PT97570A - Process for the preparation of benzothienopyridine derivatives - Google Patents

Description

This invention

It relates to compounds having pharmaceutical activity with compositions which may contain a compound of the formula (I). (Beecham Group plc) discloses a class of tetrahydrobenzothienopyridines which exhibit anxiolytic and / or anti-depressive activity.

L * O * J * J C Litl * particles *

A class of those has been found to have activity on anxiolytic and anti-depressant activity. uonipustub 5 or SMC? in

In the sequential use, compound of the formula < I > or the present invention provides a pharmaceutically acceptable salt thereof,

wherein R 1, R 2, R 2, R 2, R 3 and R 4 are independently selected from the group consisting of: Phenylalkyl, phenyl, halogen, trifluoromethyl, nitro, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, , amino by one or two alkyl groups or by groups of alkanoyl, cyano, carbamoyl or carbamoyl groups. and R6 are independently selected from hydrogen, C1-4 alkyl, C1-6 cycloalkyl, C1-6 cycloalkyl alkyl, alkenyl, C1-6 alkanoyl, C1-4 alkylsulfonyl, di-C1 -C4 alkylamino, oxobutyl, 3-hydroxybutyl, phenyl, phenylCalkyl, benzoyl, phenylalkanoyl or benzenesulfonium, any of the phenyl moieties being substituted by one or two halogens), -C1-4 alkyl, alkoxy, CF3, amino or carboxy, or R2 and R3 together are C1-4, polymethylene interrupted. Optionally substituted by oxygen or NR, wherein R4 is hydrogen or C1-6 alkyl optionally substituted by hydroxy;

R ê is hydrogen or C __ alquilo alkyl and R é is hydrogen or R © R and R form together form a C_g alquil alkylidene group at the 8 ?- and '• CO <nR; 1 is a pharmaceutically acceptable ester group.

The alkyl moieties in the variables R 1a are preferably C 1-alkyl, such as methyl, ethyl and n- and iso -propyl. 4 "

Values for Fí. include hydrogen, methyl, ethyl, n- and isopropyl, phenyl and benzyl. Preferably it is methyl.

It will be taken into consideration when selecting the variables R0 and Rt that the nitrogen atom is not directly bound. to unsaturated aliphatic carbon.

Values for R.-, and include hydrogen, methyl, ethyl, n- and iso-propyl, -, sec-, iso- and tert-butyl. n-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-C1-4 alkyl, cyclohexyl-C1-4 alkyl and cycloheptyl-

alkyl, wherein values for C1-4 alkyl include methylene and ethylene, but-2-enyl, butoxy, 1-methylprop-2-enyl, formyl, acetyl, propionyl, methylsulfanyl, 3-hydroxybutyl, 3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and benzensulfonyl, or R 4 and F 5 together form > i0 > -X- (CHâ,,) â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ (CH2) n - (CH2) n - (CH2) n - (CH2) m -, where R3 is preferably R3 is hydrogen and R3 is hydrogen. "Is hydrogen or alkyl, for example methyl.

Most preferably R3 and R4 are hydrogen.

Suitable examples of the pharmaceutical esters of the compounds of formula (I) include esters of alkyl wherein the alkyl moiety is optionally substituted by up to three halogen atoms selected from chloro, fluoro and bromo, such as methyl, ethyl, n and iso -propyl, n-, sec- and tert-butyl esters and 2,2,2-trifluoroethyl esters, C 1-6 alkenyl esters such as vinyl, prop-1-enyl, 1-methyl vinyl 3-enyl, 1-methylenepropyl and 1-methylprop-2-enyl, (in both their alkynyl forms of E and L when stereoisomerism exists), esters of such as prop-2 butyn-2-ynyl, but-2-ynyl and but-3-ynyl, , cycloa. 1-yl and o-esters such as cyclopropylmethyl. The propyl ester, prop-2-enyl, pro-C,, ciclo, cycloalkyl-C, alquilo alkyl, such as the pharmaceutically acceptable ester methyl, ethyl, 2,2,2-trifluoroethyl, p-2-ynyl cyclopropylmethyl or cyclopropylmethyl, i.e. methyl, ethyl, 2,2,2-trifluoroethyl, propyl, prop-2-enyl, prop-2-enyl, but-2-ynyl, -yl, but-3-enyl, but-2-ynyl, but-3-

Appropriate values of

Râ, â, ... are hydrogen, methyl, Bâ,,, Bâ,,, Bâ, ..., Râ, â, ef, and Râ, em are as defined above, may represent a .alpha.

There is formula (II a preferred group of compounds of the formula) or a pharmaceutically acceptable salt thereof (!)

(II) wherein R f is hydrogen or C, alquilo alquilo alkyl and R e and R são are as defined in formula (I).

Preferred values for R., and RR are as described for the corresponding variables in formula (I).

