Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to substituted sulphone and sulphonamide compounds, to pharmaceutical compositions comprising these compounds, and to the use ofthe compounds for the prophylaxis and treatment of medical conditions relating to obesity, type 2 diabetes, and/or disorders ofthe central nervous system (CNS), to achieve reduction of body weight and of body weight gain, as well as for cosmetic use.
• CNS central nervous system
• Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries.
• This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type 2 diabetes.
• Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter ofthe peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression. Multiple serotonin receptor subtypes have been identified and cloned. One of these, the 5-HTg receptor, was cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M.
• WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT6 receptor and that can be used for the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, cognitive disorders, ADHD, anorexia and bulimia schizophrenia, drug abuse.
• WO 01/32646 Al discloses compounds that bind to the 5-HT ⁇ receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
• WO 99/37623 A2 discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
• WO 99/42465 A3 discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
• EP 0 815 861 Al discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders.
• WO 99/02502 A2 discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
• WO 98/27081 Al discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
• EP 0701819 discloses compounds that bind to the 5-HTjj) receptor and that are used for the treatment of CNS disorders and obesity.
• US 6,191,141 and WO 01/12629 disclose compounds that bind to the 5-HT ⁇ receptor and that are used for the treatment of CNS disorders.
• the compounds of formula (I) show affinity for the 5- HTg receptor as antagonists at low nanomolar range.
• Compounds according to the invention and their pharmaceutically acceptable salts have 5-HTg receptor antagonist, agonist and partial agonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type 2 diabetes, to achieve reduction of body weight and of body weight gain, as well as in the treatment or prophylaxis of disorders ofthe central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, sleep disorders, migraine, anorexia, bulimia, binge disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntmgton's chorea and/or schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug abuse.
• ADHD Attention Deficit Hyperactive Disorders
• body weight disorders refers to the disorders caused by an imbalance between energy intake and energy expenditure, resulting in abnormal body (e.g., excessive) weight. Such body weight disorders include obesity.
• - ⁇ alkyl (or “C 2-6 alkenyl”) denotes a straight or branched hydrocarbon chain group having from 1 to 6 carbon atoms (or 2 to 6 carbon atoms).
• lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
• Alkenyl groups have one or more double carbon-carbon bonds in the chain.
• C ⁇ .(. alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
• examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
• C ⁇ . alkoxyalkyi denotes a straight or branched alkoxyalkyi group having from 1 to 6 carbon atoms.
• Examples of said lower alkoxyalkyi include methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t- butoxyethyl and straight- and branched-chain pentoxymethyl.
• C2-6 alkenyl refers to straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl groups, 1-pentenyl, and 1-hexenyl groups.
• C2-6 alkynyl refers to straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl, 1- propynyl, 1-butynyl, 1-pentynyl, and 1-hexynyl groups.
• halogen shall mean fluorine, chlorine, bromine or iodine.
• alkylhalide refers to an alkyl group substituted with one or more halogen groups (e.g., F, Cl, Br, I).
• cycloalkyl denotes a cyclic alkyl group having a ring size from C3 to C7, which can be saturated or partially unsaturated.
• examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, methylcyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl.
• C5. 0 cycloalkenyl denotes a cyclic alkenyl group having a ring size from C5 to Cio- Examples of said cycloalkenyl include 1 -cyclopentyl, 2-cyclo ⁇ entenyl, 1- cyclohexenyl, 1-cyclohepentyl, 1-cyclooctenyl, 1-cyclononenyl, and 1-cyclodecenyl groups.
• heterocyclic refers to a hydrocarbon ring system containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part ofthe ring. It includes saturated, unsaturated, aromatic, and nonaromatic heterocycles. Suitable heterocyclic groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl, and piperazinyl groups
• aryl refers to a hydrocarbon ring system having at least one aromatic ring.
• aryl groups include phenyl, cinnamyl, pentalenyl, indenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthryl.
