WO1997029097A1 - Sulfonamide derivatives as 5ht7 receptor antagonists - Google Patents

Sulfonamide derivatives as 5ht7 receptor antagonists Download PDF

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Publication number
WO1997029097A1
WO1997029097A1 PCT/EP1997/000446 EP9700446W WO9729097A1 WO 1997029097 A1 WO1997029097 A1 WO 1997029097A1 EP 9700446 W EP9700446 W EP 9700446W WO 9729097 A1 WO9729097 A1 WO 9729097A1
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Prior art keywords
methyl
propyl
sulfonamide
methylpiperidin
alkyl
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PCT/EP1997/000446
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French (fr)
Inventor
Ian Thomson Forbes
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Smithkline Beecham Plc
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Priority claimed from GBGB9602679.4A external-priority patent/GB9602679D0/en
Priority claimed from GBGB9613263.4A external-priority patent/GB9613263D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP9528118A priority Critical patent/JP2000504677A/en
Priority to EP97902289A priority patent/EP0883613A1/en
Publication of WO1997029097A1 publication Critical patent/WO1997029097A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
  • 5HT7 receptor antagonists are believed to be of potential use in the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders, migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, septic shock and gastrointestinal diseases.
  • the present invention therefore provides, in a first aspect, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Ar is an optionally substituted mono- or bicyclic aromatic or heteroaromatic ring;
  • R 1 is Cj.6 alkyl;
  • R2 and R ⁇ are each independently hydrogen or Ci .g alkyl
  • R4 and R5 are independently hydrogen, C ⁇ . alkyl, arylC i .5 alkyl or aryl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to
  • n 2 to 4 in the manufacture of a medicament for the treatment of disorders in which antagonism of the 5HT7 receptor is beneficial.
  • C j .g Alkyl groups may be straight chain or branched.
  • Ar is an optionally substituted mono- or bicyclic aromatic or heterocyclic ring.
  • Preferred aromatic rings include phenyl and naphthyl.
  • Preferred heteroaromatic groups include thiophene, quinoline and isoquinoline.
  • Optional substituents for aryl and heterocyclic groups include C ⁇ .
  • alkyl optionally substituted by NR 7 R 8 , C3.6 cycloalkyl, C3.6 cycloalkyi-C 1 _ ⁇ 5 alkyl, optionally substituted aryl, arylC ⁇ _6 alkyl, C2.6 aikenyl, C2-6 alkynyl, C1.6 alkylthio, cyano, nitro, halogen, CF3, C 2 F 5 , NR 7 R 8 , CONR 7 R 8 , NR 7 COR 8 , S(0) p NR 7 R 8 , CHO, OCF3, SCF3, COR 9 , CH 2 OR 9 , C0 2 R 9 or OR 9 where p is 1 or 2 and R 7 , R 8 and R 9 are independently hydrogen, Cj.g alkyl, optionally substituted aryl or optionally substituted arylCi .galkyl;
  • Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group.
  • R 1 is C ⁇ . alkyl.
  • R 1 groups include methyl and ethyl groups.
  • R ⁇ is methyl.
  • R- and R 3 are independently hydrogen or C j .g alkyl.
  • R 2 and R3 are hydrogen or methyl. More preferably one of R 2 and R ⁇ is hydrogen and the other is methyl attached to the carbon atom of the side chain adjacent to the sulfonamide nitrogen.
  • R ⁇ and R ⁇ are independently hydrogen, C j .g alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8- membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen or oxygen.
  • R ⁇ and R ⁇ form an optionally substituted 5- to 8- membered heterocyclic ring, in particular an optionally substituted 6-membered ring.
  • Optional substituents for such rings, which can be present on carbon and nitrogen atoms can be selected from suitable groups listed above and include Cj .5 alkyl.
  • R ⁇ and R* form a piperidine ring substituted by a methyl group.
  • n 2 to 4.
  • n 3;
  • Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group and R 10 is hydrogen, C ⁇ . ⁇ alkyl, cycloC _6 alkyl, arylC ⁇ _6 alkyl, CF3, C2F5 or
  • Particularly preferred compounds of the invention include: N-Methy l-N-[ 1 -methyI-3-(3-methylpiperidin- 1 -y l)propyl]- 1 -naphthalenesulfonamide,
  • N-Methyl-N-(4-piperidin- 1 -yl-butyl)- 1 -naphthalene sulfonamide N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]-3,4-dibromobenzene sulfonamide,
  • Other preferred compounds of the invention include those of examples 29 - 83 which are disclosed herein.
  • the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises (a) the coupling of a compound of formula (II):
  • R 2 and R J are as defined in formula (I), R ⁇ ' and R ⁇ ' are R ⁇ and R ⁇ respectively or protected derivatives thereof, and R6 is R* or hydrogen; or (b) coupling a compound of formula (IN):
  • Suitable leaving groups L include halogen, in particular chloro.
  • the reaction of a compounds of formulae (II) and (III) is preferably carried out in an inert solvent such as dichloromethane optionally in the presence of a base such as triethylamine.
  • suitable leaving groups L include halogen, in particular chloro.
  • Suitable reducing agents include lithium aluminium hydride. Those skilled in the art will appreciate that it may be necessary to protect R 4 and R ⁇ groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W.
  • R When R is hydrogen it can be converted to a group R* using standard alkylation procedures, for example by reaction with an alkyl halide in the presence of a base such as sodium hydride.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have 5 5HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders, migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, septic shock and gastrointestinal diseases. 0 .
  • the compounds of the invention are used to treat CNS diseases.
  • the invention also provides a compound of formula (i) and preferably a compound of formula (ii) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (i) and preferably a compound of formula (ii) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • 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 flavourings or colourants.
  • fluid unit dosage forms are prepared utilising 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.
  • the compound in preparing solutions, can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
  • the title compound was prepared from D13 in a similar way to D7 (1.lg, 78%).
  • the title compound was prepared from D14 in a similar way to D8 (0.7 lg, 87%).
  • the title compound was prepared using 3(R)methylpiperidine and a procedure similar to that in D5, D6 and E2.
  • the title compound was prepared in a similar way to E4 using Dl 5 (350 mg, 2 mmol), triethylamine (0.28 ml, 2 mmol) and 1-naphthalenesulfonyl chloride (0.46g, 64%).
  • the title compound was prepared from D15 (1 15 mg, 0.67 mmol) triethylamine (90 ⁇ l, 0.67 mmol) and benzenesulfonyl chloride (86 ⁇ l, 0.67 mmol) using a similar procedure to E4 (50 mg, 24%).
  • the title compound was prepared from D15 (1 15 mg, 0.67 mmol), triethylamine (90 ⁇ l, 0.67 mmol) and 2-naphthalenesulfonyl chloride (153 mg, 0.67 mmol) using a similar procedure to E4 (132 mg, 55%).
  • Example 9 The procedure of Example 9 was employed.
  • the reagents used were: l-(3- methylamino butyl)-2(R)-methyipiperidine, 4,5-dibromo-2-thiophenesulphonyl chloride and diisopropylethylamine.
  • the title compound was prepared using 4-methylpiperidine and 2,3- dibromothiophene-5-sulphonyl chloride in the methods described in D5, D6 and E2.
  • the title compound was prepared using 4-methylpiperidine and 3,4-dichlorophenyl sulphonyl chloride in the methods described in D5, D6 and E2.
  • the title compound was prepared using 1 -phenyipiperazine and 1 -naphthylsulphonyl chloride in the methods described in D5, D6 and E2.
  • the title compound was prepared using 1 -phenyl piperazine and 2,3- dibromothiophene-5-sulphonyl chloride in the methods described in D5, D6 and E2.
  • Example 9 The procedure of Example 9 was employed.
  • the reagents used were: l -[3- methylamino-3(R)-methylpropyl]-4-methylpiperidine, 3,4-dibromobenzenesulphonyi chloride and diisopropylethylamine.
  • Ci 7H26Br2N ⁇ 2S+H requires 483
  • Examples 21-28 were prepared by shaking a 1 : 1 mixture of the appropriate aryl sulphonyl chloride with the appropriate secondary amine in dichloromethane. After lOh, the resultant precipitate was filtered off and dried.
  • Ci4H2iN2 ⁇ 2SBr+H requires 361 and 363
  • Examples 29-83 were prepared by the following generic procedure.