The compounds of formula (I) may form acid addition salts with acids, such as, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, citric, lactic, mandelic, tartaric, and methanesulfonic,

It will be appreciated that the compounds of formula (I) wherein R6 or R5 hydrogen may exist tautomeric in more than one form, the invention extends to each of these forms and mixtures thereof.

The compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms

When referred to herein, the expression "compound of formula CI" 1 is also contemplated to include solvates thereof.

It will be appreciated that compounds of the formula < I) wherein R8 is hydrogen and R1 is other than hydrogen has a chiral center on the carbon atom adjacent to the moiety R4,

In addition, compounds in which R1 and R2 represent an alkylidene group may exist in forms E and Z, while the substituents R3, R4, R4 and R5 may contain The present invention extends to any simple stereoisomers such as enantiomers, or the like. the invention also provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof which process comprises the preparation of a compound of the formula Formula C1);

(III) wherein n is as defined in claim 1, wherein R 1 and R 2 are as defined for formula (I) or a group convertible thereto R 2 is defined in formula Cl) or. a group q? (I), is hydrogen or a protecting group in N, 3 and K together represent a keto group or a group convertible thereto, Y is a CN group or COL1, wherein Li is a leaving group ε M is hydrogen, or Y is hydrogen and M is a CN or COL J group wherein L is a leaving group; and optionally or as required, and in any appropriate order, conversion of R y when hydrogen to a N-protecting group, when Y or M is a CH 2 or COOH group, conversion of the resulting hydroxy group into a (leaving group the reaction of the latter with a compound of the formula: wherein R '' and Fu 'are FU' and R. or N-protecting groups, removal of

Any protecting group of NR 5 converting any of the leaving groups to R 2 'in CO 2 R 3, conversion of R 2, when other than R 2 into R 2, interconversion of R 2', R 2, R 2, and R 2, conversion of J and K to a keto group, separation of any stereoisomers such as enantiomers and / or formation of a pharmaceutically acceptable salt of a compound of the formula < 1). The cyclization of the enamine of formula (II) or its. tautomer may be carried out under conventional conditions in the presence of a strong base such as an alkali metal alkoxide, for example sodium methoxide in an appropriate solvent such as methanol, at an elevated temperature, or in the presence of a Lewis acid such as ZnCl 3, SnCl 3. or CuOCCH 3 - in a solvent; Acid catalysed cyclization of Letais using preferred copper (I) acetate compounds or CIV tin chloride is preferred. is especially when the cyclization to obtain of the formula (I) is carried out directly this is where R 1 'is CO 2 R 3.

Preferably J and K together represent a group which is converted to a keto group such as a protected or protected hydroxy group such as trimethyl- a protected keto group. A hydroxyethyl or tetrahydropyranyl group may be conventionally deprotected to give a hydrazide group which may be those conventionally suitably for example using oxalyl chloride / dimethyl sulfoxide or pyridinium chlorochromate to give the cetane, optionally C1-4 alkyl together and K are > exemplified by X1 and X2 are X and Z are and R1 and R2 are independently hydrogen. 'V-f' or 'polymethylphenyl groups', C1-4 alkyl, C1-4 alkoxy,

When X and Z are both oxygen, the group -X-R1-Z-R14 may be conventionally converted to an exemplary group such as by treatment with aqueous hydrochloric acid

When one of X or Z is an oxygen atom and the other is a sulfur atom, the group -XR TT and -ZR pode may be conventionally converted to a keto group, for example by treatment with aqueous hydrochloric acid or quaternization of the sulfur atom followed by hydrolysis, for example using an alkyl halide followed by water. When X and Z are both sulfur the group -X-R6 may be conventionally converted into a reaction group of one of the sulfur atoms with - gt; a heavy metal cation such as silver < ii) a quenching agent such as alkyl halide or

And an oxidizing agent such as peracetic acid to and then hydrolyzing the protecting group to provide a sodium group, for example using aqueous acetone or aqueous acetonitrile.

Preferably, Z is oxygen.

Rp. and R 9a hydrogen may be converted to an alkylidene group at the 8-position by a condensation of aldol with an appropriate aldehyde or ketone, such as acetone. The alkylene group may then be hydrogenated to give the corresponding Rp alkyl group using for example, a palladium-on-carbon silyl catalyst and

Examples of N-protecting groups include N-methyl-2- trimethylsilyl-ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride

Preferably R-? is hydrogen

Suitable examples of K 2 groups include the groups described hereinbefore, wherein R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl or C 1 -C 4 cycloalkyl. -cycloalkyl, CH = NOH, COOHH2 -, where Q is a protecting group such as

Xm JU. benzyl in which the benzyl moiety is optionally substituted on the phenyl ring by one or two of halogen, CF 3, C 1-4 alkoxy, C 1-6 alkoxy, where R 2 and R 3 are independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and phenyl or optionally substituted phenyl C 1 -C 8 alkyl, such a bed has been described above for optional substituents on the phenyl ring of a benzyl ester, or together form a C1-6 chain, polymethylene optionally interrupted by oxygen or NR3 where R3 is hydrogen or alkyl, for example morpholino or piperazino,

A protecting group G may be removed by conventional hydrolysis or by hydrogenolysis to provide the free acid which may then be esterified under conventional conditions by reaction with the appropriate alcohol R OHOH, optionally with prior conversion of the acid into the acid chloride by reaction with an agent of suitable chlorination such as thionyl chloride, or with an alkylating agent wherein X is a leaving group such as chlorine, bromine or iodine in the presence of an appropriate base such as dimethylformamide

An intermediate amide may be hydrolyzed to give the free acid which may be esterified as previously described.

