Therefore, the present invention provides formula (1): [During the ceremony, R, is hydrogen, CI-S alkyl, phenyl or phenyl c, -4 alkyl , where the phenyl moiety is one or more CI-S alkyl, CI-v alkyl, Rukoxy, C0-, alkylthisu, hydroxy, CI-7 alkanoyl, halo, trifluoromethyl, nitro, (substituted with 1 or 2 CI-alkyl groups) amino) or Cs-t alkanoyl, cyano, carbamoylate optionally substituted with a group or a carboxy group: R3 and R3 are independently hydrogen, alkyl, C8-7 cycloalkyl, C5 -Vcycloalkyl-01-4alkyl, C3-, alkenyl% C1-'F Al Kanoyl, c-alkylsulfonyl, di(C,,alkyl)aminoC1-, a phenyl, 3-oxbutyl, 3-hydroxybutyl, phenyl, phenylC1- , alkyl, benzoyl, phenyl C2-t alkanoyl or benzenesulfo where the phenyl moiety is selected from 1 or 2 halogens, C1 -, alkyl, Cl-1 alkoxy, CRs, substituted with amino or carboxy or R3 and R3 together, oxygen or NRs may be The combination forms an intervening C1-1 polymethylene, where R1 is hydrogen or hydrogen. C0-, alkyl optionally substituted with roxy: Rs is hydrogen or CI -S alkyl, and Rs is hydrogen, or R5 and R8 together to form a Cl-1 alkylidene group at the 8-position, and -COtR4 is pharmaceutically is an acceptable ester group] or a pharmaceutically acceptable derivative thereof Provide salt.

The alkyl moiety contained in symbols R to R6 is preferably methyl, ethyl, n- and Cl-5 alkyl such as iso-propyl.

Examples of R+ include hydrogen, methyl, ethyl, n- and iso-propyl, phenyl and Contains benzyl. Preferably R1 is methyl.

In the selection of R1 and R1, the nitrogen atom is directly bonded to the unsaturated aliphatic carbon. It will be understood that there is no.

Examples of R7 and R include hydrogen, methyl, ethyl, n- and iso-propyl, -, 5ec-, iso- and tert-butyl, rho, 5ec-, iso- and Neo-pentyl, cyclopentyl, cyclohexyl, cyclohebutyl, cyclope to C3-4 alkyl, cyclohexyl-〇, -4 alkyl and cyclo Butyl-〇,-,alkyl (where C6-4 alkyl examples include methylene and ethyl ), but-2-enyl, but-3-enyl, I-methylprobut-2-enyl Nyl, formyl, acetyl, propionyl, methylsulfonyl, 3-dimethyla Minobutyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, benzyl, Includes benzoyl, benzylcarbonyl and benzenesulfonyl, and R1 and R1 together form -(CH,), -X-(CH,), -, where r and S are independently 1.2 or 3, and X is a bond, 0 or NR.

For example, C4 Mataha CI polymethylene, -(CHJt-0-(CH2) t-, -(CHz)t-NR=-(CH-)t- (where R6 is preferably methyl is).

Preferably R1 is hydrogen, R1 is hydrogen or C1-, alkyl, such as methyl It is.

Most preferably R1 and R3 are hydrogen.

Suitable examples of pharmaceutically acceptable esters of compounds of formula (D) include C3-, alkyl ester (where the alkyl moiety is selected from chloro, fluoro and bromo) methyl, ethyl, n - and iso-propyl, n-1sec- and tert-butyl, and 2. 2.2-) Lifluoroethyl ester: C1-@alkenyl ester, e.g. vinyl, prob-1-enyl, prob-2-enyl, l-methylvinyl, but l-enyl, boudo-3-enyl, l-methylenepropyl and l-methylpropyl -2-enyl (both E and 2 forms if stereoisomers exist): Cs-* Alkynyl esters such as probut-2-ynyl, bud-2-ynyl and bud-2-ynyl -3-ynyl: Cs-*cycloalkyl ester and C,-, cycloalkyl -CI-4 alkyl esters, such as cyclopropylmethyl. preferably The pharmaceutically acceptable esters are methyl, ethyl, 2.2.2-) refluor loethyl, propyl, prob-2-enyl, prob-2-ynyl, boudo-3-ethyl nyl, boudo-2-ynyl, boudo-3-ynyl or cyclopropyl methyl ester That is, R4 is methyl, ethyl, 2.2.2-trifluoroethyl, Lopyl, prob-2-enyl, prob-2-ynyl, boudo-3-enyl, boudo 2-ynyl, boudo-3-ynyl or cyclopropylmethyl.

Suitable R include hydrogen, methyl, ethyl, n- and iso-propyl; Plain is preferred. Also, R$ and R1 together form 8-(1-methylethylidene) A preferred group of compounds included in formula (1) representing a group is formula (II): [wherein R, l is hydrogen or C1-, alkyl, and R3 and R4 are the same as defined in formula (+). or a pharmaceutically acceptable salt thereof.

Preferred examples of R3 and Rm' are described with respect to the corresponding symbols in formula (1). That's right.

Compounds of formula CD can be prepared using conventional pharmaceutically acceptable acids such as maleic acid, hydrochloric acid, odorous acid, etc. Hydrohydric acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid , can form acid addition salts with acids such as tartaric acid and methanesulfonic acid .