  • the title compound was prepared using 4-methylpiperidine and 3-bromo-4- chlorophenyl sulfonyl chloride in the methods described in D5, D6 and E2.
  • the affinity of test drugs for the 5-HT 7 receptor binding site can be determined by assessing their ability to displace [ ⁇ H]-5-carboxamidotryptamine from 5-HT 7 receptor clones expressed in 293 cells (To et al., 1995 and Sleight et al., 1995).
  • the cells suspension 400 ⁇ l was incubated with [ ⁇ H]-5-carboxamido- tryptamine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 45mins. Non-specific binding was measured in the presence of 5 -hydroxy tryptamine
  • test drug (10 * 1 1 to 10' ⁇ M final concentration) were added in a volume of 50ul. The total assay volume was 500 ⁇ l. Incubation was stopped by rapid filtration using a Tomtec cell harvester and radioactivity measured by scintillation counting on a Packard Topcount. The IC50 values and pKi values were calculated by INFLEXION, a non-linear iterative curve fitting programme based in EXCEL (Bowen and Jerman. 1994).

Abstract

The invention relates to compounds having 5HT7 antagonist activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.

Description

SULFONAMIDE DERIVATIVES AS 5HT7 RECEPTOR ANTAGONISTS
This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
EPA 0 021 580, EPA 0 076 072, FR 2694003, WO 9009170. EP 260901 , US 4721809, US 4720580, US 4698445, US 4665227 and US 4794196 describe sulfonamide derivatives which are disclosed as having antiarrhythmic activity. It has now suφrisingly been found that certain compounds disclosed in the above specifications, as well as structurally novel compounds, have 5HT7 receptor antagonist activity. 5HT7 receptor antagonists are believed to be of potential use in the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders, migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, septic shock and gastrointestinal diseases.
The present invention therefore provides, in a first aspect, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
R1
ArS02— N - (CR2R3)n— NR4R5
(I)
wherein:
Ar is an optionally substituted mono- or bicyclic aromatic or heteroaromatic ring; R1 is Cj.6 alkyl;
R2 and R^ are each independently hydrogen or Ci .g alkyl;
R4 and R5 are independently hydrogen, C \. alkyl, arylC i .5 alkyl or aryl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to
8-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, sulphur or oxygen; and n is 2 to 4 in the manufacture of a medicament for the treatment of disorders in which antagonism of the 5HT7 receptor is beneficial.
Cj.g Alkyl groups, whether alone or as part of another group, may be straight chain or branched. Suitably Ar is an optionally substituted mono- or bicyclic aromatic or heterocyclic ring. Preferred aromatic rings include phenyl and naphthyl. Preferred heteroaromatic groups include thiophene, quinoline and isoquinoline. Optional substituents for aryl and heterocyclic groups include C\. alkyl optionally substituted by NR7R8, C3.6 cycloalkyl, C3.6 cycloalkyi-C 1 _<5 alkyl, optionally substituted aryl, arylCι _6 alkyl, C2.6 aikenyl, C2-6 alkynyl, C1.6 alkylthio, cyano, nitro, halogen, CF3, C2F5, NR7R8, CONR7R8, NR7COR8, S(0)pNR7R8, CHO, OCF3, SCF3, COR9, CH2OR9, C02R9 or OR9 where p is 1 or 2 and R7, R8 and R9 are independently hydrogen, Cj.g alkyl, optionally substituted aryl or optionally substituted arylCi .galkyl;
Preferably Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group. Suitably R1 is C\ . alkyl. Examples of R1 groups include methyl and ethyl groups. Preferably R^ is methyl.
Suitably R- and R3 are independently hydrogen or C j.g alkyl. Preferably R2 and R3 are hydrogen or methyl. More preferably one of R2 and R^ is hydrogen and the other is methyl attached to the carbon atom of the side chain adjacent to the sulfonamide nitrogen.
Suitably R^ and R^ are independently hydrogen, C j .g alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8- membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen or oxygen. Preferably R^ and R^ form an optionally substituted 5- to 8- membered heterocyclic ring, in particular an optionally substituted 6-membered ring. Optional substituents for such rings, which can be present on carbon and nitrogen atoms can be selected from suitable groups listed above and include Cj .5 alkyl. Most preferably R^ and R* form a piperidine ring substituted by a methyl group.
Suitably n is 2 to 4. Preferably n is 3. Certain compounds of formula (I) are novel and all novel compounds of formula (I) and salts thereof form a further aspect of the invention. Preferred novel compounds are those of formula (i):
Figure imgf000004_0001
(i)
in which Ar. R^ and R^ are as defined in formula (I). Most preferred novel compounds are those of formula (ii): 10
Figure imgf000005_0001
(ϋ)
where Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group and R10 is hydrogen, C\.β alkyl, cycloC _6 alkyl, arylCι_6 alkyl, CF3, C2F5 or
Cj_6 alkyloxy.
Particularly preferred compounds of the invention include: N-Methy l-N-[ 1 -methyI-3-(3-methylpiperidin- 1 -y l)propyl]- 1 -naphthalenesulfonamide,
N-Methyl-N-[ 1 R-methyl-3-(3S-methyl-piperidin- 1 -yl)propyl]- 1 -naphthalene sulfonamide,
N-Methyl-N-[lR-methyl-3-(3R-methyl-piperidin-l-yl)propyl]- l -naphthalene sulfonamide, N-Methyl-N-[3-[l-(2R-methylpiperidinyl)propyl]]-l-naphthlenesulfonamide,
N-Methyl-N-[3-[l-(2S-methylpiperidinyl)propyl]]-l -naphthalenesulfonamide,
(±) N-Methyl-N-[3-[l-(piperidinyl)butyl]]-l -naphthalenesulfonamide,
(±) N-Methyl-N-[3-[l-(piperidinyl)butyl]]-benzene sulfonamide,
(±) N-Methyl-N-[3-[l-(piperidinyl)butyl]]-2-naphthalenesulfonamide, N-Methyl-N-[l-methyl-3-(2S-methyl-l-piperidyl)propyl]-4,5-dibromo-2-thiophene sulfonamide,
N-Methyl-N-[l-methyl-3-(2R-methyl-l-piperidyl)propyl]-4,5-dibromo-2-thiophene sulfonamide,
(±) N-Ethyl-N-[3-[l-(piperidinyl)butyl]]-l -naphthalenesulfonamide, N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]-l -naphthalene sulfonamide,
N-Methyl-N-[l R-methyl-3-(4-methylpiperidine-l-yI)propyl]-2,3-dibromothiophene-
5-sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]-3,4-dichlorobenzene sulfonamide,
N-Methyl-N-[ 1 R-methyl-3-(4-phenylpiperazin- 1 -yI)propy 1]- 1 -naphthalene sulfonamide,
N-Methyl-N-[ 1 R-methy l-3-(4-phenyipiperazin- 1 -yl)propyl]-2,3-dibromothiophene-5- sulfona ide, (±)-N-Methyl-N-[ 1 -ethyl-3 -(4-methylpiperidin- 1 -yl)propyl]- 1 -naphthalene sulfonamide,
N-Methyl-N-(4-piperidin- 1 -yl-butyl)- 1 -naphthalene sulfonamide, N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]-3,4-dibromobenzene sulfonamide,
N-Methyl-N-[lR-methyI-3-(4-methylpiperidin- l -yl)propyl]-3-methylbenzene sulfonamide,
N-Methyl-N-[3-[l-(pyrrolidinyl)propyl]]-3-chlorobenzenesulfonamide, N-Methyl-N-[3-[l-(moφholinyl)propyl]]-3-chloroben2enesulfonamide, N-Methyl-N-[3-[l -(N-methylpiperazinyl)propyl]]-3-chlorobenzenesulfonamide, N-MethyI-N-[3-[l-(pyrrolidinyl)propyl]]-4-bromobenzenesulfonamide, N-Methyl-N-[3-[l-(moφholinyl)propyl]]-4-bromobenzenesulfonamide, N-MethyI-N-[3-[l-(N-methylpiperazinyl)propyl]]-4-bromobenzenesulfonamide, N-Methyl-N-[3-[l -(moφholinyl)propyl]]-l-naphthalenesulfonamide, N-Methyl-N-[3-[l-(N-methylpiperazinyl)propyl]]-l -naphthalenesulfonamide,
N-Methyl-N-[1 R-rnethyl-3-(4-methylpiperidin- 1 -yl)propyl]3-bromo-4-chlorophenyl sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]4-chloro-3-vinylphenyl sulfonamide, N-Methyl-N-[lR-methyl-3-(4-methylpiperidine-l-yl)propyl]3-hydroxymethylphenyl sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l -yl)propyl]3-ethylphenyl sulfonamide, and pharmaceutically acceptable salts thereof. Other preferred compounds of the invention include those of examples 29 - 83 which are disclosed herein. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic. Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises (a) the coupling of a compound of formula (II):
ArSO2L
(II)
in which Ar is as defined in formula (I) and L is a leaving group with a compound of formula (III):
R6 NN— (CR ) — NRV
H
(III)
in which R2 and RJ are as defined in formula (I), R^' and R^' are R^ and R^ respectively or protected derivatives thereof, and R6 is R* or hydrogen; or (b) coupling a compound of formula (IN):
R6 ArS02— Ν — (CR2R3)n — X
(IV)
in which n, R2, R-5 and R° are as defined above and X is a leaving group with a compound of formula (V):
HΝR 'R5'
(V)
in which R4' and R^' are as defined above, or (c) treating a compound of formula (VI):
R1
ArS02— N — (CR^3),,.— CO-NR4R5 (VI) in which n, R^, R2, R3, R4' and R5' ^e as defined above with a reducing agent, and optionally thereafter if appropriate:
• removing any protecting groups;
5 • when R^ is hydrogen converting to a group Rl ;
• forming a pharmaceutically acceptable salt.
