JP2002504484A - New compound - Google Patents

Abstract

  (57) [Summary] Novel sulfonamide derivatives with CNS activity, their preparation and their use as medicaments.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel sulfonamide compound having pharmacological activity and a method for producing the same.
, Compositions containing them and their use in the treatment of CNS disorders
You. US Pat. No. 5,703,072 has dopamine receptor affinity
Bicyclic nonane and decane compounds disclosed and useful in the treatment of schizophrenia
Has been charged. U.S. Pat. No. 5,457,121 discloses cis-hexahydro-
5- (1,2,3,4-tetrahydro-2-naphthalenyl) pyrrolo <3,4, c
Disclose pyrrole as an inhibitor of serotonin reuptake. European Patent Application 08
No. 15861 is 5-HT₆Disclosed are a series of arylsulfonamide compounds that are said to have receptor activity and are useful in treating various CNS disorders. This time, 5-HT ₆ Structurally distinct classes of compounds have been found which have been found to have receptor antagonist activity.

Accordingly, the present invention provides in a first aspect a compound of formula (I):

Embedded image (I) wherein E is —SO ₂ NH— or —NHSO ₂ —; and P is phenyl, naphthyl, each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. A is a single bond, a C _1-6 alkylene or a C _1-6 alkenylene group; R ¹ is halogen, substituted with one or more fluorine atoms. C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkanoyl, amino, alkylamino or dialkylamido Bruno, SR ¹¹ (here, R ¹¹ is hydrogen or C _1-6 alkyl) or a, there have the R ¹ is phenyl, benzyl, naphthyl, each are selected from oxygen, nitrogen or sulfur 1 Two to four heteroatoms Wherein heterocyclic ring or 5 to be a 7-membered heterocyclic ring; n is 2, 3, 4 or 5; R ³ is either a group R ^5, or together with R ⁵ group ( R ⁴ is of the formula (i), (ii) or (iii): formula (i) , forming CH ₂ ) ₂ O or (CH ₂ ) ₃ O;

Embedded image Wherein R ⁶ is C _1-6 alkyl optionally substituted by one or more halogen atoms; m is 0, 1 or 2; q is 0, 1, 2, 3 or 4 ) Formula (ii)

Embedded image (Wherein R ⁶ , m and q are as defined in formula (i)); or formula (iii)

Embedded image Wherein R ⁶ , m and q are as defined in formula (I), and R ⁷ is hydrogen or C _1-6 alkyl; R ⁵ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy optionally substituted with one or more fluorine atoms, trifluoromethyl, or together with R ³ a group (CH ₂ ) ₂ O or (CH ₂ ) To form ₃ O] or a salt thereof.

[0003] An alkyl group, alone or as part of another group, may be straight-chain or branched. The term "halogen" is used herein to describe a group selected from fluorine, chlorine, bromine or iodine, unless otherwise specified.

When the group P is a bicyclic heterocycle, suitable examples are benzothienyl, indolyl,
Includes quinolinyl or isoquinolinyl. When P is a 5- to 7-membered heterocycle, suitable examples are thienyl, furyl, pyrrolyl, triazolyl, diazolyl,
Includes imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocycle can be attached to the rest of the molecule via any suitable carbon atom or, if present, nitrogen.

Preferably, P is phenyl, naphthyl, thienyl and most preferably benzothienyl. Suitably, A is a single bond, a methylene or ethylene group or -CH = CH-
Group. Preferably, A is a single bond or methylene.

Suitably, R ¹ is hydrogen, halogen, phenyl, C _1-6 alkoxy, most preferably OMe, SR ¹¹ , most preferably SMe or C _1- optionally substituted by one or more fluorine atoms. ₆ alkyl, for example methyl or trifluoromethyl. When R ¹ is a heterocyclic group, suitable examples include those described above for P. Preferably, n is 1, 2, or 3.

It will be appreciated that if the R ³ / R ⁵ groups are bonded together, the two groups must be bonded to adjacent carbon atoms on the phenyl ring. Preferably, R ³ is a group R ⁵ , especially hydrogen.

Preferably, R ⁴ is a group:

Embedded image It is.

Preferably, R ₅ is C _1-6 alkoxy, most preferably methoxy. Preferably, R ⁵ is para with respect to the sulfonamide bond.

In particular, a preferred compound of the present invention is 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [4-methoxy-3- (octahydropyrido [1,2-a] pyrazine -2-yl) phenyl] amide, S-5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid "3- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4- Methoxyphenyl], R-5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid [3-
(Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-Diazabicyclo- [3.3.1] non-4-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-diazabicyclo- [3.2.1] oct-4-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [4-methoxy-3- ( 5-methylhexahydropyrrolo [3,4-c] pyrrol-2-yl) phenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (hexahydropyrrolo- [3, 4-c] pyrrol-2-yl) -4-methoxyphenyl] amide, N- (5-bromo-3-fluoro-2-methoxyphenyl) -4-methoxy-
3- (5-methyl-cis-hexahydropyrrolo [3,4-c] pyrrol-2-yl] -benzenesulfonamide, and pharmaceutically acceptable salts thereof.