A compound of formula (1) in which R3 or R8 is hydrogen may have more than one tautomeric form. It will be understood that it can exist in the following states. The invention extends to each isomer and mixtures thereof. It is something.

Compounds of formula (D) can also form solvates, such as hydrates, and the present invention This also applies to these forms. When referred to herein, the term [formula (D of "Compound" also includes its solvates.

The compound of the formula in which R1 is hydrogen and Rs is something other than hydrogen (R, the compound adjacent to the moiety It should be understood that the chiral center has a chiral center on the carbon atom. Furthermore, R6 and Rs A compound in which forms an alkylidene group can exist in the form of E and two forms, while , substituents R1, R,, R,, R4 and R, may contain asymmetric carbon atoms . The present invention relates to single stereoisomers (e.g. enantiomers) of the compound of formula (1) or their (e.g. racemate).

The present invention also provides a method for producing the compound of formula (1) or a pharmaceutically acceptable salt thereof. Provided is a method for formula (III): [In the formula, R3 is P as defined in the formula (D, or a group that can be converted thereto) Therefore, R4゛ is converted to -COJ< or -CO,R, as defined in equation (1). R and R8 are as defined in formula (D), and R7 is hydrogen or an N-protecting group, and J and K together represent a keto group or Represents a group that can be converted, Y is a group CN or C0LI (where Ll is a leaving group ), M is hydrogen, or Y is hydrogen and M is a group CN or C0Lz (this Here L! is a leaving group) or its imine tautomerism cyclize the body; then add water, optionally or as needed, in any suitable order. Convert R1 when it is elemental to an N-protecting group, and Y or M is a group COL l or C If 0Lt, the resulting hydroxy group is converted into a leaving group and the latter is converted into a compound. HNR, 'Rs' (here Rt' and Ra' are R1 and R3 or N-protecting group) to remove the R,N-protecting group and convert the electron-withdrawing group R4' into -CO, R, and convert R+' other than R+ to R+, R1, R3, R4 , R6 and R1 are interconverted, J and are converted into keto groups, and the enantiomer-like The stereoisomers may be separated and/or the pharmaceutically acceptable salts of the compound of formula (1) may be formed. It consists of becoming.

Cyclization of the enamine of formula (IID or its imine tautomer) can be carried out under normal conditions by Alkali metal alkoxides (e.g. sodium) in a suitable solvent such as methanol at elevated temperature in the presence of a strong base such as n-butyl acetate) or Lewis acid (e.g. ZnC1t, 5nC1a or Cu0C) in a suitable solvent. OCHs) at elevated temperature.

Lewis acid-catalyzed cyclization using copper(1) acetate or tin(IV) chloride is particularly When a compound of formula (D) in which R4' is CO, R, is directly obtained by cyclization, suitable for

Preferably, J and K together represent a protected hydroxy group or a protected keto group. Represents a group that can be converted into a keto group. Trimethylsilyl and tetrahydropyranyl Protected hydroxy such as The group can be conveniently prepared (oxidized) using, for example, oxalyl chloride/dimethyl sulfoxide. Produces ketones.

Protected keto groups J and K have the formula ([ID +: J K X Ru te, K 7!1 (ZRI4teary, X and 2 are independently oxygen or sulfur, RI3 and RI4 is independently CI-s alkyl or together with one or more Cl-4 polymethylene which may be substituted with more than one CI-@alkyl group. This is exemplified by the compound

When X and Z are both oxygen, the groups -X-R1s and -Z-R, It can be conventionally converted to a keto group, for example by treatment with aqueous hydrochloric acid.

When one of X or Z is an oxygen atom and the other is a sulfur atom, for example, aqueous hydrochloric acid or quaternization of the sulfur atoms and subsequent hydrolysis (e.g. alkyl halide). to convert the groups -X-RIs and -Z-R, into keto groups by It can be converted as an example.

When X and Z are both sulfur, the groups -X-R, and -Z-R+ a are , one of the sulfur atoms with the following reagents: (i) heavy metal cations, e.g. silver (ii) a quaternizing agent, e.g. an alkyl halide, or (iii) an oxidizing agent, e.g. peracetic acid and then using e.g. aqueous acetone or aqueous acetonitrile, Conversion to a keto group can be conventionally achieved by hydrolytically removing the protecting group.

Preferably X and Z are oxygen.

R, and R1 hydrogens can be combined with a suitable aldehyde or ketone (e.g. acetone). It can be converted to an alkylidene group at the 8-position by rudol condensation. alkylidene The group is then conventionally converted to the corresponding R, alkyl using, for example, a palladium/carbon catalyst. Hydrogenated to kill group.

Examples of R,N-protecting groups are trimethylsilyl and 2-(trimethylsilyl) ethoxymethyl, which are e.g. tetra-n-butylammonium fluoride. It can be removed conventionally using a system.

Preferably R1 is hydrogen.