Suitable leaving groups L include halogen, in particular chloro. The reaction of a compounds of formulae (II) and (III) is preferably carried out in an inert solvent such as dichloromethane optionally in the presence of a base such as triethylamine.
] 0 For process (b), suitable leaving groups L include halogen, in particular chloro. For process (c) Suitable reducing agents include lithium aluminium hydride. Those skilled in the art will appreciate that it may be necesary to protect R4 and R^ groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W.
15 'Protective groups in organic synthesis' New York, Wiley (1981).
When R is hydrogen it can be converted to a group R* using standard alkylation procedures, for example by reaction with an alkyl halide in the presence of a base such as sodium hydride.
Compounds of formulae (II), (III), (IV), (V) and (VI) are commercially 0 available or may be prepared according to known methods or analogous to known methods.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5 5HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders, migraine, Parkinson's disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, septic shock and gastrointestinal diseases. 0 . Preferably the compounds of the invention are used to treat CNS diseases.
Thus the invention also provides a compound of formula (i) and preferably a compound of formula (ii) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders. 5 The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (i) and preferably a compound of formula (ii) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. 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 flavourings or colourants. For parenteral administration, fluid unit dosage forms are prepared utilising 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 sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.
The following Descriptions and Examples illustrate the preparation of compounds of the invention.
Description 1 N-[l-Methyl-3-(3-methylpiperidin-I-yl)propyl]-l-naphthalenesuIfonamide (Dl)
To a cooled mixture of l-methyl-3-(3-methylpiperidin-l-yl)propylamine [J.A.C.S. 1946 191 1 68] (lg; 5.8mmol) and triethylamine (0.6g; 5.8mmol) was added dropwise with stirring a solution of 1 -naphthalene sulfonyl chloride (1.3 ; 5.8mmol) in anhydrous dichloromethane. After 24h, the solution was diluted with additional dichloromethane (50ml) and washed with water (χ3), then dried and evaporated to give a yellow oil. The oil crystallised on standing, and the crystals were filtered off using n-pentane to afford the title compound (1.Og; 48%), m.p. 70-71 °C
Description 2
Methanesulphonic acid 2R-benzyloxycarbonyIaminopropyl ester (D2)
To a solution of N-Cbz-D-AIaninol (lOg, 48 mmol) in dichloromethane (100 ml) at 0°C was added triethylamine (13.5 ml, 96 mmol) and methanesulphonic anhydride (12.5g, 72 mmol); stirring was continued at 0°C for 30 mins. The solution was diluted with additional dichloromethane (100 ml) and washed with saturated aqueous sodium bicarbonate (x2), dried over Na2SO_ι, filtered and concentrated to give a white solid (12.2g, 89%).
Found MH+ = 288 C12H17NO5S + H requires 288
Description 3 3R-Benzyloxycarbonylaminobutyronitrile (D3)
To a solution of mesylate D2 (12.2g, 43 mmol) in dimethylformamide (200 ml) at room temperature was added sodium cyanide (3.1 g, 63 mmol). Stirring was continued at room temperature for 48 hrs and then at 60°C for 2hrs. Reaction mixture was partitioned between saturated aqueous sodium bicarbonate (200 ml) and ether (2 x 500 ml). The organic solution was dried (Na2SO_ι), filtered and concentrated to give the nitrile (8.4g, 71%) as a yellow oil.
Found MH+ = 219
C j 2H 14N2O2 + H requires 219 Description 4
3R-BenzyloxycarbonyIamino butyric acid (D4)
A solution of the nitrile D3 (6g, 27 mmol) in concentrated hydrochloric acid (60 ml) was heated to reflux for 18 hrs. The solution was then concentrated and azeotroped with toluene to give the crude amino acid which was dissolved in 5M NaOH (20 ml). The solution was cooled to 0°C, treated with benzyl chloroformate (5.9 ml, 40 mmol) dropwise and stirred at room temperature for 1 hr. The aqueous solution was washed with ether (50 ml) and then acidified with hydrochloric acid. The product was extracted with ether (3 x 100 ml) which was dried (Na2SO_ι.), filtered and concentrated to give the title compound as a clear oil (1.9g, 27% over 2 steps).
Found M+Na = 260 12H 15N04+Na requires 260
Description 5
3R-BenzyIoxycarbonylaminobutyric acid, 3S-methyIpiperidin-l-yI amide (D5)
To a solution of the acid D4 (445 mg, 1.88 mmol) in dichloromethane (25 ml) at room temperature under argon was added oxalyl chloride (100 μl, 2.07 mmol) and DMF (1 drop). Stirring was continued at room temperature for 2 hrs. The solution was concentrated and the residue redissolved in dichloromethane (20 ml) before cooling to 0°C. A solution of 3(S)-methylpiperidine (186 mg, 1.88 mmol) in triethylamine (260 μl, 1.88 mmol) and dichloromethane (2 ml) was added and the reaction stirred for an additional 2hrs. The solution was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic solution was dried (Na2S04), filtered and concentrated and the residue purified on silica eluting with 70% ethyl acetate/petrol to afford the title compound (540 mg, 90%).
Found MH+ = 319
C18H26N203 + H requires 319
Description 6 N-MethyI-N-[lR-methyl-3-(3S-methyl-piperidin-l-yl)propyIJamine (D6)
To a solution of the amide D5 (540 mg, 1.7 mmol) in THF (30 ml) was added lithium aluminium hydride (200 mg, 5.3 mmol) portionwise. The reaction was heated to reflux under argon for 3 hrs, cooled and then quenched by the cautious addition of water (0.2 ml), 10% aqueous sodium hydroxide (0.2 ml) and finally water (0.6 ml). The mixture was filtered, concentrated and then partitioned between IN HCl (20 ml) and ether (2x20 ml). The aqueous layer was basified with 5N NaOH and extracted with ether (2 x 50 ml). The organic solution was dried (Na2Sθ4) filtered and concentrated to give the title compound (240 mg, 76%).
Found MH+ = 185
C 11 H24N2+H requires 185
Description 7
Ethyl N-[3-(2R-methyI-l-piperidinyI)propyl]carbamate (D7)
A solution of (R)-3-[2-methyl-l-piperidinyl)propylamine (350 mg, 2.24 mmol) in dichloromethane (10 mi) was cooled (ice bath) and treated with triethylamine (0.34 ml, 2.46 mmol) and ethyl chloroformate (0.23 ml, 2.46 mmol) and stirred for 24 hours. Work up afforded the title compound (365 mg, 71%) as an oil.
MH+ = 229 (62%).