The compounds of formula (I) are customary pharmaceutically acceptable acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid And acid addition salts with acids such as tartaric acid and methanesulfonic acid. The compounds of formula (I) may also form solvates, such as hydrates, and the present invention also extends to these forms. Also, as used herein, the term "compound of formula (I)" is understood to include these forms.

Certain compounds of formula (I) can exist in stereoisomeric forms, including diastereomers and enantiomers, and the present invention extends to each of these stereoisomeric forms and mixtures thereof, including racemates. Different stereoisomeric forms may be separated from one another by conventional methods, and any given isomer may be obtained by stereospecific or asymmetric synthesis. The present invention also extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: (a) when E is a group —NHSO ₂ —,

Embedded image (II) wherein R ¹ , P, n and A are as defined in the formula (I) or a protected derivative thereof and a compound of the formula (III):

Embedded image (III) wherein R ³ , R ⁴ and R ⁵ are as defined in formula (I) and L is a leaving group; or (b) E is a group- When SO ₂ NH—, formula (IV):

Embedded image (IV) wherein R ¹ , P, n and A are as defined in formula (I) and L is a leaving group, and a compound of formula (V):

Embedded image (V) wherein R ³ , R ⁴ and R ⁵ are as defined in formula (I) or a protected derivative thereof, followed by: removal of any protecting group Providing a method which may comprise the formation of a pharmaceutically acceptable salt.

Suitable leaving groups include halogens such as chloro or bromo, especially chloro. Reaction of compounds of formulas (II) and (III) and formulas (IV) and (V)
The reaction of the compound is typically in an inert solvent such as dichloromethane or acetone and is carried out by mixing the two reagents together. Such a reaction may be performed in the presence of a base.

[0015] Those skilled in the art will appreciate that certain groups may need to be protected. Suitable protecting groups and methods for their attachment and removal are conventional in the field of organic chemistry, for example, Greene TW 'Protective groups in organic synthesi
s' New York, Wiley (1981). For example, suitable protecting groups for piperazine groups include BOC, COCCl ₃ , COCF ₃ and methyl, the latter of which can be removed by treatment with 1-chloroethyl chloroformate according to standard methods. Good.

The compounds of formulas (II) to (IV) are commercially available or may be prepared according to known or analogous or following methods. The following procedure is illustrative rather than limiting.

A compound of formula (III) wherein R ⁴ is a group of formula (iii): 4-methoxy-3- (5-methyl-cis-hexahydropyrrolo [3,4-c ] Pyrrol-2-yl) -benzenesulfonyl chloride is described in Buchwald (Tet. Lett. 199).
7, 38, 6359-6362) with cis-hexahydro-2-methylpyrrolo [3,4-c] pyrrole hydrochloride (US Pat. No. 5,457,121) using a palladium coupling reaction according to the general method disclosed in US Pat. It can be prepared by coupling bromoanisole. The resulting amine can be treated with chlorosulfonic acid in dichloromethane to give the desired compound.

The aryloctahydropyrido [1,2-a] pyrazine of formula (V), wherein R ⁴ is a group of formula (i), is obtained by a synthetic method as shown in Scheme 1. be able to.

Scheme 1

Embedded image

Alternatively, using a modified method based on the use of a suitably protected proline derivative, the hexahydropyrrolo [1,2] of general formula (V) may be synthesized using a synthetic method as shown in Scheme 2. -A] pyrazine can be prepared. It is noted that both enantiomers can be prepared starting from the appropriate chiral proline.

Scheme 2

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

The compounds of formula (I) and their pharmaceutically acceptable salts have 5HT ₆ receptor antagonist activity and have anxiety, depression, epilepsy, obsessive-compulsive disorder, migraine, cognitive memory impairment,
For example, Alzheimer's disease, Parkinson's disease, ADHD (Attention Deficit Disorder / Hyperactivity Syndrome), sleep disorders (including disorders of circadian rhythm), eating disorders such as anorexia and pathological starvation, panic attacks, cocaine, Potential for use in treating certain CNS disorders such as withdrawal from drug abuse such as ethanol, nicotine and benzodiazepines, schizophrenia, and disorders associated with head injury such as spinal cord trauma and / or hydrocephalus It is thought that there is.