Suitable examples of radicals R4° include the radicals described above for -CO,R, COR, (where and R1 is hydrogen, CI-@alkyl, C5-tcycloalkylc1-4alkyl or or c, -7 cycloalkyl), CH=NOHSCOtHSCo! Q (Here Q is a protecting group such as benzyl, and the benzyl moiety is in the phenyl ring. 1 or 2 halogens, CF, C,-, alkoxy, Cl-6 alkyl or nitro), cyano and -C0NRJ+. (child Here, R1 and R1° are independently hydrogen, CI-II alkyl, C3-, alkoxy Cl, phenyl and phenylCl-4 alkyl, where the phenyl moiety is substituted as described above for the optional substituents on the phenyl ring of the benzyl ester. or R1 and R3° may be combined with oxygen or NR, , optionally intervening Cl-, form a polymethylene chain, where R1+ is hydrogen or C0-, alkyl, forming e.g. morpholino or piperazino ) is included.

The protecting group Q is removed by conventional hydrolysis or hydrogenolysis to produce the free acid; This is then reacted with a suitable alcohol R,OH (optionally thionyl chloride). Either the acid is preconverted to the acid chloride by reaction with a suitable chlorinating agent such as , or a suitable solution such as potassium carbonate in an inert solvent such as dimethylformamide. alkylating agents R, X (where X is chloro, bromo, iodo esterification under normal conditions by reacting with a leaving group such as can be done.

The intermediate amide can be hydrolyzed to the free acid and then esterified as described above. Wear.

R4゛cyano group can be reacted with a suitable alcohol R40H under anhydrous acidic conditions. Toyoriimidiester is converted and then the group -Co! Hydrolyzed to R4.

R,'　CH=NOH group is dehydrated by a suitable dehydrating agent such as formic acid at elevated temperature to form a silicone. The cyano group generated by conversion to ano is converted to CO, R, as described above. another As a method, the CH═NOH group is converted to formyl by hydrolysis and converted into formyl, such as Crys. can be oxidized to the free acid using a suitable oxidizing agent.

R,' COR, group is converted to CO, R via acid by haloform reaction and esterification. , is converted to .

Suitability of leaving groups L1 and when Y or M is COL+ or COCl Examples include hydroxy, more preferably alkoxy such as C1-, alkoxy (e.g. ethoxy, methoxy). Compound of formula ([11) or its equivalent Cyclization of the mine tautomer also yields a product with a hydroxy group at the 4-position of the pyridine ring. Tarasu. This hydroxy group is a halogen such as phosphorus oxychloride or phosphorus oxybromide. By reaction with a chlorinating agent, a leaving group as defined below for L, preferably a chlorinated Halo, like Lo, can be converted. Leaving groups are usually used for nuclear aromatic substitution Toluene, methanol, ethanol, pyridine, dimethylformamide under Compound HNR1'R,' at elevated temperature in an inert solvent such as dioxane or dioxane. will be replaced by In addition, this reaction also occurs when 1 (NR1'R1° (others) acts as a solvent. It can also be carried out in a medium (not containing a solvent).

The R1 or R8 protecting group, such as p-methoxybenzyl, is removed by conventional methods. can do.

Conversion of R1 and R3 hydrogens to other R, /R, can be achieved by alkylation of primary amines or It is carried out according to conventional methods for acylation. Acylation is performed using a suitable halogenated acyl This can be done by reaction with However, other than hydrogen or acyl groups R*/R* means that in the compound of formula (111), Y or M is COL, or C OL, the leaving group as discussed above to the compound HNRz'R-' It is preferable to introduce by substituting with .

Pharmaceutically acceptable salts are prepared in conventional manner by reaction with appropriate acids or derivatives. be able to.

A compound of formula (IID) is a compound of formula (IV): (IV) The compound of formula (V)・ [In each formula, R+', R-', Ra, R7, R1, Y, J and K are the formula (II as defined in I), L is a leaving group, and M is as defined in formula (IID) or L and M together represent a bond]. It will be done.

Intermediates of formula (Ill) and (1v) are novel and constitute another aspect of the invention .

Suitable examples of leaving groups include halogens such as chloro and bromo, and acetoxy. C+-a acyloxy, C+-a alkoxy such as methoxy or ethoxy (preferably or methoxy), or NR,R, (where R1 and R1 are independently hydrogen or Or C1-.

alkyl or - together with oxygen or NR, optionally intervening C2, , forms a polymethylene chain, where Rc is substituted with hydrogen or hydroxy C+-g alkyl which may be L is hydroxy It is understood that the compound of formula (V) exists as more than l tautomers when Good morning.

The reaction between the compound of formula (1) and the compound of formula (V) can be carried out under the usual conditions for a condensation reaction. Toluene, benzene, ethanol, pyridine, dimethylformamide or or p-toluenesulfone at elevated temperature in an inert solvent such as dioxane. Water is optionally separated in the presence of an acid or a catalyst such as camphor sulfonic acid. However, it will be implemented.

For the production of a compound of formula (1) where R1 is hydrogen, the following compound of formula (V) is used. Will be: (1) L and M together represent a bond, or L is hydroxy and U is hydrogen and Rlo is C1-, an alkoxycarbonyl group. Compound of formula ([V) reaction with is followed by a decarboxylation step to obtain R+ hydrogen: (ii) L is In the leaving group, R1' is hydroxy. R1゛゛hydroxy of the generated compound is first chlorinated by conventional chlorination with a chlorinating agent such as phosphorus oxychloride. substitution followed by reductive dehalogenation under conventional conditions (e.g. zinc in acetic acid). It is converted to hydrogen by Conversion to R+ hydrogen is performed by converting the compound of formula (III) into carried out before the cyclization or, more preferably after the cyclization; (iii) L is separated. Upon degrouping, M and R4' are both C3-, alkoxycarbonyl and R+' is It is hydrogen.