• heteroaryl refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S.
• heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups.
• One object ofthe present invention is a compound having the general formula (I):
• ring B is a five-membered heterocyclic or heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen, with the proviso that when D contains an oxygen atom, D is heteroaryl;
• each W is independently — N-, -(CH)-, or -C- provided that not more than three groups W are -N- in both rings A and B together;
• P is any one of formula (a), (b) or (c)
• P and R can be attached to any carbon atom that allows the substitution in one of either the A- or B-ring, or when ring A contains at least one nitrogen atom and P is (c), then P can also be attached to any nitrogen in ring B that allows the substitution;
• aryl-C ⁇ -6 alkyl (e) cinnamyl, (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, mono- or bi-cyclic heterocyclic ring, each containing 1 to 4 heteroatoms, selected from oxygen, sulfur, and nitrogen,
• a bicyclic ring system comprising at least one heterocyclic ring according to (f) and a group Ar, wherein the group Ar is substituted in one or more positions with (a) H, X or Y, or
• R 2 is (a) H
• R 1 and R 2 are linked to form a group -CH 2 CH 2 OCH 2 CH 2 - or
• v is 0-2
• X and Y are independently (a) H, (b) halogen, (c) C1.6 alkyl, (d) CF 3 ,
• R 4 and R 5 are independently (a) H,
• R 4 and R 5 are linked to form a group -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 - or (CH 2 ) 3-5 ;
• R is a group selected from any one of
• R is independently
• P and R 3 can be attached to the same ring or to different rings of rings A and B;
• R is selected from any one of
• R is a group selected from any one of
• R 3 is a group selected from any one of
• a naphthalene ring has the following position numbers:
• P Ps denote the position on the naphthalene ring.
• a pyrrole ring as connected to an A ring, has the following position numbers:
• P 1 -P 3 denote the position on the pyrrole ring.
• R 1 and R 2 are linked to form a group -CH 2 CH 2 OCH 2 CH 2 -;
• X and Y are H
• R and R 5 are each independently H or C ⁇ . 3 alkyl
• R 3 is selected from any one of
• R is selected from any one of
• R 6 is independently
• R is selected from any one of
• R 6 is independently
• R ⁇ is selected from any one of
• R 6 is independently (a) H, (b) C ⁇ -3 alkyl,
• R 6 is H or methyl.
• R 3 is piperazine; homopiperazine; 2,6-dimethylpiperazine; 3,5- dimethylpiperazine; 2,5-dimethylpiperazine; 2-methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine; 3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydro-pyrazine; or 4-pyrrolidin-3 -yloxy. It is preferred that the groups Y and X are attached to any unsubstituted carbon atom.
• D is pyrrolyl, thienyl or furanyl.
• R 1 and R 9 are as defined in claim 1.
• R 2 is H.
• Another object of the present invention is a compound of the general formula (II)
• R 1 , x, y, X, and Y are as defined in claim 1, and R 3 is as defined in claim 2.
• Another object of the present invention is a compound of the general formula (III)
• R , x, y, X, and Y are as defined m claim 1, and R is as defined in claim 2.
• Another object of the present invention is a compound of the general formula (IV)
• P is ofthe formula (c), R 1 , x, y, X, and Y are as defined in claim 1, and R 3 is as defined in claim 2, and wherein D is a five-membered heteroaryl ring, said ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution.
• D is a thiophene and P is attached to the D ring, giving a skeleton as any ofthe following:
• D is pyrrole and P is attached to the nitrogen atom in the D ring, giving a skeleton as any ofthe following:
• D furan and P is attached to the D ring, giving a skeleton as any ofthe following:
• Another object of the present invention is a compound of the general formula (V)
• P is ofthe formula (c) as defined in claim 1
• R , x, y, X, Y, and R are as defined in claim l
• D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution.
• Another object of the present invention is a compound of the general formula (V)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, Y, and R 3 are as defined in claim 1, and wherein D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution.