Accordingly, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutic, particularly in the treatment or prevention of the above disorders. The present invention is further directed to a method of treating or preventing the above disorders in a mammal, including a human, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Providing a method comprising:

In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of the above disorders. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention, which can be prepared by mixing suitably at ambient temperature and normal pressure, are usually applied for oral, parenteral or rectal administration and as such, tablets, capsules, oral solutions , Powders, granules, lozenges, reconstitutable powders, injectable or injectable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tablet formers, lubricants, disintegrants and acceptable wetting agents. May be contained. Tablets may be coated according to methods well known in normal pharmaceutical practice.

The oral solution may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or a dry product for constitution with water or other suitable vehicle before use. It may be in a form. Such solutions may contain conventional additives, such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavoring or coloring agents. May be contained.

For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents are dissolved in the vehicle. After filling into the vial, the composition can be frozen and the water removed under vacuum to enhance stability. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and cannot be sterilized by filtration. The compound is
After sterilization by exposure to ethylene oxide, they can be suspended in a sterile vehicle. Beneficially, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Depending on the method of administration, the composition may comprise from 0.1% to 99% by weight, preferably 1% by weight.
It may contain from 0 to 60% by weight of active substance. The dosage of the compound used in the treatment of the above disorders will vary in the usual way with the severity of the disorder, the weight of the patient and other similar factors. However, as a general rule, a suitable unit dose is 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; It may be administered one or more times, for example two or three times a day, the total daily dose being in the range from 0.5 to 100 mg; such treatments may extend for weeks or months.

When administered in accordance with the present invention, no unacceptable toxicological effects are expected with the compounds of the present invention. The following description and examples illustrate the preparation of the compounds of the present invention.

Description Example 1 (2-methoxy-5-nitrophenyl) piperidin-2-ylmethylamine (
D1) A mixture of 2-bromomethylpiperidine hydrobromide ¹ (3.0 g, 11.6 mmol) and 2-methoxy-5-nitroaniline (34.8 mmol, 5.85 g) in chlorobenzene (100 mL) was prepared. Heat under reflux for 17 hours. The solvent was removed and the residue was dissolved in dichloromethane (100 mL), washed with a 10% aqueous sodium hydroxide solution (3 × 20 mL) and dried (MgSO ₄ ). The solvent was removed and the residue was purified by column chromatography on silica gel (eluting with a dichloromethane-methanol gradient) to give the title compound (D1) as a dark green solid (1.45 g, 47%). MS: m / z (MH +) = 266 1.TA Crabb and RF Newton, Tetrahedron, 1968, 24, 2485.

Description Example 2 {2-[(2-methoxy-5-nitrophenylamino) methyl] piperidine-
1-yl @ acetic acid ethyl ester (D2) (2-methoxy-5-nitrophenyl) piperidin-2-ylmethylamine (
D1) (0.27 g, 1 mmol), ethyl bromoacetate (0.15 mL, 1.3)
A mixture of 5 mmol) and triethylamine (0.19 mL, 1.35 mmol) in dry ethanol (20 mL) was heated under reflux for 4 hours. Remove the solvent,
The residue was dissolved in dichloromethane (70 mL) and aqueous sodium hydrogen carbonate solution (2
washed with x10mL), dried (MgSO _4). The solvent was removed and the residue was purified by column chromatography on silica gel (eluting with a dichloromethane-methanol gradient) to give the title compound (D2) as a tan gum (0.
21 g, 60%). MS: m / z (MH +) = 352

Description Example 3 2- (2-methoxy-5-nitrophenyl) hexahydropyrido [1,2-a
] Pyrazin-3-one (D3) {2 [(2-methoxy-5-nitrophenylamino) methyl] piperidine-1
-Yl @ acetic acid ethyl ester (D2) (0.3 g, 0.85 mmol) and gold
Mixture of sodium genus (20 mg, 0.87 mmol) in dry dioxane (8 mL)
The mixture was heated under reflux for 40 minutes. The mixture was concentrated to a small volume and dichloromethane (5
0 mL), washed with brine (2 × 10 mL) and dried (MgSO _Four ). The solvent was removed and the residue was purified by column chromatography on silica gel (eluting with a dichloromethane-ethyl acetate gradient) to give the desired product (D3
) Was obtained as a tan oil (0.08 g, 31%). MS: m / z (MH +) = 306

Description Example 4 2- (5-amino-2-methoxyphenyl) hexahydropyrido [1,2-a
] Pyrazin-3-one (D4) 2- (2-methoxy-5-nitrophenyl) hexahydropyrido [1,2-a
] Pyrazin-3-one (D3) (0.04 g) and Pd / C (0.05 g) in ethanol (15 mL) were stirred at room temperature under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration and washed with ethanol (2 × 15 mL). The filtrate and washings were combined and evaporated to dryness. The residue was evaporated with dry toluene (2 × 10 mL) to give the title compound (D4) as a colorless gum (0.035 g, 97%)
. MS: m / z (MH +) = 276