The compound of formula (IV) is K, Gewald et at, Chem, B er, 94 (1966), formula (Vl): [wherein R5, R1, J and K are as defined in formula CI ID] The compound, such as diethylamine, in an inert solvent such as methanol or ethanol is prepared by reacting with NCCH, Y and sulfur in the presence of a suitable base. .

The compound of formula (vl) is a known compound or is prepared analogously to a known compound be able to.

The compound of formula (V) is a known compound or can be prepared analogously to a known compound. I can do that. For example, in formula (V) where M is hydrogen, L is OH, and R1 is CH, Compounds R, J, Clemens and J, A, Hyatt, J, A method similar to that described in Org, Chem, 1985502431 is prepared by the reaction of diketene with a suitable alcohol R,OH. R 3゛ is phenyl, M is hydrogen, L is ethoxy, R4゛ is ethoxycarbonyl A compound of formula (V) which is V, L, Leighton, Amer, Ch em, Journal (1898).

A group of intermediates has the formula (VII): (Vll1 [In the formula, R4'' is changed to R4'' as defined in formula (Ill) or CO, R, is a group that can be replaced with , Rt', R*', J and KILL are as defined in equation (III). , R4, Rs and R1 are as defined in formula (1), provided that X is NR1 R$, J and K together represent a keto group, and R1 is R3 , R4'' is something other than CO2R, or a salt thereof; Consists of esters or amides. The novel compound of formula (Vll) is also included in the present invention. constitute a part.

An example of R4' other than CO, R, is C0IH.

In another aspect, the invention provides that X is NR,R, R4' is C0IR, and Rlo is R8, and J and K together represent a group that can be converted into a keto group. The compound is deprotected and the stereoisomers, such as enantiomers, optionally separated and modeled. and/or forming a pharmaceutically acceptable salt of a compound of formula (1). (Provides a method for producing the compound D or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of formula (D or a pharmaceutically acceptable salt thereof, and a formulation Pharmaceutical compositions containing a pharmaceutically acceptable carrier are provided.

The pharmaceutical compositions of the invention can be prepared by mixing, suitably at ambient temperature and atmospheric pressure. It is formulated as a drug and is generally adapted for oral or parenteral administration; Tablets, capsules, oral liquid preparations, powders, granules, lozenges, ready-to-use preparations It may be a powder, or a solution or suspension for injection or infusion. Usually, Compositions that can be administered orally are preferred.

Tablets and capsules for oral administration are in unit dosage form and contain binders, fillers, etc. Contains conventional excipients such as tablet lubricants, disintegrants and acceptable wetting agents. Ru. Tablets can be coated by methods well known in the pharmaceutical industry. .

Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups or may be in the form of an elixir or mixed with water or other suitable vehicle before use. It may also be in the form of a dry product prepared at the time of use. Such liquid preparations are suspended additives, emulsifiers, non-aqueous vehicles (including edible oils), preservatives, and optionally flavoring agents. Contains conventional additives such as colorants or colorants.

For parenteral administration, liquid unit dosage forms can be prepared containing a compound of the invention or its pharmaceutically acceptable dosage form. It is prepared using soluble salts and a sterile vehicle. The compound is Depending on the vehicle and concentration, it may be suspended or dissolved in the vehicle. When preparing solutions , dissolve the compound and filter sterilize it before filling and sealing it into a suitable vial or ampoule. Ru. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents are also dissolved in the vehicle. Ru. To increase stability, freeze the composition after filling into vials and rinse with water under vacuum. Remove. Parenteral suspensions are prepared in substantially the same manner, except that the compound is added to the vehicle. suspended instead of dissolved in water and cannot be filter sterilized. Compound is sterile Sterilize by exposure to ethylene oxide before suspending in vehicle. Advantageously, the compound Surfactants and wetting agents are included in the composition to promote homogeneous distribution.

The composition contains 0.1-99% by weight of active substance, preferably 10-60% by weight. Contains depending on the method of application.

Doses of this compound used to treat CNS disorders such as anxiety and depression are typically will vary depending on the severity of the disease, patient weight, and other similar factors. However However, as a general guideline, a suitable unit dose is 0.05-1000 mg, or more. Suitably it may be 0.05-20.0 mg, for example 0.2-5 mg. It takes A unit dose may be administered more than once a day (e.g., two or three times a day to administer the total amount for the day). The dose should be in the range of about 0.01-100 mg/kg. this kind of treatment can be continued for a long period of time.

The present invention further provides a non-toxic and effective amount of a compound of formula (1) or a pharmaceutically acceptable amount thereof. for CNS diseases, especially anxiety, and a pharmaceutically acceptable carrier. or depression).

The invention further provides for administering to a patient a non-toxic and effective amount of a compound of formula CD or a pharmaceutically acceptable amount thereof. CNS disease in mammals (including humans) consisting of administering Shitsuru salt (particularly anxiety or depression).