A cyano group R4 'may be converted to anhydrous acidic conditions on an imino ester by reaction with the appropriate alcohol R4 is then hydrolyzed to give the group -CH2 R4'

A L-1 = NOOH group may be converted to cyano by dehydration with a suitable dehydrating agent such as formic acid at an elevated temperature, and the cyano group being converted to CO₂R tal as above. Alternatively, the CH = NCH group may be converted to formyl by oxidized hydrolysis to the free acid using a suitable oxidizing agent such as CrO 2 and esterified as described above.

COR1 R2 groups may be converted to C1-4 alkyl by means of an acid by halogen reaction and esterification.

Suitable examples of leaving groups and when Y or M is COL ou or COL₂ include hydroxy and, more preferably, alkoxy such as C,, alco alkoxy, for example ethoxy or methoxy.

X Cyclization of the compound of the formula < 111 > or its imine tautomer gives rise to a resulting compound having a hydroxy group at the 4-position of the pyridine ring. The hydroxy group may be converted into a leaving group such as those described below for L, preferably as chlorine, by reaction with a halogenation agent such as phosphorus oxychloride or oxybromide of > phosphor. The leaving group may be displaced by the compound, IMB under conventional conditions for aromatic displacements HNK._, h1'0 > at elevated temperatures in an inert solvent such as toluene, methanol, ethanol, pyridine, dimethylformamide or dioxane. Alternatively, the reaction may be carried out in HNPtR / R4, which functions as the solvent.

A protecting group R.-j 'or R' " such as p-methoxybenzyl may be removed conventionally. The conversion of hydrogen R e and R / to R / may be carried out according to conventional procedures for the alkylation or acylation of a primary amine. The acylation may be

I carried out by reaction with the appropriate acyl halide. However, R 2 / R 3 other than hydrogen or acyl groups are preferably introduced via the route in which Y or M is COL, or CO, in the compound of the formula

D formula (III), by displacement of the separation group with compound HNRâ, "Râ," as discussed above.

Pharmaceutically acceptable salts may be conventionally prepared by reaction with the appropriate acid or derivative. be prepared by the

Compounds of formula (III) may react with a compound of the formula < IV1) s Υ

a compound of formula CV);

(V)

R 1, R 2, R 3, R 4, J, and K are as defined in formula (I), L is a leaving group and H is as in formula (III) or. L and M together are R4 ', defined in which a bond has been defined,

Intermediates of formula (III) and (IV) are novel and constitute a further aspect of the present invention,

Suitable examples of the leaving group L include halogens, such as chlorine and bromine, hydroxy, acyloxy such as acetoxy, C-alkoxy, such as methoxy or ethoxy, preferably raethoxy or NR 1 R 2, wherein R 1 and R 2 are independently hydrogen, . together form a polymethyl chain optionally interrupted by oxy or NR 1 where R 2 is hydrogen or C 1-6 alkyl optionally substituted by hydroxy. When L is hydroxy, it will be appreciated that the compound of formula (V) exists in msis in a tautomeric form. Reaction of a compound of formula < IV > with a compound of formula (V) may be carried out under conventional conditions for condensation reactions, at elevated temperatures in an inert solvent such as toluene, benzene, ethanol, pyridine, dimethylformamide or dioxane, optionally in the presence of a catalyst such as para-toluene sulfonic acid or 1-camphorsulfonic acid, with separation of water if appropriate.

For the preparation of compounds of the formula (I) wherein R1 is hydrogen, the compound of formula (V) wherein: L and H together represent a bond or L is hydroxy and M is hydrogen, and R3 is a C1-6 alkoxycarbonyl. The reaction is reacted with the compound of the formula < IV > may then be followed by a decarboxylation step to give hydrogen; L is a leaving group and R '' ' is hydroxy. In the resulting compound, the hydroxy R 1 'can be converted into hydrogen by first replacing it with chlorine by conventional chlorination with a chlorinating agent such as phosphorus oxychloride followed by reductive dehalogenation under standard conditions, for example synco in acetic acid. The conversion to hydrogen can be carried out before or more preferably after the compound of the formula (III) is cciszed. (iii) L is a leaving group, M and 'are both methyl and R is hydrogen.