Description Example 5 4-methoxy-3- (octahydropyrido [1,2-a] pyrazin-2-yl) phenylamine (D5) 2- (5-amino-2-methoxyphenyl) hexahydropyri Do [1,2-a
A solution of pyrazin-3-one (D4) (0.035 g, 0.13 mmol) and borane-THF complex (1 M solution, 1 mL) in tetrahydrofuran (5 mL) was heated at reflux for 4 hours. Dry methanol (2 mL) was added and the solvent was removed.
The residue was redissolved in dry methanol (5 mL) and cesium fluoride (0.035 g
, 0.23 mmol) and dry potassium carbonate (0.035 g, 0.25 mmol). The mixture was then heated under reflux for 5 hours. The solvent was removed and the residue was partially dissolved in dichloromethane (30 mL) and brine (3 × 10 mL)
Washed with water (1 × 10 mL) and dried (MgSO ₄ ). Removal of the solvent afforded the desired product (D5) as a slightly tan glass (0.03 g, 90
%). MS: m / z (MH +) = 262

Description Example 6 [N- (tert-Butoxycarbonyl) -L-prolinyl] -2-methoxy-5-nitrobenzeneamide (D6) Ethyl chloroformate (1.3 mL, 14 mmol) was added to N- (tert-butanol). Butoxycarbonyl) -L-proline (3.0 g, 14 mmol) and 4-methylmorpholine (1.54 mL, 14 mmol) in tetrahydrofuran (30 mL)
) Was added dropwise at −10 ° C. The resulting mixture was stirred at −10 ° C. for 10 minutes,
2-Methoxy-5-nitroaniline (2.35 g, 14 mmol) was added. The mixture was stirred at −10 ° C. for 30 minutes, then at room temperature for 17 hours. The precipitate was removed by filtration and washed with tetrahydrofuran (3 × 20 mL). The filtrate and washings were combined and evaporated to dryness. The residue was diluted with dichloromethane (100 m
L) was dissolved in, and washed with aqueous sodium bicarbonate solution (2 × 30 mL), dried (Na ₂ SO _4). The solvent was removed and the product was purified by column chromatography on silica gel (eluting with a dichloromethane-ethyl acetate gradient) to give the title amide (D6) as a colorless glass (3.81 g, 75%). MS: m / z (MHNa +) = 389

Description Example 7 S-Pyrrolidine-2-carboxylic acid (2-methoxy-5-nitrophenyl) amide (D7) [N- (tert-butoxycarbonyl) -L-prolinyl] -2-methoxy-5-nitrobenzene Amide (D6) (1.8 g, 4.93 mmol), trifluoroacetic acid (2.65 mL) and water (0.1 mL) in dichloromethane (15 mL).
(mL) was stirred at room temperature for 17 hours. The solvent was removed and the residue was toluene (2x
(40 mL). The resulting solid was dissolved in dichloromethane (200 mL) and washed with aqueous sodium hydrogen carbonate (2 × 50 mL). The aqueous layer was extracted with dichloromethane (4 × 50 mL), the combined extracts were dried (Na ₂ SO ₄ ) and finally the solvent was removed to give the title compound (D7) as a cream solid (1.01 g) , 77%). MS: m / z (MH +) = 266

Description 8 S-1-Bromoacetylpyrrolidine-2-carboxylic acid (2-methoxy-5-nitro-phenyl) -amide (D8) S-Pyrrolidine-2-carboxylic acid (2-methoxy-5-nitro) -Phenyl)-
Amide (D7) (0.2 g, 0.75 mmol) and N, N-diisopropylethylamine (0.13 mL, 0.75 mmol) in dichloromethane (10 mL)
) At −10 ° C. in bromoacetyl bromide (1 mL).
(0.75 mmol, 0.07 mL) was added dropwise. The obtained reaction mixture was cooled to -10C
For 30 minutes and then at room temperature for 20 minutes. Then, dichloromethane (
50 mL), dilute it with aqueous sodium bicarbonate (1 x 20 mL), water (
1 × 20 mL) and dried (Na ₂ SO ₄ ). The solvent was removed and the residue was co-evaporated with toluene (2 × 20 mL) to give the product (D8) (0.29 g).
It was used in the next step without purification. MS: m / z (MH +) = 387