The invention also provides treatment and/or prevention of CNS disorders, particularly anxiety or depression. provides a compound of formula () or a pharmaceutically acceptable salt thereof for use in .

The invention further provides for the treatment and/or prognosis of CNS disorders (particularly anxiety or depression). The compound of formula (1) or its pharmaceutically acceptable Provide for the use of vine salt.

The following examples illustrate the preparation of compounds of the invention.

Production example I K, Gewald et al, Chem, Ber, 1966, 94 1,4-Cyclohexanedione mono- The title compound was prepared from ethylene ketal (49% yield).

NMR(CDC1,)δ: 1.95 (2H, t), 2.72 (4H, m), 4.02 (4H, s), 4.72 (2H, bs).

Manufacturing example 2 N~3-(2-(3-cyano-6,6-ethylenedioxy-4.5.6.7-te) Trihydrobenzo [bl aminonitrile (old) in timesitylene (400 ml) (13.16g: 55.7nvnol) and ethyl β-ethoxycrotonate ( A mixture of 26 g (164 iunol) was heated under reflux for 1.5 hours, then evaporated. It was dried and solidified. The residue was chromatographed on Kieselgel 60. Elution was with a gradient of 2% methanol in dichloromethane. The product is converted into Vetrol ( The title compound was obtained as a yellow solid (11,9 g, 61%).

Melting point 115-118°C NMR(CDC1,)δ: 1.30 (3H, t), 1.95 (2H, t), 2.10 (3H, s ), 2.85 (4H, m), 4.02 (4H, s) B 4.20 (2H, q), 4.90 (IH, s).

Enamidiester D2 (11.7 g, 33.6 g in toluene (400 ml) mmol) in a 1M solution of sodium ethoxide in ethanol (40 ml). and heated under reflux for 2.5 hours. The reaction mixture was cooled and diluted with ethyl acetate. Added to half-saturated aqueous ammonium chloride solution. Filter this mixture and separate the organic phase. , dry NaJ(L) and evaporate under vacuum to give a brown oil. TLC alumina chromatographed with a gradient of 0-2% methanol in dichloromethane. Elution gave the title compound as a yellow gum (7g, 60%).

NMR (CDC11) δ: 1.4o (3)1. t), 2.05 (2H, t), 2.70 (3) 1. s), 3. oO(2H,s), 3.23(2HCt).

4.05 (4H, s), 4.38 (2H, q), 6.60 (2H, bs) .

4-amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[ blcheno[2,3-bl pyridine-3-carboxylic acid ethyl ester (El, Ra=CtHs) Ketal D3 (4,62g, A solution of 13.3 mmol) was treated with water (10 ml) and concentrated hydrochloric acid (2 ml). , heated at reflux under nitrogen for 24 hours. Additional concentrated hydrochloric acid (2 ml) was added and the mixture was heated at reflux for 8 hours and then stored at approximately 5°C for 12 hours. White solids are produced by filtration. A crystalline solid (3.5 g) was obtained and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. did. The organic phase was separated, dried (Na25O4) and concentrated in vacuo, allowing crystallization to occur. It's so bad. After storage at approximately 5°C for 12 hours and filtration, the title compound was obtained as a white crystalline solid ( 2,37g.

59%).

Melting point 159-161″C Actual value: C, 59,32; H, 5,19; N, 9.17C+ aH+ Calculated value as *N*O*S; C, 59, 19: ratio 5.30: N, 9.2 ONMR (CDCI δ: 1.42 (3H, t), 2.71 (3H, s), 2.80 (2H, t ), 3.45 (2H, t), 3.78 (2H, s) B 4.40 (2H, q), 6.55 (2Lbs).

Example 2 4-amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[ b] Cheno[2,3-bl pyridine-3-carboxylic acid cyclopropylmethyl ether Stell (E2. R4”CH2-C-C5Hs) Using methods similar to those described in Preparation 2, Preparation 3 and Example 1, D 1 and 3-oxo-butyric acid cyclopropyl methyl ester, the intermediate 4-amino No-7゜7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydrobe Nzo[blcheno[2,3-bl pyridine-3-carboxylic acid cyclopropylmethane] The title compound was prepared via the methyl ester.

Melting point 168°C (from ethyl acetate) Actual measurement value: C, 61, 89: H, 5, 51, N, 8.53C+i)I+sN *Calculated value as OsS: C, 61,80; H, 5,49; N, 8.4 8%b] Pyridine-3-carboxylic acid methyl ester CE3. Ra=CH5) From DI and methyl acetoacetate using a method similar to that of Example 2, the intermediate 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tet lahydrobenzo[blcheno[2,3-bl pyridine-3-carboxylic acid methyl ester] The title compound was prepared via Stell.

Melting point 202-6°C (from ethyl acetate) Actual measurement value: C, 57, 95: H, 4, 86; N, 9.65C + 4HI 4N! Calculated value as OIS: C, 57, 92: H, 4, 86, N, 9. 65% DI and 3-oxobutyric acid protease using a method similar to that of Example 2. From the pyl ester, the intermediate 4-amino-7,7-ethylenedioxy-2-methyl -5,6,7,8-tetrahydrobenzo[blcheno[2,3-bl pyridine] The title compound was produced at a total percentage of 11% via -3-carboxylic acid propyl ester. .