• Another object of the present invention is a compound of the general formula (VI)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X and Y are as defined in claim 1, and R is as defined in claim 2.
• Another object of the present invention is a compound of the general formula (VII)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R is H, X and Y are as defined in claim 1, and R 3 is as defined in claim 4.
• Another object of the present invention is a compound of the general formula (VIII)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, Y, and R 3 are as defined in claim 1.
• Another object of the present invention is a compound of the general formula (JX)
• R 7 in formula (IX) is:
• Another object of the present invention is a compound of the general formula (X)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R is H, X,
• Y, and R 3 are as defined in claim 1.
• Another object of the present invention is a compound of the general formula (XI)
• P is ofthe formula (a) or (b) as defined in claim 1, preferably wherein R is H, X and Y are as defined in claim 1, and R is as defined in claim 4.
• Another object of the present invention is a compound ofthe general formula (XII):
• Preferred compounds ofthe formula (IX) are N-(4-methylphenyl)-4- ⁇ iperazin- 1 -yl- lH-pyrrolo [3 ,2-c]pyridine-2-sulfonamide hydrochloride;
• Another object ofthe present invention is a process for the preparation of a compound above, said method comprising the steps of:
• step (c) synthesis of a sulfonamide by reacting the aminonaphthalene obtained in step (b) with a suitable sulfonyl chloride.
• Another object ofthe present invention is a process for the preparation of a compound above, wherein
• P is , said method comprising the steps of: preparation ofthe heteroaromatic 5-member ring fused halogen-substituted pyridine, reduction of an aromatic nitro group; aromatic nucleophilic substitution with a thiol via a diazointermediate; oxidation ofthe thiol derivative to a sulphone; introduction of a halogen atom by electrophilic aromatic substitution; aromatic nucleophilic substitution ofthe halogen with a diamine.
• Another object ofthe present invention is a process for the preparation of a compound above, wherein
• P is , said method comprising the steps of: preparation ofthe heteroaromatic 5- member ring fused pyridine; introduction of a carboxylic moiety; conversion ofthe carboxylic moiety to amine by Curtius rearrangement; reaction ofthe amine group with a sulphonylchloride.
• Another object ofthe present invention is a process for the preparation of a compound above, wherein
• P is , said method comprising the steps of: preparation ofthe heteroaromatic 5- member ring fused pyridine; introduction of sulfonylchloride moiety by nucleophilic addition; reaction of sulphonylchloride moiety with an aniline to obtained a sulfonamide; aromatic nucleophilic substitution ofthe chloro with a diamine.
• the compounds ofthe formulae (I) to (XII) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
• pharmacologically acceptable addition salts as mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
• Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
• Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succimc acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
• organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methan
• Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
• the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
• the compounds ofthe invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
• Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
• the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
• the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
• Liquid formulations maybe prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
• Another object ofthe present invention is a compound above for use in therapy.
• Another object ofthe present invention is a compound above, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R is substituted in position 1 on the naphthalene ring, for use in the treatment or prophylaxis of a 5-HTg receptor related disorder, such as obesity, type II diabetes, and/or disorders ofthe central nervous system, to achieve reduction of body weight and of body weight gain.
• a 5-HTg receptor related disorder such as obesity, type II diabetes, and/or disorders ofthe central nervous system
• Another object ofthe present invention is a compound above for use in the treatment or prophylaxis of disorders ofthe central nervous system.
• Another object ofthe present invention is a compound above, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R 3 is ofthe formula
• Another object ofthe present invention is a compound above, and for the case when ring D is a py ⁇ ole ring, P is. ofthe formula (c) and R 3 is ofthe formula
• Another obj ect of the present invention is a pharmaceutical formulation comprising a compound above as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
• Another object ofthe present invention is a pharmaceutical formulation comprising a compound above, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, as an active ingredient, for use in the treatment or prophylaxis of a 5-HTg receptor related disorder, such as obesity, type II diabetes, and/or disorders ofthe central nervous system, to achieve reduction of body weight and of body weight gain.