Description 8
N-MethyI-3-(2R-methyI-l-piperidinyl)propylamine (D8)
The material from D7 (365 mg, 1.6 mmol) in tetrahydrofuran (10 ml) was treated with lithium aluminium hydride (182 mg, 3 eq.) and heated to reflux for 24 hours. Work up in the usual way afforded the title compound as an oil (200 mg, 73%)
MH+ = 171 (100%).
Description 9 Ethyl N-[3-(2S-methyl-l-piperidiπyl)propyl]carbamate (D9)
A solution of (S)-3-(2-methyl-l-piperidinyl)propylarnine (500 mg, 3.2 mmol) dichloromethane ( 10 ml) was cooled (ice-bath) and treated with triethylamine (0.29 ml, 3.5 mmol) and ethyl chloroformate (0.33 ml, 3.5 mmol) and stirred for 24 hours. Work up afforded the title compound as an oil (524 mg, 72%).
MH+ = 229 (100%) Description 10 N-Methyl-3-(2S-methyl-l-piperidinyl)propylamine (D10)
The material from D9 (504 mg, 2.3 mmol) in tetrahydrofuran (30 ml) was treated with lithium aluminium hydride (262 mg, 6.9 mmol) and heated to reflux overnight. Work up in the usual way afforded the title compound as an oil (400 mg, 100%).
MH+ = 171 (100%)
Description 11 l-(l-piperidinyI)-butan-3-one (Dl 1)
A stirred, cooled (ice-bath) solution of methylvinylketone (lOg, 0.14 mol) and piperidine (14.1 ml, 0.14 mol) in dichloromethane (150 ml) was treated with iron III chloride (anhydrous, 2.2g, 0.1 mol eq.) and stirred over a weekend. The mixture was filtered, the filtrate concentrated and the residue chromatographed on silica (flash 5% MeOH/DCM to 10% MeOH/DCM) to afford the title compound (19.8g, 91%)
MH+ = 156 (100%)
Description 12 l-(l-piperidinyl)-3-butanone oxime (D12)
A suspension of Dl 1 (19.8g, 0.127 mol) in water (200 ml) was treated with hydroxylamine hydrochloride (9.7g, 0.14 mol) and sodium carbonate (14.8g, 0.14 mol), heated to reflux for four hours and cooled. The solution was extracted into ether, the organics dried and concentrated to afford the title compound (13.6g, 63%) as an orange solid.
MH+ = 171 (100%)
Description 13
(±) l-(l-piperidinyl)-3-aminobutane (D13)
A suspension of lithium aluminium hydride (670 mg, 17.6 mmol) in tetrahydrofuran (20 ml) cooled by ice bath was treated dropwise with cone, sulfuric acid (0.45 ml) and stirred for 1 hour. A solution of D12 (lg, 5.88 mmol) in THF (5 ml) was added dropwise and the suspension heated to reflux overnight. Usual work up afforded the title compound (0.96 g, 100%).
Description 14 (±) Ethyl N-[3-(l-piperidinyl)-l-methylpropyl]carbamate (D14)
The title compound was prepared from D13 in a similar way to D7 (1.lg, 78%).
MH+ = 229 (100%)
Description 15
(±) l-MethyI-3-(l-piperidinyl)-N-methylaminopropane
The title compound was prepared from D14 in a similar way to D8 (0.7 lg, 87%).
MH+ = 171 (100%).
Description 16
(±)-Methyl 3-N-Methylaminopentanoate (D16)
A 2M methanolic solution of methylamine (44 ml, 88 mmol) was added dropwise over 15 minutes to a stirred solution of methyl 2-pentenoate (5g, 44 mmol) in ethanol (50 ml). After lh the reaction mixture was evaporated to dryness to afford the title compound (3.75g. 58%) as a colourless oil.
Found MH+ = 146 C7H15NO2+ H requires 146
Description 17 (±)-3-N-MethyIaminopentanol (D17)
Methyl 3-N-methylaminopentanoate D16 (3.67g; 25.3 mmol) in ether (20 ml) was added dropwise over 15 minutes to a stirred solution of lithium aluminium hydride (2. OOg; 52.7 mmol) in ether (40 ml). After 72h the reaction mixture was cooled to 0°C and water (2.3 ml), 10% NaOH (3.5 ml) and finally water (4.7 ml) were added. The mixture was diluted vvith ether (50 ml), stirred for lh, then filtered through kieselguhr. The filtrate was dried and evaporated to dryness to afford the title compound (2.96g; 100%) as a colourless oil. Found MH+ = 1 18 CgH^NO + H requires 1 18
Description 18
(±) N-Methyl-N-[l-ethyl-3-chloropropyl)-l-naphthalenesulfonamide (D18)
A mixture of 1 -naphthalenesulfonyl chloride (1.74g; 7.7 mmol), 3-N-methylamino pentanol D17 (0.36g, 3.1 mmol) and diisopropylethylamine (1.6 ml, 9.0 mmol) in toluene (30 ml) were stirred at reflux for 72h. After cooling to room temperature, the mixture was filtered through kieselguhr and evaporated to dryness. Purification by flash column chromatography afforded the title compound (0.69g, 69%) as a colourless oil.
Found MH+ = 326
C i6H2θSN0 Cl+H requires 326
Description 19 l-(3-Aminopropyl)piperidine (D19)
A suspension of lithium aluminium hydride (13.75g; 0.36 mol) in dry THF (500 ml) at 0° under Ar was treated with cone. H2SO4 (9.2 ml) dropwise. After 1 hour at 0°, the suspension was treated with 1 -piperidinepropionitrile (lOg; 72 mmol) in dry THF (50 ml) and allowed to reach room temp, overnight. The reaction mixture was treated with diethyl ether (400 ml), cooled to 0° and treated with a solution of 10% NaOH (aq) (21 ml) in water (55 ml) dropwise. Allowed to reach room temp, and filtered through kieselguhr, washing the pad with diethyl ether (2x200 ml). The filtrate was evaporated in vacuo to a pale yellow liquid (8. lg; 79%).
MH+ = 143
CgHi g^+H requires 143
Description 20 l-(3-EthoxycarbonyIamino)piperidine (D20)
A solution of 1 -(3-aminopropyl)piperidine D19 (8. lg; 57 mmol) in dichloromethane (100 ml) at 0° was treated with triethylamine (1 1 ml; 79 mmol) and ethyl chloroformate (7.6 ml; 79 mmol) dropwise. Allowed to reach room temp, overnight, washed with H2O (2x), dried and evaporated in vacuo to an orange oil (1 1.2g; 92%).
MH+ = 215 C 11 H22N2O+H requires 215
Description 21 l-(3-Methylaminopropyl)piperidine (D21)
A solution of l-(3-ethoxycarbonylamino)piperidine D20 (1 1.2g; 52 mmol) in dry THF (500 ml) at 0° under Ar was treated with lithium aluminium hydride (5.97g; 16 mmol) portionwise and heated at reflux overnight. Cooled to 0° and treated with a solution of 10% NaOH (aq) (9.1 ml) in H O (23 ml) dropwise followed by addition of diethyl ether (200 ml). The quenched reaction mixture was filtered through kieselguhr washing with diethyl ether. The filtrate was dried over Na2Sθ4 and evaporated in vacuo to an amber liquid (8.0g; 98%).
MH+ = 157
CcjH2θN2+H requires 157
Example 1
N-Methyl-N-[l-methyl-3-(3-methyIpiperidin-l-yl)propyl]-l- naphthalenesulfonamide hydrochloride (El)
Sodium hydride (80mg; 3.2mmol) was added slowly to a stirred solution of sulfonamide Dl (0.91g; 2.5mmol) in dimethylformamide (28ml). After lh, iodomethane (0.36g; 3.2mmol) in a small volume dimethylformamide was added dropwise, and allowed to stir at room temperature overnight. The solution was then concentrated, and dichloromethane (70ml) added, then washed with water (χ2), aqueous sodium hydroxide, and finally water. The organic solution was then dried and evaporated to dryness. Formation of the hydrochloride salt was achieved by treatment with ethanolic HCl. (68%) m.p. 178°C
Found MH+ =375 C21H30N2O2S+H require 375 Example 2
N-Methyl-N-[lR-methyl-3-(3S-methyl-piperidin-l-yl)propyI]-l-naphthalene sulfonamide (E2)
To a solution of the amine D6 (230 mg, 1.25 mmol) in dichloromethane (5 ml) was added diisopropyiethylamine (220 μl, 1.26 mmol) and 1 -naphthylsulphonyl chloride (285 mg, 1.26 mmol). The reaction was allowed to warm to room temperature with stirring over 3 hrs. The solution was diluted with dichloromethane (15 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The organic solution was dried (Na2SO4), filtered and concentrated and the residue purified on silica eluting with ethyl acetate to afford the title compound (300 mg, 64%).