Melting point 141-2°C (from ethyl acetate/60:80 petroleum ether) NMR (d a DMS δ: 0.95 (38, t, J=7Hz), 1.75 (2H , sx, J=7Hz), 2.55 (3H, sj.

2.70 (2H, t, J=6Hz), 3.40 (2) 1. t, J=6f (z), 3.70 (2H, s).

4.25 (28, t, J=7Hz), 6.75 (2H, bs).

Example 5 4-amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo[ blcheno[2,3-b]pyridine-3-carboxylic acid prob-2-enyl ester (E5. R4=CHlCH=CH) Follow the same method as described in Example 2. from DI and 3-oxo-acetic acid prob-2-enyl ester using 4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetra hydrobenzo[tl]cheno[2,3-bl pyridine-3-carboxylic acid pro- The title compound was prepared at a total percentage of 8% via 2-enyl ester.

Melting point 148-150℃ (from ethyl acetate) NMR (CDC1,) δ: 2.74 (3H, s), 2.80 (2H, t, J=8.5Hz), 3.45 ( 2H, m).

3.70 (2H, s), 4.85 (2H, l11), 5.30-5.5 0 (2H, In), 5.95-6.18 (IH, bm), 6.60 (2 H, wide).

Using a method similar to that described in Example 2, DI and 3-oxo-butyric acid 2 - from boudo-2-ynyl ester, intermediate 4-amino-7,7-ethylenediox cy-2-methyl-5,6,7,8-tetrahydrobenzo[blcheno[2,3- The title compound was synthesized via bl pyridine-3-carboxylic acid boudo-2-ynyl ester. It was manufactured at a number ratio of 5%.

Melting point 190-2°C (from ethyl acetate) NMR (CDCIs) δ: 1.90 (3H, t, J = 3Hz), 2.74 (3H, s), 2.80 (2H, tJ=8Hz).

3.45 (2H, m), 3.70 (2H, S), 4.90 (2H, q , J=3Hz), 6.55 (21 (, wide s).

Using a method similar to that described in Example 2, acetoacetic acid 2.2.2- From fluoroethyl and DI, intermediate 4-amino-7,7-ethylenedioxy -2-Methyl-5,6゜7.8-tetrahydrobenzo[ti1cheno[2,3- bl via pyridine-3-carboxylic acid 2.2.2-trifluoroethyl ester The title compound was produced at a total percentage of 1%.

Melting point 140-6℃ NMR (CDC1*) δ: 2.55 (3H, s), 2.80 (2H, t , J=6Hz), 3.40 (2H,t, J=6Hzj.

3.65 (2H, s), 4.70 (2H, qj□8Hz), 6.70 (2H, wide S).

I11/z = 358 (M”).

DI and 3-oxo - from butyric acid boudo-3-enyl ester, intermediate 4-amino-7,7-ethylenedi Oxy-2-methyl-5,6,7,8-tetrahydrobenzo[blcheno[2, The title compound via 3-bl pyridine-3-carboxylic acid boudo-3-enyl ester was manufactured.

Melting point 130-2°C (from ethyl acetate) NMR (CDC11) δ: 2.55 (2H, m), 2.70 (3H, s ), 2.85 (28,t, J=8.5Hz).

3.45 (2H, t, J=8.5Hz), 3.70 (2H, s), 4.45 (2H, t, J=8.5Hz), 5.10-5.25 (2H, br, m), 5.80-5.95 (18, br, m), 6.60 (2H, br, s) .

Using a method similar to that described in Example 2, DI and 3-oxo-butyric acid From the do-3-ynyl ester, the intermediate 4-amino-7,7-ethylenedioxy= 2-Methyl-5゜6,7.8-tetrahydrobenzo[b]cheno[2,3-bl The title compound is produced via pyridine-3-carboxylic acid boudo-3-ynyl ester. did. However, the cyclization step was performed using 5nC1 in n-butyl acetate.

Melting point 167-8℃ NMR (CDCI delta: 2.05 (1) (, t, J=2.8Hz), 2. 70 (2H, dtj=2.8.8.5)1z).

2.75 (3H, s), 2.80 (2H, t, J=8.5Hz), 3. 45 (2H, m), 3.70 (2H, s).

4.45 (2H, t, J=8.5Flz), 6.60 (2H, wide S).

Example i.

4-amino-2-methyl-8-(1-methyl-1-ethylidene)-7-oxo- Using acetic acid steel (1) according to the methods of 5,6,7,8-tetra Production Example 2 and Production Example 3 cyclization product of amine D1 and 3-oxobutyric acid boudo-3-enyl ester. was converted into 39% yield. Similar to the method of Example 1, reduction with aqueous hydrochloric acid/acetone was performed. After 48 hours of downstream processing, the crude product was obtained in 93% yield. Chromatog with silica Purify the title compound by purifying the title compound by eluting with 30% ethyl acetate/n-pentane. A sample was collected and recrystallized from ethyl acetate to give yellow crystals.