• a 5-HTg receptor related disorder such as obesity, type II diabetes, and/or disorders ofthe central nervous system
• Another object ofthe present invention is a compound above as an active ingredient, for use in the treatment or prophylaxis of disorders ofthe central nervous system.
• Another object ofthe present invention is a pharmaceutical formulation comprising a compound above, for the case when rings A and B are both phenyl, P is any one of formula
• Another object ofthe present invention is a pharmaceutical formulation comprising a compound above, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R 3 is ofthe formula
• Another object ofthe present invention is a method for the treatment or prophylaxis of a 5- W receptor related disorder, such as obesity, type II diabetes, and/or disorders ofthe central nervous system, to achieve reduction of body weight and of body weight gain, which comprises administering to a subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need of such treatment an effective amount of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R is substituted in position 1 on the naphthalene ring.
• a subject e.g., a mammal, a human, a horse, a dog, or a cat
• P is any one of formula (a) or (c) substituted in position 7 on the na
• Another object ofthe present invention is a method for the treatment or prophylaxis of disorders ofthe central nervous system, which comprises administering to a subject in need of such treatment an effective amount of one or more compounds of any ofthe formulae described above, their salt forms or compositions that include the compounds or their salt forms.
• Another object ofthe present invention is a method for the treatment or prophylaxis of type II diabetes, which comprises administering to a subject in need of such treatment an effective amount of one or more compounds of any ofthe formulae described above, their salt forms or compositions that include the compounds or their salt forms, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R is ofthe formula
• Another object ofthe present invention is a method for the treatment or prophylaxis of obesity, which comprises administering to a subject in need of such treatment an effective amound of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R is ofthe formula
• Another object ofthe present invention is a method for modulating 5-HTg receptor activity, comprising administering to a subject in need thereof an effective amount of one or more compounds of any ofthe formulae described above, their salt forms or compositions that include the compounds or their salt forms.
• Another object ofthe present invention is the use of one or more compounds of any ofthe formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, for the manufacture of a medicament for use in the treatment or prophylaxis of a 5-HTg receptor related disorder, such as obesity, type II diabetes, and/or disorders ofthe central nervous system, to achieve reduction of body weight and of body weight gain.
• a 5-HTg receptor related disorder such as obesity, type II diabetes, and/or disorders ofthe central nervous system
• Another obj ect of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms for the manufacture of a medicament for use in the treatment or prophylaxis of disorders ofthe central nervous system.
• Another obj ect of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R 3 is ofthe formula
• Another object ofthe present invention is the use of one or more compounds of any ofthe formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when ring D is a pyrrole ring, P is ofthe formula (c) and R 3 is ofthe formula
• the methods delineated herein can also include the step of identifying that the subject is in need of treatment of obesity, type II diabetes, or disorders ofthe central nervous system, or in need of reducing body weight and of body weight gain.
• the invention further relates to cosmetic use of one or more compounds of any ofthe formulae described herein, for causing loss of weight, as well as cosmetic compositions containing said compounds.
• the invention relates to a non-therapeutic metod for impriving the bodily appearance of a mammal, including a human, in which the method comprises orally administering to said mammal one or more compounds of any ofthe formulae described herein.
• an effective amount refers to an amount of a compound that confers a therapeutic effect on the treated subject.
• the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
• the compounds ofthe invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
• the amount of active compounds is between 0.1-95% by weight ofthe preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.
• the typical daily dose ofthe active substance varies within a wide range and will depend on various factors such as, for example, the individual requirement of each patient and the route of administration.
• oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance, preferably 50 to 150 mg per day.
• the invention relates to methods of making compounds of any ofthe formulae herein comprising reacting any one or more ofthe compounds ofthe formulae delineated herein, including any processes delineated herein.
• the compounds ofthe formulae above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods.
• the chemicals used in the above-described synthetic route may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents.