Description Example 9 S-2- (2-methoxy-5-nitrophenyl) hexahydropyrrolo [1,2
-A] pyrazine-1,4-dione (D9) S-1-bromoacetylpyrrolidine-2-carboxylic acid (2-methoxy-5-nitro-phenyl) amide (D8) (0.28 g, 0.7 mmol) And NaH
A mixture of (50 mg, 60% dispersion in mineral oil) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours. Then an additional amount of NaH was added and the mixture was stirred at room temperature for a further 17 hours. The precipitate was removed by filtration, and dichloromethane (60 m
L). The filtrate and washings were combined and evaporated to dryness. The residue was co-evaporated with toluene (2 × 10 mL). The product was purified by column chromatography on silica (eluting with a dichloromethane-methanol gradient) to give the title compound (D9) as a colorless solid (after two steps, 0.079 g, 3
4%). MS: m / z (MH +) = 306

Description Example 10 S-2- (5-amino-2-methoxyphenyl) hexahydropyrrolo [1,2
-A] pyrazine-1,4-dione (D10) S-2- (2-methoxy-5-nitrophenyl) hexahydropyrrolo [1,2
-A] pyrazine-1,4-dione (D9) (0.07 g) and Pd / C (0.
08g) in ethanol-ethyl acetate (8: 2, 40 mL) was stirred at room temperature under a hydrogen atmosphere for 7.5 hours. The catalyst was removed by filtration and ethanol (3 × 15
mL) and ethyl acetate (1 × 15 mL). The filtrate and washings were combined and evaporated to dryness. The product was purified by column chromatography (eluting with a dichloromethane-methanol gradient) to give the title compound (D10) as a colorless solid (0.056 g, 89%). MS: m / z (MH +) = 276

Description Example 11 S-3- (Hexahydropyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenylamine (D11) S-2- (5-amino-2-methoxyphenyl) Hexahydropyrrolo [1,2
-A] pyrazine-1,4-dione (D10) (0.055 g, 0.2 mmol)
And borane-THF complex (1 M solution, 1.2 mL) in tetrahydrofuran (5
(mL) was heated under reflux for 5 hours. Then an additional amount of borane-THF complex (1 M solution, 0.6 mL) was added and the reaction was heated under reflux for another 2 hours. The solution was diluted with dry methanol (5 mL) and the solvent was removed. The residue was co-evaporated with dry benzene (2 × 5 mL) and redissolved in dry methanol (5 mL). Cesium fluoride (0.8 mmol, 0.12 g) and dry potassium carbonate (0.8
(7 mmol, 0.12 g) was added to the solution and the mixture was heated under reflux for 17 hours.
Then an additional amount of methanol (5 mL), cesium fluoride (0.8 mmol, 0
. 12 g) and dry potassium carbonate (0.87 mmol, 0.12 g)
Reflux was continued for another 6 hours. Cesium fluoride (0.4 mmol, 0.06 g) and dry potassium carbonate (0.43 mmol, 0.06 g) were added again and reflux was reduced to 3%.
Continued for hours. The solvent was removed and the residue was partially dissolved in dichloromethane (50 mL), washed with brine (3 × 20 mL), water (1 × 10 mL) and dried (
Na ₂ SO _4). Removal of the solvent gave the title compound (D11) as a tan gum (0.042 g, 85%). MS: m / z (MH +) = 248

Description Example 12 2- (2-methoxyphenyl) -5-methyl-cis-octahydropyrrolo [3
, 4-c] pyrrole (D12) cesium carbonate (15 g, 46 mmol), palladium (II) acetate (0.1
5 g, 0.7 mmol) and 2,2′-bis (diphenylphosphine) -1,
1'-Binaphthyl (0.63 g, 1 mmol) in dry 1,4-dioxane (50
(mL) was degassed, purged with argon and sonicated for 10 minutes. 2-
Bromoanisole (3.3 mL, 27 mmol) and cis-hexahydro-2
-Methylpyrrolo [3,4-c] pyrrole hydrochloride [US 5,457,121 (1
995)] (1.9 g) was added and the whole was further degassed, purged with argon and
Sonicated for 0 minutes. The stirred mixture was then refluxed for 20 hours under argon.
The mixture was diluted with dichloromethane (200 mL) and 1 M sodium hydroxide solution (100 m
L). The aqueous layer was further extracted with dichloromethane (50 mL), the organic extracts were dried (MgSO ₄₎ the combined and concentrated to an oil under vacuum. The oil was purified by column chromatography on silica gel, eluting with a gradient of dichloromethane / methanol to give the title compound (D12) as a solid (1.2 g,
56%). ¹ H NMR (CDCl ₃ , 250MHz) 2.34 (3H, s), 2.43-2.48 (2H, m), 2.62-2.69 (2H, m
), 2.85-2.92 (2H, m), 2.99-3.04 (2H, m), 3.34-3.41 (2H, m), 3.85 (3H, s)
, 6.80-6.94 (4H, m); (MH +) 232