Found MH+ = 375 C21H30N2°2S + H requires 375
Example 3
N-MethyI-N-[lR-methyI-3-(3R-methyl-piperidin-l-yl)propyl]-l-naphthalene sulfonamide (E3)
The title compound was prepared using 3(R)methylpiperidine and a procedure similar to that in D5, D6 and E2.
Found MH+ = 375 C21H30N2O2S+H requires 375
Example 4 N-Methyl-N-[3-[l-(2R-methyIpiperidinyl)propyl]J-l-naphthlenesuIfonamide (E4)
A solution of D8 (200 mg, 1.17 mmol) and triethylamine (0.16 ml, 1 eq.) in dichloromethane ( 10 ml) cooled by ice-bath was treated with a solution of naphthalene- 1 -sulfonyl chloride (265 mg, leq) in dichloromethane. The solution was stirred overnight. Work up and chromatography (10% methanol/dichloromethane) afforded the title compound (156 mg, 37%).
MH+ = 361 (100%)
Example 5 N-Methyl-N-[3-[l-(2S-methylpiperidinyl)propyl]]-l-naphthaIenesulfonamide
(E5)
A solution of D10 (400 mg, 2.3 mmol) and triethylamine (0.32 ml, 2.3 mmol) in dichloromethane (10 ml) cooled by ice bath, was treated with a solution of naphthalene- 1 -sulfonyl chloride (533 mg, 2.3 mmol) and stirred overnight. The solution was thoroughly washed (10% NaOH), dried and concentrated. Chromatography (10% MeOH/DCM) afforded the title compound (450 mg, 54%).
MH+ = 361 (52%)
Example 6 (±) N-Methyl-N-[3-(l-(piperidinyl)butyI]]-l-naphthaIenesulfonamide (E6)
The title compound was prepared in a similar way to E4 using Dl 5 (350 mg, 2 mmol), triethylamine (0.28 ml, 2 mmol) and 1-naphthalenesulfonyl chloride (0.46g, 64%).
MH+ = 361 (100%)
Example 7
(±) N-MethyI-N-[3-[l-(piperidinyl)butyl]]-benzene sulfonamide (E7)
The title compound was prepared from D15 (1 15 mg, 0.67 mmol) triethylamine (90 μl, 0.67 mmol) and benzenesulfonyl chloride (86 μl, 0.67 mmol) using a similar procedure to E4 (50 mg, 24%).
MH+ = 31 1 (100%).
Example 8 (±) N-MethyI-N-[3-[l-(piperidinyl)butyl]]-2-naphthalenesulfonamide (E8)
The title compound was prepared from D15 (1 15 mg, 0.67 mmol), triethylamine (90 μl, 0.67 mmol) and 2-naphthalenesulfonyl chloride (153 mg, 0.67 mmol) using a similar procedure to E4 (132 mg, 55%).
MH+ = 361 (100%)
Example 9 N-Methyl-N-[l-methyl-3-(2S-methyl-l-piperidyl)propyIJ-4,5-dibromo-2- thiophene sulfonamide (E9)
To a solution of l-(3-methylaminobutyl)-2(S)-methylpiperidine (184 mg; 1.0 mmol) in dry dichloromethane (3 ml) containing diisopropylethylamine (174 μl; 1.0 mmol) was added 4,5-dibromo-2-thiophenesulphonyl chloride (341 mg; 1.0 mmol) and shaken at room temp, overnight. The reaction mixture was washed with H2O and applied to a Waters sep-pak silica gel column, eluting with ethyl acetate to yield the title compound as a clear, colourless gum (300 mg; 61%).
MH+ = 489 Cj5H24Br2N2S2θ2+H requires 489
Example 10 N-Methyl-N-[l-methyl-3-(2R-methyl-l-piperidyl)proρyI]-4,5-dibromo-2- thiophene sulfonamide (E10)
The procedure of Example 9 was employed. The reagents used were: l-(3- methylamino butyl)-2(R)-methyipiperidine, 4,5-dibromo-2-thiophenesulphonyl chloride and diisopropylethylamine.
MH+ = 489 C15H24BΪ N2S2O2+H requires 489
Example 11
(±) N-Ethyl-N-[3-[l-(piperidinyl)butyl]]-l-naphthalenesulfonamide (El 1)
1-NaphthalenesuIphonyl chloride (0.15g, 0.7 mmoles) and (±) N-ethyl-4- (piperidinyl)-2-butylamine (0.12g, 0.7 mmoles) were mixed in dichloromethane (10 mL) and stirred at ambient temperature for 18 hrs. The mixture was then washed with saturated sodium hydrogen carbonate, dried (Na2SU4) and purified on silica gel eluting with 1-3% methanol/dichloromethane. This gave the title compound El 1 (0.13g. 52%).
NMR (CDCI3) δ: 1.05 (3H, d, J=8Hz), 1.15-2.19 (I H, ), 3.25-3.41 (2H, m), 3.81- 3.95 ( I H. m), 7.50-7.71 (3H, m), 7.91 (I H. d. J=10Hz), 8.05 (IH, d, J=10Hz), 8.29 (IH, d. J=10Hz), 8.69 (IH, d, J=10Hz). MH+ = 375
C21H30N2O2S + H requires 375
Example 12 N-Methyl-N-[lR-methyI-3-(4-methylpiperidin-l-yl)propyl]-l-naphthalene sulfonamide
The title compound was prepared using 4-methyl piperidine in the methods described in D5, D6 and E2.
Found MH+ = 375 21H30N2°2S+H requires 375
Example 13 N-MethyI-N-[lR-methyl-3-(4-methylpiperidine-l-yl)propyI]-2,3- dibromothiophene-5-sulfonamide (E13)
The title compound was prepared using 4-methylpiperidine and 2,3- dibromothiophene-5-sulphonyl chloride in the methods described in D5, D6 and E2.
Found MH+ = 487/489/491 Cl 5H24Br2N2O S2+H requires 487/489/491
Example 14 N-Methyl-N-[lR-methyl-3-(4-methyIpiperidin-l-yl)propyl]-3,4-dichlorobenzene sulfonamide (E14)
The title compound was prepared using 4-methylpiperidine and 3,4-dichlorophenyl sulphonyl chloride in the methods described in D5, D6 and E2.
Found MH+ = 393/395 C17H26CI2N2O2S+H requires 393/395 Example 15
N-Methyl-N-[lR-methyl-3-(4-phenylpiperazin-l-yl)propyIJ-l-naphthalene sulfonamide (E15)
The title compound was prepared using 1 -phenyipiperazine and 1 -naphthylsulphonyl chloride in the methods described in D5, D6 and E2.
Found MH+ = 438 C25H31 N3O2S+H requires 438
Example 16
N-Methyl-N-[lR-methyl-3-(4-phenylpiperazin-l-yl)propyl]-2,3- dibromothiophene-5-sulfonamide (E16)
The title compound was prepared using 1 -phenyl piperazine and 2,3- dibromothiophene-5-sulphonyl chloride in the methods described in D5, D6 and E2.
Found MH+ = 550/552/554 Ci9H25Br2N3O2S2+H requires 550/552/554
Example 17
(±)-N-Methyl-N-[l-ethyl-3-(4-methylpiperidin-l-yl)propyI]-l-naphthalene sulfonamide (E17)
A mixture of Dl 8 (0.67g, 2 mmol), 4-methylpiperidine (0.20g, 2 mmol), potassium carbonate (300 mg) and sodium iodide (25 mg) in acetonitrile (30 ml) were stirred at reflux for 48h. After cooling to room temperature, the mixture was filtered through kieselguhr and evaporated to dryness. Purification by flash column chromatography afforded the title compound (0.72g, 92%) as a yellow foam.