Compounds of the formula aa (XV / d) are prepared from the compounds of the formula (VI): ## STR1 ## in which R.sup.6 is hydrogen,

R 2, R 2, R 3, R 4, and R 5 are as defined in claim 1, fl a. formula with WCCH.7Y is sulfur in the presence of a base such as a mine in an inert solvent such as methanol or ethanol.

where < 111 > ? dietii

Compounds of formula < VX) or are known compounds or may be prepared in a manner analogous to the known compounds. For example, compounds of the formula < V) wherein M is hydrogen, L is OH and R4 is CH3 may be prepared by reacting diketene with the appropriate alcohol R1 OH using a method similar to that of RJ Cleroens and JA Hyatt, J. Org. Chem., 1985, 24, 2431, the compound of the formula V> wherein R 1 'is phenyl, M is hydrogen, L' is R 2 ', R 2' is ethoxycarbonyl is described by V.L. leiqhton Amer. Chem. Journal (1986), 21, 133).

A formula (VI) class of intermediates comprises compounds or an ester or amide salt thereof: a.

(VII)

r 'as defined in formula &lt; III &gt; or a group convertible to COâ,,Râ, ..., Râ, ..., Râ, ..., Do you smell? k *, R2 " R 2, R 3 and R 4 are as defined in the formula <I>, since when X is NR 1 R 2, R 2, R 3 and R 4 are as defined in formula The compounds of the formula (I) are a keto group and R 1 'and R 1' are as defined above,

Exemplary R_ &quot; &quot; when different from CO, R- include

In a further aspect, the invention also provides a process for the preparation of a compound of the formula (I) or. a pharmaceutically acceptable salt thereof which process comprises the deprotection of a compound of formula &lt; V11 &gt; wherein X is NR 10, R 13, and R? is Rj? and J and K together represent a group convertible to a keto group and thereafter optional separation of stereoisomers such as enantiomers and / or formation of a pharmaceutically acceptable salt of a compound of formula (I). The present invention also provides a pharmaceutical composition which comprises a compound of the formula &lt; I) or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared by mixing, suitably at room temperature and at atmospheric pressure, is usually adapted for oral or parenteral administration and as such may be in the form of tablets, capsules, powders, granules, lozenges, reconstitutable powders for the oral route, or solutions or suspensions for injection or infusion. Oral compositions are generally preferred.

Tablets and capsules for oral administration can ~ κ ρ r! &Quot; -. and â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- The tablets may be coated according to methods well known in the ordinary pharmaceutical art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavoring agents or dyes.

For parenteral administration, fluid dosage unit forms are prepared using a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle. In the preparation of solutions, the compound may be dissolved for injection and sterilized by filtration prior to introduction into an appropriate vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents are dissolved in the carrier. To increase stability, the composition may be frozen after introduction into a vessel with the water removed under vacuum. Are the parenteral suspensions prepared substantially? likewise, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be carried out by filtration. The compound can be sterilized by 18

The dose of the compound used in the treatment of BNC disorders such as anxiety or depression will usually vary according to the degree of impairment, the patient's body and other similar factors. However, as a general guideline the dosage units may vary between Θ, Θ 5 and "ΘΘΦ mg. preferably between 0, 5 and 2 mg / kg, for example 0.2 and 0.1 mg, and such dosage units may be in the range of 0.1 to 10 mg / kg. more than one VOS per day, for example two to x. r * §e-V1 per day. so that dc 3 will be seen in u. The dose may be increased for a number of weeks or months.

exposure to ethylene oxide antigen from the suspension in a sterile vehicle. 1. A surfactant or a surfactant. The compound of formula (I) is prepared according to the general formula (I). can contain from 0.1% to 99% by weight. in the range of 10 to 00% by weight of the active material. It depends on the method of measurement. The invention further provides a pharmaceutical composition for use in the treatment of disorders of the CM, in particular anxiety and depression which composition comprises a non-toxic, effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for treatment in the art. 1 a rs s i ed ed DS human beings, which in an amount not to ïI &gt; or a salt thereof. The invention further provides for and / or prophylaxis of; disorders of the SMC, or depression in mammals, including comprising administering to the patient toxic, effective, a pharmaceutically acceptable compound of the formula of the particular use formula,

The invention also provides a compound (1), or a pharmaceutically acceptable salt thereof for the treatment and / or prophylaxis of CNS disorders, for anxiety or depression. The invention further provides the use of a compound of the formula Cl), or. of a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prophylaxis of CNS disorders, in particular anxiety or depression.