Description Example 13 4-methoxy-3- (5-methyl-cis-hexahydropyrrolo [3,4-c]
Pyrrole-2-yl) -benzenesulfonyl chloride (D13) 2- (2-methoxyphenyl) -5-methyl-cis-octahydropyrrolo [3
A solution of [, 4-c] pyrrole (D12) (0.5 g, 2.2 mmol) in dry dichloromethane (3 mL) was added over 5 minutes to ice-cold chlorosulfonic acid (3 mL) under argon. After stirring at 0 ° C. for 0.25 hours and then at room temperature for 1 hour, the solution was slowly poured onto a stirred mixture of ice (50 g) and dichloromethane (50 mL). The mixture was basified by the addition of an excess of a saturated solution of sodium carbonate and the layers were separated. The aqueous layer was further extracted with dichloromethane (50 mL) and the combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (D13) as a foam (0.25 g, 34%).

Example 1 5-Chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [4-methoxy-3- (octahydropyrido [1,2-a] pyrazin-2-yl) phenyl] amide (E1)

Embedded image 4-methoxy-3- (octahydropyrido [1,2-a] pyrazin-2-yl) phenylamine (D5) (0.03 g, 0.11 mmol), 5-chloro-3
-Methylbenzo [b] thiophene-2-sulfonyl chloride (0.042 g, 0
. 15 mmol) and triethylamine (0.02 mL, 0.15 mmol)
Of dichloromethane in dichloromethane (2 mL) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (1 × 10 mL)
) And dried (MgSO ₄ ). The solvent was removed and the product was purified by column chromatography on silica gel (eluting with a dichloromethane-methanol gradient) to give the title compound (E1) as a cream solid (0.01
9g, 32%). H (250MHz, CDCl3), 1.28 (3H, m), 1.73 (3H, m), 2.08 (3H, m), 2.19 (3H, s
), 2.43 (1H, m), 2.68 (1H, m), 2.84 (2H, m), 3.00 (1H, m), 3.21 (1H, m),
3.82 (3H, s), 6.46 (1H, d, J = 2.34 Hz), 6.73 (2H, m), 7.42 (1H, m),
7.65 (1H, d, J = 1.91 Hz), 7.72 (1H, d, J = 8.62 Hz). MS: m / z (MH +) =
506

Example 2 S-5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid [3-
(Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenyl] amide (E2)

Embedded image S-3- (Hexahydropyrrolo [1,2-a] pyrazin-2-yl) -4-methoxy-phenylamine (D11) (0.04 g, 0.16 mmol), 5-chloro-3-methylbenzo [ b] Thiophene-2-sulfonyl chloride (0.04
A solution of 5 g (0.16 mmol) and pyridine (0.1 mL, 1.2 mmol) in dichloromethane (4 mL) was stirred at room temperature for 2 days. The mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (2 × 10 mL) and dried (Na ₂ SO ₄ ). The solvent was removed and the product was purified by column chromatography on silica gel (eluting with a dichloromethane-methanol gradient) to give the title compound (E2) as a pink glass (0.047 mg).
, 59%). H (250MHz, CDCl3), 1.31 (1H, m), 1.82 (3H, m), 2.10 (3H, m), 2.22 (3H, s
), 2.41 (1H, m), 2.60 (1H, m), 3.02 (1H, m), 3.17 (3H, m), 3.81 (3H, s)
, 6.51 (1H, d, J = 2.08 Hz), 6.70 (2H, m), 7.43 (1H, m), 7.66 (1H, d,
J = 1.90 Hz), 7.74 (1H, d, J = 8.60 Hz). MS: m / z (MH +) = 492

Example 3 R-5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3-
(Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenyl] amide (E3) According to the same procedure as described in Example 2, the title compound (E3) was converted to N- (ter).
Prepared from (t-butoxycarbonyl) -D-proline. Yield 28% H (250MHz, CDCl3), 1.30 (1H, m), 1.81 (3H, m), 2.11 (3H, m), 2.22 (3H, s
), 2.38 (1H, m), 2.60 (1H, m), 3.01 (1H, m), 3.18 (3H, m), 3.80 (3H, s)
, 6.50 (1H, d, J = 2.16 Hz), 6.70 (2H, m), 7.44 (1H, m), 7.66 (1H, d,
J = 1.90 Hz), 7.74 (1H, d, J = 8.60 Hz). MS: m / z (MH +) = 492

The following examples may be prepared by a similar procedure as described in Examples 1 and 2.