Found MH+ = 389 C22H32N2°2S+H require 389
Example 18 N-Methyl-N-(4-piperidin-l-yl-buryl)-l-naphthalene sulfonamide (E18)
To a solution of N-methyl-N-(4-piperidin-l -yl-butyl)amine (300 mg, 1.76 mmol) and diisopropylethylamine (325 μl. 1.86 mmol) in dichloromethane (5 ml) at 0°C was added 1 -naphthylsulphonyl chloride. Stirring was continued at room temperature for 15 hrs. The solution was diluted with dichloromethane (20 ml) and washed with 10% aqueous sodium hydroxide (10 ml). The organic solution was dried (Na2Sθ4), filtered and concentrated and the residue purified on silica eluting with ethyl acetate to afford the title compound (500 mg, 78%).
Found MH+ = 361 C2θN28N2C*2S+H requires 361
Example 19
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yI)propyI]-3,4-dibromobenzene sulfonamide (E19)
The procedure of Example 9 was employed. The reagents used were: l -[3- methylamino-3(R)-methylpropyl]-4-methylpiperidine, 3,4-dibromobenzenesulphonyi chloride and diisopropylethylamine.
MH+ = 483
Ci 7H26Br2N θ2S+H requires 483
Example 20
N-Methyl-N-[lR-methyI-3-(4-methylpiperidin-l-yl)propyl]-3-methylbenzene sulfonamide (E20)
The procedure of E9 was employed using l-[3-methylamino-3(R)-methylpropyl]-4- methylpiperidine, 3-methylbenzenesulfonyl chloride and diisopropylethylamine.
MH+ = 339
C18H30N2°2S+H requires 339.
Examples 21-28 were prepared by shaking a 1 : 1 mixture of the appropriate aryl sulphonyl chloride with the appropriate secondary amine in dichloromethane. After lOh, the resultant precipitate was filtered off and dried.
Example 21
N-Methyl-N-[3-(l-(pyrrolidinyl)propyl]J-3-chlorobenzenesulfonamide hydrochloride (E21) M+H observed 317 and 319 Ci4H2iN2θ2SCl+H requires 317 and 319
Example 22 N-Methyl-N-[3-[l-(morpholinyl)propyl]]-3-chIorobenzenesulfonamide hydrochloride (E22)
M+H observed 333 and 335 C14H21N2O3SCI+H requires 333 and 335
Example 23
N-MethyI-N-[3-[l-(N-methylpiperazinyI)propyl]]-3-chlorobenzenesulfonamide hydrochloride (E23)
M+H observed 346 and 348
C15H24N3O2SCI+H requires 346 and 348
Example 24
N-Methyl-N-[3-[l-(pyrrolidinyl)propylJ]-4-bromobenzenesulfonamide hydrochloride (E24)
M+H observed 361 and 363 Ci4H2iN2θ2SBr+H requires 361 and 363
Example 25
N-Methyl-N-[3-[l-(morpholinyl)propyl]]-4-bromobenzenesulfonamide hydrochloride (E25)
M+H observed 377 and 379 Ci4H2 ιN2θ3SBr+H requries 377 and 379
Example 26
N-MethyI-N-[3-[l-(N-methylpiperazinyl)propylj]-4-bromobenzenesuIfonamide hydrochloride (E26)
M+H observ ed 390 and 392 15H24N3°2SBr+H requires 390 and 392 Example 27
N-Methyl-N-[3-[l-(morphoIinyI)propyl]]-l-naphthalenesulfonamide hydrochloride (E27)
M+H observed 349
C18H24N2O3S+H requires 349
Example 28
N-Methyl-N-[3-[l-(N-methyIpiperazinyl)propylJ]-l-naphthalenesulfonamide hydrochloride (E28)
M+H observed 362 C19H27N3O2S+H requires 362
Examples 29-83 were prepared by the following generic procedure.
l-(3-Methylaminopropyl)piperidine D21 (1.0 mmol) was dissolved in dry dichloromethane (3 ml) containing diisopropylethylamine (1.0 mmol) and treated with a sulphonyl chloride (1.0 mmol). Shaken at room temp, overnight, washed with H2O and purified by column chromatography eluting with ethyl acetate.
Figure imgf000026_0001
Example No. Ar MH+
29 1 -naphthyl 347
30 5-dimethylamino- 1 -naphthyl 390
31 phenylmethyl 311
32 4-bromophenyl 376
33 4-acetamidophenyl 354
34 2, 1 ,3-benzoxadiazol-4-yl 339
35 2,1 ,3-benzothiadiazol-4-y 1 355
36 2-thienyl 303
37 4-phenylsulphonylthienyl 443
38 4-(phenyl)phenyl 373
39 2,3-dibromo-5-thienyl 461
40 3-bromophenyl 376
41 3,5-dichlorophenyl 366
42 2,3,5,6-tetramethylphenyl 353
43 5-bromo-2,3-dichloro-4-thienyl 450
44 2-(trifluoromethyl)phenyl 365
45 2,3-dichlorophenyl 365
46 3-chloro-2-methylphenyl 345
47 2,3.4-trichlorophenyl 399
48 3,4-dichlorophenyl 365
49 8-quinolyl 348
50 phenyl 297
51 2-(2-pyridyI)-5-thienyl 380
52 3,4-dibromophenyl 455
53 3-(trifluoromethyl)phenyl 365
54 2-acetamido-4-methyl-5-thiazolyl 375
55 5-bromo- l -naphthyl 426
Figure imgf000027_0001
Example No. Ar MH+
56 2-bromophenyl 376
57 3-bromo-2-chloro-5-thienyl 416
58 4-bromo-2-chloro-5-thienyl 416
59 2-bromo-5-thienyl 382
60 2-chloro-5-thienyl 337
61 2-naphthyl 347
62 2,5-dibromo-3,6-difluorophenyl 491
63 2,5-dichloro-4-thienyl 371
64 5-chloro-3-methyl-2-benzothienyl 401
65 3-(phenyl)phenyl 373
66 4-methylphenyl 31 1
67 3-chlorophenyl 331
68 4-iodophenyl 423
69 4-t-butylphenyl 353
70 4-methoxyphenyl 327
71 3 -methylphenyl 31 1
72 4-n-propylphenyl 339
73 4-chloro-2,5-dimethylphenyl 359
74 4-cyanophenyI 322
75 3 -chloro-4-methy Iphenyl 345
76 3-vinylphenyl 322
77 3-ethylphenyl 324
78 4-vinylphenyl 322
79 4-ethylphenyl 324
80 4-fluorophenyl 314
81 3-( 1 -methoxy vinyl)phenyl 366
82 3-acetylphenyl 339
83 4-chlorophenyl 331 , 333 Example 84
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yI)propyl]3-bromo-4- chlorophenyl sulfonamide.
The title compound was prepared using 4-methylpiperidine and 3-bromo-4- chlorophenyl sulfonyl chloride in the methods described in D5, D6 and E2.
Found MH+ 437/439/441 Cι7H2 N2θ2SClBr+H requires 437/439/441
Example 85
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyI]4-chloro-3- vinylphenyl sulfonamide
A solution of E84 (50 mg, 0.1 1 mmol), vinyltributyltin (33 μl, 0.1 1 mmol) and tetrakistriphenylphosphine palladium (O) (10 mg) in triethylamine (15 μl, 0.1 1 mmol) and DMF (5 ml) was heated to 100°C under an argon atmosphere for 12 hours. The reaction mixture was cooled and concentrated and the residue purified on silica gel eluting with 5% methanol/dichloromethane to give the title compound.
Found MH+ = 385/387 C19H29CIN2O2S+H requires 385/387
Example 86
N-Methyl-N-[lR-methyl-3-(4-methylpiperidine-l-yl)propyl]3- hydroxymethylphenyi sulfonamide
A mixture of N-methyl-N-[lR-methyl-3-(4-methylpiperidin-l -yI)propyl]3- carboxyphenyl sulfonamide (950mg, 2.6 mmol) and lithium aluminium hydride (350 mg, 9.2 mmol) in THF (40 ml) was stirred at room temperature for 3 hrs, cooled to 0°C and treated with a solution of water (0.35 ml), 10% aqueous sodium hydroxide (0.35 ml) and finally water (1.05ml). The quenched reaction mixture was filtered through kieselguhr washing with diethyl ether. The filtrate was dried with Na2SO4 and evaporated to afford the title compound (440 mg, 48%).
Found MH+ = 355 C18H30N2°3S+H requires 355 Example 87
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l-yl)propyl]3-ethylphenyl sulfonamide
A solution of E85 in ethanol was hydrogenated over platinum oxide for 3 hours. The reaction mixture was then filtered and concentrated to give the title compound.