The following examples illustrate the preparation of the compounds of the invention: 1-Ammonio-6-ethylenediamethylcarbonitrile (Dl) 45, 7-tetrahydronaphthalene iof ene-3-

NH2

The title compound was prepared from 1,4-cyclohexanedione and the title compound was prepared using a similar procedure to that of K Oewald et al., Chem. Ber "1966, 94 (yield 49%). NMR (CDClâ,ƒ) s), 4.72 (2H, bs), 95 (2H, t), 2.72 (4H, m), 4.02 (4H,

Description 2:% ή Η - · ** · I-i. Li Ν-3 ·

6.6 Ο ϊ ϊ X 1 Γ Γ d d d Ο Ο Ο Ο Ο 4 4 4 4 4 4 4 4. (I.e. t -butylaminopropionate, and the like. &quot; Buteripi.cc &quot; ethyl ester &lt; D2) &gt; 0

A mixture of aminonitrile (D1) (13.16 g, 55%, mmol) and ethyl B-ethoxycroionate (26 g, 164 mmol) in mesitylene (4 ml) was heated under reflux The residue was chromatographed on Kieselgel 60 and eluted with a dichloromethane gradient of 2% methanol. The product was triturated with petrol &lt; p, &gt; 4 &apos; -6 ° C) and filtration gave the title compound as a yellow solid (11.9 g, 61%) mp 115-180 ° C. 1 H-NMR (CDCl 3): δ 2.10 (3H, s), 2.85 (4H, m), 1.30 4, δ2 (4H, S)? 4.20 &lt; 2H, q) 3 at 1.90 &lt; 1H, s). 21

Description 3 4-Amino-7,7-diisopropyl-5-methyl-5,6,7,8-tetrahydro-benzo-Cb-thieno2,5-bpyridine-5-carboxylic acid, ethyl ester &lt; D3)

A solution of the sulfosuccinimide D2 (11.7 g, 33.6 mmol) in toluene (4 ml) was treated with a solution of sodium ethoxide in ethanol (4 ml) and heated to reflux for 2.5 hours. The mixture was filtered, the organic phase separated, dried (Na 2 SO 4) and evaporation in vacuo gave a brown oil. Alumina chromatography for thin-plate chromatography, eluting with 0-2% methanol on a dichloromethane gradient, provided the title compound

(%) As a yellow gum NMR (CDCl3): Î »max 1.4Â ° (3H, t), 2.05 (2H, t), 2.70 (3H, s), 3.23 (2H, t), 4.05 (4H, s), 4.38 (2H, q), δ, 601 (2H, bs).

ΕκθίΤίρΙο 1

4-Amino-2-methoxy-7-Î'-5β, 6,7,8-tetrahydrobenzo [b] thieno [2,3-a] pyridine-5-carboxylic acid, 5-ethyl ester R, &gt;

A solution of i. (200 mL) was treated with water (1 mL of <2 mL) and then warmed to 24 hours. 2 m), and the mixture was further heated to reflux for 8 hours, then stored at 5 ° C for 12 hours. Filtration provided a white crystalline solid (3.5 g) which was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, dried (Na2 SO4) and concentrated in vacuo then crystallization took place. After storage at 5 ° C for 12 hours, filtration provided the title compound as a crystalline solid &lt; 2.37 g, 59%).

mp 159-161 ° C. Found: C, 59.32; H, 5.19; N, 9.17. Found: C, 59.19; H, 5.30; N, 9.24; (3H, t), 2.71 (3H, s), 2.40 (2H, q), 6.55 (2H, bs). 2, hm (2li, t), 3.40 (2θ, t), 3, / 8 &lt; 2H,

? lT? M X Q

4-Amino-2-methyl-7-oxindole-5,6. 3-carboxymethyl-5-naphthoic acid, is C C-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t-C t ben-C or E3, E3, E2, Fc, E2,

The title compound was prepared from D1 and cyclopropylmethyl ester 3-oxo-butyric acid by means of trahydrofuran-2-carboxy-2,3,3-hvdyridine-3-carboxylic acid, cyclopropylmethyl ester using a similar procedure to that described in Description 2, Description 3 ε Example 1 = Î »max 168Â ° (from ethyl acetate) Found: C, 89.89; H, 5.51; N, 8.53 C H requires C, 61.8; H, 5.49: M, 8.48% Example 3

Acrid 4-aryl .1. 2-methyl-7-oxo-6,7,8-tetrahydro-phenylethyl-3-thieno2,3-bpyridine-3-carboxylic acid, methyl ester (E5, R5) The title compound was prepared from D1 and methyl acetoacetate via the intermediate 4-antino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydronaphthieno2,2- 3-pyridine-3-carboxylic acid, methyl ester using a procedure similar to that of Example 2, m.p. 202-6 ° from ethyl acetate)