Melting point 136-8℃ NMR (CDC1,) δ: 2.25 (3H, s), 2.27 (3H, s ), 2.25 (2H, a+), 2.74 (3H, sj.

2, 80 (2H, t, J=8.5Hz), 3.40 (2H, t, J= 8.5Hz), 4.42 (2H, t, J=8.5Hzj.

5, 10-5.25 (2H, wide m), 5.75-5.98 (IH, wide 01), 6.70 (2H, wide S).

Geller and 5eifter, (1960) Psychopha Based on the method first described in Rmacologia, 1.482-492 The potential anxiolytic effect was evaluated using the Geller-Sater method. This method is It has been found that it is possible to select drugs that have an analgesic effect (Cookand Sep. inwall, (1975) “Mechanism of Action” of Benzodiazepines Mechanism of action of azevins) ed, Co5ta, E, and Greenga rd, P,, Raven Press.

New York, pp. 1-28).

Rats were given a variable interval 30 s schedule (Vt30) to press the lever to obtain food. ) to train. 5 minute VI30 plan, 2-5 minute plan (FR5) (this total The image shows that every 5 lever presses, the food is delivered with a gentle 0.5 second foot shock. (supplied with pellets). The entire experiment lasts approximately 30 minutes. rats are common Generally, under the VI30 plan, the ratio of lever pressing was high, and during the FR5 “conflict” period, the ratio of lever pressing was high. The response rate is low. Anxiolytic drugs increase the proportion of suppressed responses in rats during “conflict” periods. raise

Prior to testing, drugs are administered intraperitoneally or orally to 3-8 rats per group.

The result is the percentage increase in the square root of the total number of lever presses during the FR5 “conflict” period. It is expressed as The square root transformation is performed statistically using the parametric method (ANOVA). It is necessary to normalize the data for analytical analysis.

2. [”’S]-TBPS binding to rat cerebral cortical membrane in vitro The cerebral cortex of a rat was homogenized in 20 times the volume of 0.32M sucrose, and Centrifuge at 000g for 20 minutes (4°C). Remove the supernatant and weigh 50.000g ( Centrifuge again at 4°C for 20 minutes. After that, P, Bellet is 20 times the capacity of Trisk Suspend in enoic acid buffer (pH 7.1) and centrifuge at 50.000g (4℃, 20 minutes). I care. Repeat this washing step three times and finally add the pellet to 20 times the volume of buffer. Resuspend and store at -70°C before use.

Tissue suspension (50μl) contained 0.2M NaCl and 5xlO-8M GAB^. [”S]-TBPS (2 nM) in triscitrate buffer (pH 7,1) Incubate together (25°C, 120 minutes). Non-specific binding was reduced to 10-’M. Measured in the presence of bicrotoxin. Test drugs at various concentrations (10-', 1 0-@, lO-'' and 10-'M final concentration) in a volume of 50 μl.

The total assay volume is 500 μl. 5. Rapid production using a katron cell harvester. Stop incubation by rapid filtration and perform liquid scintillation spectrometry. Measure radioactivity by metering. ICs. is a test drug that blocks specific binding by 50% Calculate as the concentration of a substance.

Test results Compound Dose Increase in response during “conflict” period (mg/kg) Example 1 20p, o, +52% Compound E2 also showed no significant response during the "struggle" period at a dose of 20 mg/kg p,o. showed an increase.

Compound IC8゜ Example 1 13 μM, 17, czM (2 horn measurement value) Example 2.6.7 and Compounds 1 and 10 exhibited ICs of less than 20 μU.

international search report international search report Continuation of front page (72) Inventor Forbes, Ian Thomson United Kingdom CM 195E Idea Essex Barlow The Pinnacles Coldharbour Road, Street Miss Klein Beecham Pharmaceuticals (72) Inventor Tompso Marvin UK CM 195 Aday Essex Barlow The Pinnacles Cold Harbor Road, SmithKline Beecham Pharma Inside Shchikarz

Claims (36)