Example 4 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-Diazabicyclo- [3.3.1] non-4-yl) -4-methoxyphenyl] amide (E4)

Embedded image

Example 5 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-Diazabicyclo- [3.2.1] oct-4-yl) -4-methoxyphenyl] amide (E5)

Embedded image

The following examples may be prepared by a procedure similar to that described in Example 1, using the method described in US-5457121.

Example 6 [4-Methoxy-3- (5-methylhexahydropyrrolo [3,4-c] pyrrol-2-yl) phenyl 5-chloro-3-methylbenzo [b] thiophene-2-sulfonate ] Amide (E6)

Embedded image

Example 7 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (hexahydropyrrolo- [3,4-c] pyrrol-2-yl) -4-methoxyphenyl] amide (E7)

Embedded image

Example 8 N- (5-bromo-3-fluoro-2-methoxyphenyl) -4-methoxy-
3- (5-methyl-cis-hexahydropyrrolo [3,4-c] pyrrol-2-yl] -benzenesulfonamide hydrochloride (E8)

Embedded image 5-bromo-3-fluoro-2-methoxy-aniline (160 mg, 0.73
Mmol) and 4-methoxy-3- (5-methyl-cis-hexahydropyrrolo [3,4-c] pyrrol-2-yl) -benzenesulfonyl chloride (D13)
(240 mg, 0.73 mmol) in dichloromethane (4 mL) was stirred under argon for 18 hours. The solution was concentrated under vacuum and the residue was purified by column chromatography eluting with a dichloromethane / methanol gradient to give the title compound (E8) as a foam (95 mg, 24%). (MH +) 514/516

Assay method for 5-HT6 antagonist activity: Test compounds are dissolved at a concentration of 1 or 10 mM in polyethylene glycol: dimethylsulfoxide (1: 1) and 5 mM Tris buffer (pH 7.7, 25 ° C.)
) And diluted to 0.1 mM. Dissolution was aided by the addition of 0.02 mL of 5M HCl, heating to 40 ° C., and sonication for 10 minutes. Serial dilutions of test compounds in the same buffer are performed using TECAN 5052 or Biomek.
The test was performed using any of 2000 Workstations. A sample (0.05 mL) of the diluted test compound was prepared in incubation buffer.
05 mL of radioligand [ ³ H] -LSD and 0.4 mL of HeLa_5HT6 cells prepared in an incubation buffer (Dr. D. Sibley, NIH,
(See Table 1) obtained from Bethesda and mixed with a suspension of the cleaning membrane preparation (see Table 1). Table 2 details the incubation conditions for each assay. The incubation buffer is 50 mM Trizma (Sigma, UK) pH 7.7, 25
° C., was 4 mM MgCl _2. After incubation at 37 ° C, Packard TopC
ount) format in Packard Filterma
The mixture was filtered using te). Filters were washed with 4 x 1 mL aliquots of ice-cold incubation buffer. Dry the filter, 0.04m
L of Microscint 20 (Packard). IC ₅₀ values were estimated from counts per minute using a four parameter logistic curve fitted to EXCEL (2). K _i values were calculated using the method of Cheng and Prusoff (3). pIC ₅₀ and pK _i are −log ₁₀ of molar IC ₅₀ and K _i , respectively.

[0055]

[Table 1]

[0056]

[Table 2]

References 1. Monsma, FJ, Shen, Y., Ward, RP, Hamblin, MW, Sibley, DR. 1
993. Cloning and expression of a novel serotonin receptor with high affi
Nolity for tricyclic psychotropic drugs. Mol. Pharmacol., 43, 320-327. 2. Bowen, WP, Jerman, JC. 1995. Nonlinear regression using spread
Sheets. Trends in Pharmacol. Sci., 16, 413-417. 3. Cheng, YC, Prussof, WH. 1973. Relationship between inhibition
constant (Ki) and the concentration of inhibitor which causes 50% inhibi
tion (IC50) of an enzymatic reaction. Biochem. Pharmacol., 92, 881-894.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4985 A61K 31/4985 31/4995 31/4995 A61P 1/14 A61P 1/14 3/04 3 / 04 25/06 25/06 25/08 25/08 25/14 25/14 25/16 25/16 25/18 25/18 25/20 25/20 25/22 25/22 25/24 25/24 25 / 28 25/28 25/30 25/30 25/32 25/32 25/34 25/34 43/00 111 43/00 111 C07D 471/04 120 C07D 471/04 120 471/08 471/08 487/04 137 487/04 137 140 140 (C07D 487/08 (C07D 487/08 207: 02 207: 02 241: 04) 241: 04) (C07D 471/04 (C07D 471/04 211: 26 211: 26 (C07D 471 / 08 (C07D 471/08 211: 56 211: 56 (C07D 487/04 (C07D 487/04 (C07D 487/04 (C07D 487/04 (72) Inventor Stephen Mark Bromidge Gillis, CM 19.5 ADB, Essex, Harlow, Third Avenue, New Frontiers Science Park South, SmithKline Beecham Pharmaceuticals (72) Inventor Harina Teresa Seraphy Novska UK, CM 19.5 ADB, Essex, Harlow, New Frontiers Science Park South, SmithKline Beecham Pharmaceuticals F-term (reference) 4C050 AA01 AA03 BB04 CC04 CC08 EE02 FF01 GG01 HH01 HH03 4C065 AA03 AA04 BB04 BB12 CC01 DD02 EE02 4C086 AA01 AA02 AA03 AA04 CB03 CB05 CB09 MA01 MA04 NA14 ZA02 ZA12 ZA15 ZA16 ZA18 ZC39 ZC42