Found: C, 57.95, H, 4.86, N, 9.65. Requires C, 57.92; H, 4.86; N, 9.65%

Example 4

4-Amino-2-methyl-7-oxo-5-oxo-5,6,7,6-tetrahydro-benzoylbenzoylE2, -bipyridine-3-carboxylic acid; prolyl ester (E4 "R, = CH" .CH, -CH-,) &gt; The title compound is prepared in a total yield of 11% from D1 and 3-quinolinecarboxylic acid, propyl ester via the intermediate 4-amine-7,7-ethoxyethyl- methoxy-5- [6- 8- have you been robbing zo3 b3 tisnctS? 3-carboxylic acid-3-carboxylic acid ester using a procedure similar to that of Example 2, mp 141 DEG-141 DEG (from ethyl acetate / petroleum ether 60:80 ) &gt;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒMRM (d, DIâ,,S0): 0395 t-1-J1 H, t, J = 7 Hz) (2H, d, J = 8Hz), 2.85 (3H, d, J = 8Hz); ~ T f g jT »tç / 0 < 2H 3 t 3 Λ · W 6H *? 1 H-NMR (CDCl3):? (2H, t, J = 7Hz), 6.4 (2H, t, J = 6Hz), 7.4 (2H, i -7 ~ OK 0-5 16.7, 8- * tramadol roben: ·: Ο Γ · b J t iene · Γ. 2, -b .1 ΡΧΓ ΡΧΓ ΡΧΓ ΡΧΓ "" "3 1-yl, 2-oxo-2-phenyl-1-isopropyl- The title compound was prepared as a total yield of 8% from D-1α-propyl-2-propyl-2-methyl ester by the addition of methyl (4-amino-7,17-t-thienyl) oxy] -2-methyl-5.65 7, S-tetradecenes, -C (3-thienyl) -2- The title compound was prepared as described in Example 2 (a) and (b) in the same manner as in Example 2 (a).

P. mp 148 DEG-150 DEG C. (from ethyl acetate): 1 H NMR (CDCl3): Î'(3H, s) for example. (2H, t, J = 3Hz), 3.45 (2H, m). ?  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ3.50 (2H, s) hm &gt;  € ƒâ € ƒâ € ƒ5.95-6 g (1H, brm), 6.60 (2H, broad) A 7 V H · S 8 -tetrahydro-benzo [b] thieno [2,3-b] indole-3-carboxylic acid tert -but-2-yn-1-one , The title compound was prepared in a total yield of 5X from D1 and 3-oxo-butyric acid, 2-but-2-ynyl ester by means of of the intermediate 4-amino-7,7-ethylenedi o acid &gt; 2-methyl-5,6,7,8-tetrahydrobenzo [b] thieno [2,3-b] pyridine-3-carboxylic acid, but-2-ynyl ester using a procedure similar to that described in Example 2, p. 190-2 ° C from ethyl acetate) â € ƒâ € ƒâ € ƒ1 H NMR (CDCl3, Î') S 1.90 <3H? (2H, t, J = 3Hz), 2.74 (3H, s), 2.8 (2H, t, J = 8Hz) 90 (2H, qs, J = 3Hz), 6.55 (2H, broad s)

Example

4-aminophen-2-yl] -7- [oak] - 5,6,7,6-tetrahydronaphthalene. The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure described in Example 1 and the title compound was prepared as a white solid. prepared in a total yield of 1% from 2,2,2-trifluoromethyl acetoacetate and Di by means of the intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8- tetrahydro-furan-3-ol, 2,3-b] pyrrole-3-carboxylic acid, 2,2,2-trifluoroethyl ester using a similar procedure to Example 2. mp 140-6 ° NMR (CDCl3) S·. 2.55 (3H, s), 2.86 (2H, t, J = 6Hz), 3.44 (2H, t, J = 6Hz), 3.65 (2H, s ), 4.70 (2H, q, J = 8Hz), 6.7 (2H, broad s). 4 &lt; J &lt; 1 &gt; ? it

Example 8 &gt; 4-Amino-2-methyl-7-oxo-5,6,7,3-tetrahydrobenzo [b] pyridine-3-carboxylic acid, but-5-enyl ester (E8, The title compound was prepared from D1 and 3-oxo-butyric acid, but-3-enyl ester by intermediates of the intermediate 4-amino-7,7-dimethyl-2- tetrahydro-benzo [b] thieno [2,3-b] pyridine-3-carboxylic acid, but-3-one ester using copper (I) acetate following a similar procedure to that of Example 2,

Federal Police. 130-2 * from ethyl acetate). &gt; 8 '' '' '' '' '' '' '-' '' '' ' λ.'μ Π jj m &gt; , 2.7 (3H, s). p.85 (2H, t, 3-B Hz), t, J = 8.5 Hz), Î'[(2H, s), 4.02 (2H, t). 0 = 8.5 Hz), (2H, br, m &gt;, 5.80-6.95 (1H, br, m), 1.60 (2H, br, s).

Ex.

4-Amino-2-methyl-7-o-o-5,6,7, S-tetrahydrobenzolbenzenecarboxylic acid <2,3-b] pyridine-3-carboxylic acid [ ------ J ----- φ. The title compound was 5% complete from D1 and acid prepared in 3-oxo-butyric yield, 4-amino-7,7-ethylenedibenz-3-butyl ester A similar procedure to that of the cyclization was carried out in methyl ester via the oxo-2-methyl-5,6,7,8-tetrahydrobenzotinyl ether intermediate, but- 3-yl ester using Example 2, but wherein the n-butyl acetate step using SnCl3. mp 167-8 °

1 H NMR (CDCl 3) δ 2.22 (3H, t, J = 2.8Hz), 2.70 (2H, dt, J = 2.8, 8.5 Hz), 2.75 (3H, s), 2H, t, J = 8.5Hz), 3.45 (2H, m), 3.70 (2H, s). 4.45 (2H, t, J = a, b Hz), 6.60 &lt; 2H, br s). 28

Example 1 5,6,7,8-Tetra-but-3-

4-Amino-2-methyl-2-methyl-8-cyclohexylbenzo [b] thiobenzo [2, 3-enyl] (E) -1- -3-carboxylic acid,

The amine D1 was converted to the 3-oxobutyric acid but-3-enylic acid crystallized product using copper acetate (Π) in% yield by the method of Description 2 and Description

3. Treatment with aqueous acid for 48 hours yields a crude product containing 9 g of silica using 30% pure sample acetate of the title compound.