Found MH+ = 353 C19H32N2°2S+H requires 353
Pharmacological Data
[3H]-5-Carboxamidotryptamine binding to human 5-HT 7 receptor clones expressed in 293 cells in vitro.
The affinity of test drugs for the 5-HT 7 receptor binding site can be determined by assessing their ability to displace [^H]-5-carboxamidotryptamine from 5-HT 7 receptor clones expressed in 293 cells (To et al., 1995 and Sleight et al., 1995).
The cells suspension (400μl) was incubated with [^H]-5-carboxamido- tryptamine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 45mins. Non-specific binding was measured in the presence of 5 -hydroxy tryptamine
(10"°M). Ten concentrations of test drug (10* 1 1 to 10'^M final concentration) were added in a volume of 50ul. The total assay volume was 500μl. Incubation was stopped by rapid filtration using a Tomtec cell harvester and radioactivity measured by scintillation counting on a Packard Topcount. The IC50 values and pKi values were calculated by INFLEXION, a non-linear iterative curve fitting programme based in EXCEL (Bowen and Jerman. 1994).
Bowen, W. and Jerman, J. ( 1994). Br. J. Pharmacol., 1 12, 440P.
Sleight, A.J., Carolo, C..Petit, N.,Zweingelstein. C. and Bourson, A. (1995). Mol.
Pharmacol., 47, 99.
To, Z.P., Bonhaus, D.W., Eglen, R.M. and Jakeman, L.B. ( 1995). Br. J.
Pharmacol., 15, 107.
• Testing Results: The compounds of Examples 1-83 have pKi's in the range <5.2 7.8

Claims

Claims:
1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
R1 ArS02— N — (CR2R3)n— NR4RS
(I)
wherein:
Ar is an optionally substituted mono- or bicyclic aromatic or heteroaromatic ring;
R1 is C j.6 alkyl;
R2 and RJ are each independently hydrogen or C i .g alkyl; R4 and R5 are independently hydrogen, Ci .g alkyl, arylCj.g alkyl or aryl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to
8-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, sulphur or oxygen; and n is 2 to 4 in the manufacture of a medicament for the treatment of disorders in which antagonism of the 5HT7 receptor is beneficial.
2. Use according to claim 1 in which Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group.
3. Use according to claim 1 or 2 in which R^ is methyl.
4 Use according to any one of claims 1 to 3 in which one of R^ and R^ is hydrogen and the other is methyl.
5 Use according to any one of claims 1 to 4 in which R4 and R^ form an optionally substituted 5- to 8-membered heterocyclic ring.
6. A compound of formula (i):
Me
I ArSO — N ^ / NR4R5
Me (0
in which Ar, R4 and R^ are as defined in formula (I).
7. A compound of formula (ii):
10
Figure imgf000032_0001
(ϋ)
where Ar is a naphthyl group, a substituted phenyl group, or a dibromothienyl group and R1 0 is hydrogen, Cι _6 alkyl, cycloC3_6 alkyl, arylC ι _6 alkyl, CF3, C2F5 or
C 1.6 alkyloxy.
8. A compound of formula (I) which is:
N-methyl-N-[l-methyl-3-(3-methylpiperidin-l-yl)propyl]-l -naphthalenesulfonamide,
N-Methyl-N-[ 1 R-methyl-3-(3 S-methyl-piperidin- 1 -yl)propyl]- 1 -naphthalene sulfonamide,
N-Methyl-N-[ 1 R-methy l-3-(3R-methyl-piperidin- 1 -yl)propylJ- 1 -naphthalene sulfonamide,
N-Methy l-N-[3-[ 1 -(2R-methylpiperidinyl)propyl]]- 1 -naphthlenesulfonamide,
N-Methyl-N-[3-[ 1 -(2S-methylpiperidinyl)propyl]]- 1 -naphthalenesulfonamide,
(+) N-Methyl-N-[3-[l -(piperidinyl)butyl]]-l -naphthalenesulfonamide,
(+) N-Methyl-N-[3-[l-(piperidinyI)butyl]]-benzene sulfonamide, (+) N-Methyl-N-[3-[l -(piperidinyl)butyl]]-2-naphthalenesulfonamide,
N-Methyl-N-[l-methyl-3-(2S-methyl-l-piperidyl)propyl]-4,5-dibromo-2-thiophene sulfonamide,
N-Methyl-N-[l-methyl-3-(2R-methyl-l-piperidyl)propyl]-4,5-dibromo-2-thiophene sulfonamide, (+) N-Ethyl-N-[3-[l-(piperidinyl)butyl]]-l -naphthalenesulfonamide,
N-Methyl-N-[1 R-methy 1-3 -(4-methylpiperidin- 1 -yl)propyl]- 1 -naphthalene sulfonamide,
N-Methyl-N-[ 1 R-methy l-3-(4-methy lpiperidine- 1 -yl)propyI]-2,3-dibromothiophene-
5-sulfonamide, N-Methyl-N-[l R-methyl-3-(4-methylpiperidin- l -yl)propyl]-3,4-dichlorobenzene sulfonamide,
N-Methy !-N-[l R-methy l-3-(4-phenylpiperazin- l -yl)propyl]-l -naphthalene sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-phenylpiperazin-l -yl)propyl]-2,3-dibromothiophene-5- sulfonamide, (±)-N-Methyl-N-[ 1 -ethyl-3-(4-methylpiperidin- 1 -yl)propy!j- 1 -naphthalene sulfonamide,
N-Methy l-N-(4-piperidin- 1 -yl-butyl)- 1 -naphthalene sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin- l -yl)propyl]-3,4-dibromobenzene sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l -yl)propyI]-3-methylbenzene sulfonamide,
N-Methyl-N-[3-[l-(pyrrolidinyl)propyl]]-3-chlorobenzenesulfonamide,
N-Methyl-N-[3-[l-(mo holinyl)propyl]]-3-chlorobenzenesulfonamide, N-Methyl-N-[3-[l-(N-methylpiperazinyl)propyl]]-3-chlorobenzenesulfonamide,
N-Methyl-N-[3-[l-(pyrrolidinyl)propyl]]-4-bromobenzenesulfonamide,
N-Methyl-N-[3-[l-(morpholinyl)propyl]]-4-bromobenzenesulfonamide,
N-Methyl-N-[3-[l-(N-methylpiperazinyI)propyl]]-4-bromobenzenesulfonamide,
N-Methyl-N-[3-[i-(moφholinyl)propyl]]-l -naphthalenesulfonamide, N-Methyl-N-[3-[l -(N-methylpiperazinyl)propyljJ- 1 -naphthalenesulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin- l -yl)propyl]3-bromo-4-chIorophenyl sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l -yl)propyl]4-chloro-3-vinylphenyl sulfonamide, N-Methyl-N-[lR-methyl-3-(4-methylpiperidine-l -yl)propyI]3-hydroxymethylphenyl sulfonamide,
N-Methyl-N-[lR-methyl-3-(4-methylpiperidin-l -yl)propyl]3-ethylphenyl sulfonamide, and pharmaceutically acceptable salts thereof.
9. A compound according to any one of claims 6 to 8 for use in therapy.
10. A pharmaceutical composition which comprises a compound according to any one of claims 6 to 8 and a pharmaceutically acceptable carrier or excipient.