Claims (11)

[Claims] (1) Formula (I): (I) wherein E is —SO ₂ NH— or NHSO ₂ —; and P is a phenyl, naphthyl, bicyclic ring containing from 1 to 4 heteroatoms each selected from oxygen, nitrogen or sulfur. A is a single bond, a C _1-6 alkylene or a C _1-6 alkenylene group; R ¹ is halogen, substituted with one or more fluorine atoms. C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkanoyl, amino, alkylamino or dialkylamino , SR ¹¹ (where R ¹¹ is hydrogen or C _1-6 alkyl), or R ¹ is phenyl, benzyl, naphthyl, each one or more selected from oxygen, nitrogen or sulfur. Bicycle containing four heteroatoms A heterocyclic or 5- to 7-membered heterocyclic ring; n is 2, 3, 4 or 5; R ³ is a group together is a group R ^5, or a R ⁵ (CH ₂ ) forming ₂ O or (CH ₂ ) ₃ O; R ⁴ is of the formula (i), (ii) or (iii): formula (i) Wherein R ⁶ is C _1-6 alkyl optionally substituted by one or more halogen atoms; m is 0, 1 or 2; q is 0, 1, 2, 3 or 4 ) Formula (ii) Wherein R ⁶ , m and q are as defined in formula (i); or in formula (iii) Wherein R ⁶ , m and q are as defined in formula (I), and R ⁷ is hydrogen or C _1-6 alkyl; R ⁵ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy optionally substituted with one or more fluorine atoms, trifluoromethyl, or together with R ³ a group (CH ₂ ) ₂ O or (CH ₂ ) ₃ O] or a salt thereof. 2. The compound according to claim 1, wherein P is phenyl or benzothienyl. 3. The compound according to claim 1, wherein A is a single bond. 4. The compound according to claim 1, wherein R ³ is hydrogen. 5. The method according to claim 1, wherein R ⁵ is C _1-6 alkoxy.
Item. 6. The compound according to any one of claims 1 to 5, wherein R ⁵ is para with respect to the sulfonamide bond. 7. A 5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid [4-methoxy-3- (octahydropyrido [1,2-a] pyrazine-2]
-Yl) phenyl] amide, S-5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3-
(Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenyl, R-5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid [3-
(Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-Diazabicyclo- [3.3.1] non-4-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (1
, 4-diazabicyclo- [3.2.1] oct-4-yl) -4-methoxyphenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [4-methoxy-3- ( 5-methylhexahydropyrrolo [3,4-c] pyrrol-2-yl) phenyl] amide, 5-chloro-3-methylbenzo [b] thiophen-2-sulfonic acid [3- (hexahydropyrrolo- [3, 4-c] pyrrol-2-yl) -4-methoxyphenyl] amide, N- (5-bromo-3-fluoro-2-methoxyphenyl) -4-methoxy-
The compound according to claim 1, which is 3- (5-methyl-cis-hexahydropyrrolo [3,4-c] pyrrole-2-yl] -benzenesulfonamide, and a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7 for use in therapy. 9. A compound as claimed in any one of claims 1 to 7 for use in the treatment of cognitive memory disorders, Parkinson's disease, schizophrenia and / or depression. 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient. (A) when E is a group —NHSO ₂ —, of the formula (II): (II) wherein R ¹ , P, n and A are as defined in the formula (I) or a protected derivative thereof and a compound of the formula (III): (III) wherein R ³ , R ⁴ and R ⁵ are as defined in formula (I) and L is a leaving group; or (b) E is a group- In the case of SO ₂ NH—, formula (IV): (IV) wherein R ¹ , P, n and A are as defined in formula (I) and L is a leaving group, and a compound represented by formula (V): (V) wherein R ³ , R ⁴ and R ⁵ are as defined in formula (I) or a protected derivative thereof, followed by: removal of any protecting group -A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may involve the formation of a pharmaceutically acceptable salt.