The title compound was obtained, which was recrystallized from ethyl acetate / n-pentane to give the title compound which was recrystallized from ethyl acetate / n-pentane. The title compound was prepared as yellow crystals, mp 136 DEG-8 DEG C. NMR (CDCl3): δ (3H, s), 2.55 (2H, s), 2.55 (2H, m) . 9 t * T i 3H s &gt; , 2.86 (2H, t, J = 8.5 Hz), 3.40 (2H, t, J = 8.5 Hz); , 4.42 (2H, t, J = 8Hz, 5Hz), 5.10-5.25 (2H, broad m), 5.75-5.98 (1H, m) 6.79 (2H, s); mplo)

Physiological Data 1 »Beiler-Seifter Process

Potential antigenic properties were evaluated using the Beiler-Seifter process based on the process originally described by Beyer and Seifter, (196) Psychopharmacology, 1, 482-492. The process was found to be selective for drugs with anxiolytic properties CCook and Sepinwallj (1975) &quot; Mechanism of Action of Benzodiazepines &quot; Costa, E., Greengard, P., Raven Press, New York, pp. 1-28), 81 trained rats in a variable interval scheme of 30 seconds to press a lever to obtain a feed premium The 5 minute sessions of the VI3 regimen alternate with 2-5 minutes of a regimen (FR5) wherein each pressure on the lever is followed by the presentation of an alimentary pill together with a gentle shock on the paw of 5 seconds. total study lasts for approximately 30 minutes. Rats typically respond with high degrees of lever pressure in scheme VI.3 € 5 and with haiKos degrees of response in the 'FR5' conflict session. Anxiolytic drugs increase the degrees of response suppressed in the &quot; conflict &quot; session

Drugs are given intraperitoneally or orally to groups of 3-8 rats before the test. "

The results are square root of the session number of &quot; conflict &quot; FR required to normalize expressed with the percentage increase in the total of requests on the lever in the 5 '. The transformation of the square root is air data for statistical analysis &lt; AnuVA) using parametric methods

2 'Γ' ~ 'connection' The rat cerebral cortex reins are homogenized in 20 sucrose sera (0.532H) and centrifuged at 120Â ° C for 20 minutes &lt; 4Â ° C). The flocculant is removed and centrifuged at 50.degree.-0.0 g (4øC, 2 minutes). The Fv pellet is then suspended in 20 g. volume of buffer 5 Tris citrate (pH 7,51) and centrifuged at 50 ° C. 4 ° C, 20 minutes). This stripping step is then repeated three times and the slurry is finally dried in 20 volumes of buffer and capped at -70 ° C. The tissue suspension &lt; 50 μΐ) is incubated &lt; 25 ° C. 1.20 mini Li tOS &gt; com Γ. -TBPS (2nM) in 4% NaCl and 2M NaCl. 5 κ. "A". 10 π Bi ABA med iUd in the pr ipsis. Hysi π 7 7 7 7 7 í í í í í í 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

(4) and (10)

I are added in a volume of 50 μl. The total assay volume is 500 μl. The incubation is stopped by rapid filtration using an apparatus to collect SKatron cells and the radioactivity is measured by liquid scintillation spectrometry. concentration of test drug which inhibits 5% of the specific binding t t

Result of Test

Seis Isr-Seif tssr Process

Compound

Increased Dose. response, in \ mq / kq) confit session &quot; &gt;

Example 1 Compound E2 also showed a significant increase in response in the 'conflict' session at a dose of 20 mg / kg p, D.

Process for binding to 3-HT2HS

Compound IC: H-1

Example 1 13 μη? 1 / μη (2 parts)

I

Compounds of Examples 2, 20 μΜ. less than 50

Claims (1)