PCT/EP1997/000446 1996-02-09 1997-01-27 Sulfonamide derivatives as 5ht7 receptor antagonists WO1997029097A1 (en)

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Publication number Priority date Publication date Assignee Title
WO1999002502A2 (en) * 1997-07-11 1999-01-21 Smithkline Beecham Plc Sulphonamide derivatives being 5-ht6 receptor antagonists and process for their preparation
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WO2005005387A1 (en) * 2003-07-10 2005-01-20 Aston University Sulfonamide derivatives as 5ht7 receptor antagonists
US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2313918A1 (en) * 1975-06-09 1977-01-07 Choay Sa 2-METHOXY BENZENESULFONAMIDES N-SUBSTITUTE, PROCESS FOR THE PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM
EP0021580A1 (en) * 1979-05-16 1981-01-07 BEECHAM - WUELFING GmbH &amp; Co. KG Sulphonamide derivatives, a process for their preparation and their use as medicines
EP0064445A1 (en) * 1981-04-23 1982-11-10 Choay S.A. N-substituted 2,4-dialkoxybenzene sulfon amides
EP0076072A2 (en) * 1981-09-24 1983-04-06 BEECHAM - WUELFING GmbH &amp; Co. KG Sulphonamides
US4714700A (en) * 1982-04-20 1987-12-22 Choay S.A. N-substituted 2,4-dialkoxy benzenesulfonamides and pharmaceutical compositions
FR2694003A1 (en) * 1992-07-21 1994-01-28 Beecham Laboratoires New tertiary amino substd. sulphonamide(s) - are useful in the prophylaxis and treatment of cardiac arrhythmia e.g. ventricular arrhythmia and ischaemic disorders of rhythm.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2313918A1 (en) * 1975-06-09 1977-01-07 Choay Sa 2-METHOXY BENZENESULFONAMIDES N-SUBSTITUTE, PROCESS FOR THE PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM
EP0021580A1 (en) * 1979-05-16 1981-01-07 BEECHAM - WUELFING GmbH &amp; Co. KG Sulphonamide derivatives, a process for their preparation and their use as medicines
EP0064445A1 (en) * 1981-04-23 1982-11-10 Choay S.A. N-substituted 2,4-dialkoxybenzene sulfon amides
EP0076072A2 (en) * 1981-09-24 1983-04-06 BEECHAM - WUELFING GmbH &amp; Co. KG Sulphonamides
US4714700A (en) * 1982-04-20 1987-12-22 Choay S.A. N-substituted 2,4-dialkoxy benzenesulfonamides and pharmaceutical compositions
FR2694003A1 (en) * 1992-07-21 1994-01-28 Beecham Laboratoires New tertiary amino substd. sulphonamide(s) - are useful in the prophylaxis and treatment of cardiac arrhythmia e.g. ventricular arrhythmia and ischaemic disorders of rhythm.

Cited By (52)

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WO1999002502A3 (en) * 1997-07-11 1999-06-03 Smithkline Beecham Plc Sulphonamide derivatives being 5-ht6 receptor antagonists and process for their preparation
US6316450B1 (en) 1997-07-11 2001-11-13 Smithkline Beecham P.L.C. Compounds
WO1999002502A2 (en) * 1997-07-11 1999-01-21 Smithkline Beecham Plc Sulphonamide derivatives being 5-ht6 receptor antagonists and process for their preparation
EP1003514A1 (en) * 1997-07-25 2000-05-31 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
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US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7285553B2 (en) 1998-05-19 2007-10-23 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US6486173B2 (en) 1998-06-30 2002-11-26 Bristol-Myers Squibb Pharma Company 5-HT7 receptor antagonists
US6239143B1 (en) 1998-06-30 2001-05-29 Dupont Pharmaceuticals Company 5-HT7 receptor antagonists
WO2000037082A1 (en) * 1998-12-18 2000-06-29 Smithkline Beecham P.L.C. Use of 5-ht7 receptor antagonists for treating neuronal degeneration resulting from ischemic events
WO2000056712A1 (en) * 1999-03-23 2000-09-28 Smithkline Beecham Plc Sulfonamide derivatives as 5-ht7 receptor antagonists
US6660751B1 (en) 1999-03-23 2003-12-09 Smithkline Beecham P.L.C. Sulfonamide derivatives as 5-HT7 receptor antagonists
US6440988B1 (en) 1999-05-18 2002-08-27 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-HT7 receptor to treat disorders of the bladder
EP1181287A1 (en) * 1999-06-01 2002-02-27 Smithkline Beecham Plc Sulfonamide compounds with pharmaceutical activity
EP1273568A3 (en) * 2001-07-04 2003-08-06 Consiglio Nazionale Delle Ricerche Novel diazo derivatives and process for their preparation
US6740741B2 (en) * 2001-07-04 2004-05-25 Consiglio Nazionale Delle Ricerche Diazo derivatives and process for their preparation
EP1273707A3 (en) * 2001-07-04 2004-10-13 Consiglio Nazionale Delle Ricerche Method for the deacidification of paper products
EP1273707A2 (en) * 2001-07-04 2003-01-08 Consiglio Nazionale Delle Ricerche Method for the deacidification of paper products
EP1273568A2 (en) * 2001-07-04 2003-01-08 Consiglio Nazionale Delle Ricerche Novel diazo derivatives and process for their preparation
WO2003048118A1 (en) * 2001-12-03 2003-06-12 Merck Sharp & Dohme Limited 5-ht7 receptor antagonists
US7276607B2 (en) 2001-12-03 2007-10-02 Merck Sharp & Dohme Limited 5-HT7 receptor antagonists
US7928121B2 (en) 2002-02-19 2011-04-19 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7553965B2 (en) 2002-11-07 2009-06-30 Laboratories Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7101892B2 (en) 2003-05-15 2006-09-05 Merck Sharp & Dohme Ltd. Sulfone derivatives as 5-HT7 receptor ligands
WO2005005387A1 (en) * 2003-07-10 2005-01-20 Aston University Sulfonamide derivatives as 5ht7 receptor antagonists
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
WO2005103023A1 (en) * 2004-04-20 2005-11-03 Sterix Limited Phenylsulfonamide derivatives for use as 11-beta-hydroxysteroid dehydrogenase inhibitors
ES2257167A1 (en) * 2004-08-18 2006-07-16 Laboratorios Del Dr Esteve, S.A. New dihydro-1H-isoquinoline compounds are 5-hydroxytryptamine-7 inhibitors useful for the treatment of e.g. sleep disorder, shift worker syndrome, depression, migraine, anxiety, psychosis, schizophrenia and pain
WO2006018308A1 (en) * 2004-08-18 2006-02-23 Laboratorios Del Dr. Esteve, S.A. 5-ht7 receptor antagonists
US7211584B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor ligands
US7211585B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
ES2257168A1 (en) * 2004-08-18 2006-07-16 Laboratorios Del Dr Esteve, S.A. 5-HT7 receptor antagonists
EP1630158A1 (en) * 2004-08-18 2006-03-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
WO2006018309A1 (en) * 2004-08-18 2006-02-23 Laboratorios Del Dr. Esteve, S.A. 5-ht7 receptor antagonists
US8148397B2 (en) 2004-08-18 2012-04-03 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
EP1630159A1 (en) * 2004-08-18 2006-03-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8188115B2 (en) 2004-08-18 2012-05-29 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7345057B2 (en) 2004-12-28 2008-03-18 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7662862B2 (en) 2004-12-28 2010-02-16 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
WO2006123020A1 (en) * 2005-05-18 2006-11-23 Juvantia Pharma Ltd Oy Peptidomimetics selective for the somatostatin receptor subtypes 1 and/or 4
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US8883808B2 (en) 2005-08-04 2014-11-11 Janssen Pharmaceutica N.V. Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy
WO2008013556A1 (en) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy
KR100917041B1 (en) * 2007-07-26 2009-09-10 한국과학기술연구원 New compounds of 5-ht7 receptor antagonist
EP2151777A1 (en) 2008-08-01 2010-02-10 Laboratorios Del. Dr. Esteve, S.A. Method for screening of 5HT7 receptor ligands based on a new pharmacophore model and a descriptor's profile filter
EP2149373A1 (en) 2008-08-01 2010-02-03 Laboratorios Del. Dr. Esteve, S.A. 5HT7 receptor ligands and compositions comprising the same
US8883796B2 (en) 2013-02-08 2014-11-11 Korea Institute Of Science And Technology Biphenyl derivatives, pharmaceutical composition comprising the same, and preparation method thereof
US9663464B2 (en) 2015-02-24 2017-05-30 Korea Institute Of Science And Technology Carbazole derivatives acting on 5-HT7 receptor
WO2018117406A1 (en) 2016-12-22 2018-06-28 한국과학기술연구원 Azepine derivative acting as 5-ht7 receptor modulator
US10435408B2 (en) 2016-12-22 2019-10-08 Korea Institute Of Science And Technology Azepine derivatives as 5-HT7 receptor modulators
KR20220136635A (en) 2021-04-01 2022-10-11 한국과학기술연구원 6-chloro-2′-methoxy-biphenyl derivatives for regulating activity of 5-HT7 serotonin receptor and pharmaceutical composition comprising the same as an active ingredient

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