[Claims] 1. Formula (I): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [During the ceremony, R1 is hydrogen, C1-6 alkyl, phenyl or phenylC1-4 alkyl where the phenyl moiety is one or more C-6 alkyl, C1-6 alkyl Coxy, C1-6 alkylthio, hydroxy, C2-7 alkanoyl, halo, to Lifluoromethyl, nitro, (substituted with 1 or 2 C1-6 alkyl groups) (optional) amino, or C2-7 alkanoyl, cyano, carbamoylate optionally substituted with a group or a carboxy group; R2 and R2 are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-6 alkenyl, C1-7 a Lucanoyl, C1-6 alkylsulfonyl, di-(C1-6 alkyl)amino C 1-6 alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C1-4 alkyl, benzoyl, phenyl C2-7 alkanoyl or benzene sulfonyl, where each phenyl moiety has one or two halogens. C1-6 alkyl, C1-6 alkoxy, CF2, amino or carboxy or R2 and R2 together may be substituted with oxygen or NR 6 forms an optionally intervening C2-6 polymethylene, where R6 is hydrogen or is C1-6 alkyl optionally substituted with hydroxy: R6 is hydrogen or is C1-6 alkyl, and R6 is hydrogen, or R■ and R■ are the same to form a C1-6 alkylidene group at the 8-position: and -CO2R4 is a pharmaceutical is a pharmaceutically acceptable ester group] or its pharmaceutically acceptable ester group. Urushio. 2. C1-6 alkyl, where R4 is optionally substituted with up to 3 halo atoms, C2 -6 alkenyl, C2-6 alkynyl, C2-6 cycloalkyl or C3-6 2. A compound according to claim 1, which is cycloalkyl-C1-4 alkyl. 3. Claim 1, wherein R1 is hydrogen, C1-2 alkyl, phenyl or benzyl. or the compound described in 2. 4. Claim 1- wherein R2 and R3 are independently hydrogen or C1-6 alkyl. 3. The compound according to any one of 3. 5. 5. A compound according to any one of claims 1-4, wherein R3 is hydrogen. 6. 6. A compound according to claim 5, wherein R■ and R■ are both hydrogen. 7.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydroben Zo[b]thieno[2,3-b]pyridine-3-carboxylic acid ethyl ester. 8.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydroben cyclopropylmethyl zo[b]thieno[2,3-b]pyridine-3-carboxylate ester. 9.4-amino-2-methyl-7-oxo-5,6,7,8-tetrahydroben Zo[b]thieno[2,3-b]pyridine-3-carboxylic acid methyl ester. 10.4-amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe Nzo[b]thieno[2,3-b]pyridine-3-carboxylic acid propyl ester. 11.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe Prop-2-enyl nzo[b]thieno[2,3-b]pyridine-3-carboxylate ester. 12.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe Nzo[b]thieno[2,3-b]pyridine-3-carboxylic acid p-2-ynyle Stell. 13.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe Nzo[b]thieno[2,3-b]pyridine-3-carboxylic acid 2,2,2-trif fluoroethyl ester. 14.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe But-3-enyl pyridine-3-carboxylic acid Stell. 15.4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahydrobe But-3-ynyl-enzo[b]thieno[2,3-b]pyridine-3-carboxylic acid Stell. 16.4-Amino-2-methyl-8-(1-methyl-1-ethylidene)-7-o xo-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b]pyridi -3-carboxylic acid put-3-enyl ester. 17. 17. A pharmaceutically acceptable salt of a compound according to any one of claims 7-16. 18. A compound according to claim 1 as described in any one of Examples 1-10. 19. A method for producing a compound as defined in claim 1, comprising formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R1' is defined in formula (I) R1 as defined above or a group convertible thereto, and R4' is defined in formula (I). It is an electron-withdrawing group that can be converted to -CO2R4 or -CO2R4 as expected, and R5 or and R5 are as defined in formula (I), and R7 is hydrogen or an N-protecting group. , J and K together represent a keto group or a group that can be converted into a keto group, and Y is a group CN or COL1 (where L1 is a leaving group) and M is hydrogen or is hydrogen and M is the group CN or COL2 (where L2 is the leaving group) ] or its imine tautomer; then optionally or optionally, in any suitable order, R7 when hydrogen is an N-protecting group. and when Y or M is a group COL1 or COL2, the generated hydrogen By converting the roxy group into a leaving group, the latter can be converted into the compound HNR2'R3' (where R2' and and R3' are R2 and R3 or an N-protecting group) to form an R7N-protecting group. The protecting group is removed, the electron-withdrawing group R4' is converted to -CO2R4, and R1' other than R1 is Convert to R1, mutually convert R2, R3, R4, R5 and R■, and convert J and K to conversion into a keto group, separation of stereoisomers such as enantiomers and/or conversion of formula (I) The above method comprising forming a pharmaceutically acceptable salt of the compound. 20. Formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) [In the formula, R4'' is in claim 19 A group that can be converted to R4' or CO2R4 as defined, and X is NR2'R 3', OH or chloro, and R1', R2', R3', J and K are and R4, R5 and R6 are as defined in claim 1. Yes, except that X is NR2R3 and J and K together represent a keto group. and when R1' is R1, R4'' is other than CO2R4] compound or its salt, ester or amide. 21.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid ethyl Luester. 22.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid Lopropyl methyl ester. 23.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Methyl tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylate Luester. 24.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid pro- Pyrester. 25.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid pro- P-2-enyl ester. 26.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid but -2-ynyl ester. 27.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid 2, 2,2-trifluoroethyl ester. 28.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid -3-enyl ester. 29.4-Amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- Tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid -3-ynyl ester. 30. 30. A salt of a compound according to any one of claims 21-29. 31. A compound of formula (VII) as defined in claim 20 [wherein X is NR2R3 , R4'' is CO2R4, R1' is R1, and J and K are [represents a group that can be converted into a keto group] and then optionally converts the enantiomer into a keto group. separation of such stereoisomers and/or pharmaceutically acceptable compounds of formula (I). A process for producing a compound as defined in claim 1, comprising forming a salt. 32. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. A product. 33. A compound according to claim 1 for use as an active therapeutic substance. 34. The compound according to claim 1 for use in the treatment and/or prevention of CNS diseases. Compound. 35. The compound according to claim 1 in the manufacture of a medicament for the treatment or prevention of CNS diseases. use of things. 36. comprising administering to a patient a non-toxic and effective amount of a compound according to claim 1. A method for treating and/or preventing a CNS disease in mammals including humans.