A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof; R. \ / &gt; (I) and wherein R 1 is hydrogen, C 1 -10 -alkyl, phenyl or phenyl-C 1-4 -alkyl wherein the phenyl moiety is optionally substituted by one or more C 1-10 alkyl, alkylthio, hydroxy, C alc-alkanoyl, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C, .. alquilo alkyl groups or by C _r alc alkanoyl, cyano, carbamoyl or carbocycloalkyl; And. are independently selected from hydrogen, -COR. alkyl, C1-4 alkyl. cycloalkyl, C-, C ,, ciclo ciclo cycloalkyl, C ,, alquilo alquilo alkyl, C-S al alkenyl, C _ _ alc alkanoyl, C^^ al alkylsulfonyl, di-C_A alquil alkyl) amino-C "alquilo alquilo alkyl, 3-oxobutyl, 3- hydroxyalkyl, phenyl, phenyl; alkyl, benzoyl, phenyl-C2-7 alkanoyl, or benzenesulfonyl any of the phenyl moieties being substituted by one or two halogens). alkyl, Cp, alkoxy, CF-, amino or x- Carboxy, or R-, and Fp together are C1-4. polymethylene optionally interrupted by oxygen or NR *. wherein R4 is hydrogen or C1-6 alkyl optionally substituted by hydroxy or R8 is hydrogen or C1-4 alkyl; alkyl and R? R1 is hydrogen or R1 and R2. . . R 3 is a pharmaceutically acceptable ester group which comprises cyclizing a compound of the formula (III) or its imin tautomer; R4 'is R4a as defined in formula CI &gt; or a group convertible thereto, R 1 'is such. (I), or an attractor group of convertible electrodes in -CO2, R3 and R4 are as defined in formula (1), Â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ , or Y is hydrogen and M is a CN group. COL.7, wherein L1-j is a leaving group and thereafter optionally or in the form of 1-. Π ecessár i. 0, and in any order i appropriating hydrogenase in an Apo COL group. or the conversion of the group 1 in which R 2 'is RV and R 3 is the radical of the last group in which R 2' is R 5 and R 6 is hydrogen. the conversion of any protecting group of NR-γ, the conversion of; any electrically attracting group R 2 'in CO 2 R 3, the conversion of R 1' when different from R 1 into R 1, the interconversion of R 2 ', R 2, R 3'. R11 and R10? the conversion of J and K to a keto group, a. separation of formation of any stereoisomers such as enantiomers and / or that of a pharmaceutically acceptable salt of a compound of formula (I). A process for the preparation of a compound as defined in claim 1 which comprises deprotecting a compound of the formula X (VII) wherein X is, R 1 'is CO 2 -, -CH 2 and R 2' is H, and J and K together represent a group convertible to a keto group and then optionally separating any stereoisomers such as enantiomers and / or forming a pharmaceutically acceptable salt of a compound of formula (I). The term of Formula (I) of claim 1, wherein the alkyl is optionally substituted by up to three halo atoms. alkylthio. 1a, LZ- &amp;; cycloalkyl or cycloalkyl-C 1 -C 4 -alkyl. The process according to any one of the preceding claims, wherein R 1 is hydrogen, C 1 -C 4 -alkyl, alkyl, phenyl or benzyl. A process according to any one of the preceding claims, wherein R 1 and R 2 are independently hydrogen or C 1-6 alkyl. 4-amino-3-pyridin-3-yl) -4-amino-b] pyridine-3-carboxylic acid, 4-amino- amino-3-pyridine-3-carboxylic acid 4-amino-3-pyridine-3-carboxylic acid 4-amino- 4-amino-3-pyridine-3-carboxylic acid 4-amino-bpyridin-3-yl) -D-O- 7-carboxylic acid, ester. A process according to any one of claims 1 to 5, characterized in that R 1 is hydrogen. 2-yl] -5,6,7,8-tetrahydrobenzo [e] eneene E2, carboxylic acid, isothiecarboxylic acid, 2-ethylhexyl-5,6,7,7- B-tetrahydrobenzazepine or 12-carboxylic acid, cyclopropyl ester. 2-methyl-7-oxo-5,6,7,8-tetrahydro-biphenyl-2-carboxylic acid, methyl ester, 2-methyl- S-tetrahydrobenzo [b] thien-2-ene E2, Carboxylic acid, prop-2-enyl ester, 2-methyl-7-oxo-5,6,7, -tetrahydro-benzoic acid ester, carboxylic acid, but-2-ynyl ester, 2-methyl-7-oxo-5,6,7,8-tetrahydrobenzo [b] ezene E, carboxylic acid, 2,2,2-trifluoroethyl ester, • 2-methyl-7-OXO-5,6,7,8-tetrahydrobenzo [b] thieno [2, carboxylic acid, but-3-enyl ester], 8-1-ethylhexane (1-methyl-1-ethylidene) -7-oxa-5,6,7-tetrahydroisoquinoline-4-carboxylic acid, A compound according to claim 1, wherein R 1 is hydrogen, or a pharmaceutically acceptable salt of any of the foregoing. 9§. 5. A process for the preparation of a pharmaceutical composition comprising mixing a compound of claim 1 with a pharmaceutically acceptable carrier. or prophylaxis for administering to claim 1, being from about 1 to 10 mg of a compound of formula (I) according to any of the preceding claims. of active compound per kilogram of body weight per day. Lisbon, May 6, 1991 Official Agent of Industrial Property RUA VtCTOR COROON, 10-A 3.a 12CX) LISBOA