• the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis ofthe compounds of any ofthe formulae described above, their salt forms, or compositions that include the compounds or their salt forms.
• various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
• Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.
• Preparative HPLC/MS was performed on a Waters/Micromass Platform ZQ system equipped with System A: ACE 5 C8 column (19x50mm), eluents: MilliQ water, MeCN and MilliQ/MeCN/0.1%TFA and system B: Xte ⁇ a MS C18, 5 ⁇ m column (19x50mm), eluents: MilliQ water, MeCN and NH 4 HCO 3 (1 OOmM).
• Analytical HPLC were performed on Agilent 1100, column: ACE 3 C8 (system A) or column: YMC-Pack (system B), eluents: MilliQ/0.1%TFA and MeCN. Elemental analyses were performed on a Vario El instrument. Preparative flash chromatography was performed on Merck silica gel 60 (230- 400 mesh).
• HPLC purifications were performed on preparative HPLC/ Mass system using YMC Combi prep ODS-AQ column, 56x20 mm, Gilson pumps, Dynamax UV-1 detector and Finnigan Mass detector.
• the used eluents were H 2 O and CH 3 CN, both with 0.1% TFA.
• the purity ofthe compounds was determined by HPLC. Elemental analysis was performed at Structural Chemistry Department, Biovitrum AB, Sweden. Melting points, when given, were obtained on a B ⁇ chi or a Gallenkamp melting point apparatus and are unco ⁇ ected.
• 6-Bromo-4-chloroquinoline (5.0 g, 20.6 mmol), tert-butyl- 1 -piperazine (4.1 g, 22 mmol), triethylamine (3 mL, 22 mmol) and DMSO (20 mL) were mixed and heated overnight in an oil bath at 100°C.
• the reaction was cooled and diluted with diethyl ether and washed with water (5x), dried (MgSO 4 ) and evaporated.
• the residue was filtered through a short column of silica (2.5-5 %) MeOH in CH 2 C1 2 and evaporated. Yield 8.02 g. (97 %). Brown liquid.
• EXAMPLE 11 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-l-ylquinoIine hydrochloride tert-Butyl 4- ⁇ 6-[(4-tert-butylphenyl)thio]quinolin-4-yl ⁇ piperazine-l-carboxylate (0.60 g, 1.3 mmol) was dissolved in TFA (12 mL) and stirred for 30 minutes before H 2 O 2 (0.65 mL, 6.3 mmol) was added. The mixture was stirred for 2 hours and water (5 mL) was added. The mixture was evaporated and the residue was taken up in water and washed with diethyl ether (2x).
• the crude product was dissolved in TFA (5 mL) and sti ⁇ ed for 15 minutes before 30 % H 2 O 2 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH 2 C1 2 (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with CH 2 C1 2 (3x), dried (MgSO 4 ) and evaporated.
• the crude product was purified by preparative HPLC 5-95 water/acetonitrile collecting on m/z 395.2. After evaporation the free amine was dissolved in CH 2 C1 2 and and excess of HCI in diethyl ether was added and the mixture was evaporated. Yield 0.015 g (7 %).
• the mixture was diluted with THF and filtered through a plug of silica and evaporated.
• the crude product was dissolved in TFA (5 mL) and stirred for 15 minutes before 30 % H 2 O 2 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH C1 2 (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with CH Ci2 (3x) dried (MgSO ) and evaporated.
• the crude was purified by preparative HPLC 5-95 water/acetonitrile collecting on m/z 421.1. After evaporation the free amine was dissolved in CH 2 C1 2 and excess of HCI in diethyl ether was added and the mixture was evaporated.
• 6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with tert-butyl 1,4-diazepane- 1-carboxylate (3.7 g, 18.8 mmol) and K 2 CO 3 (4 g, 29 mmol) in DMSO at 100 °C overnight. After cooling the mixture was poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO 4 ) and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc:hexane 1 : 1 to 2: 1 giving 2.1 g (36 %) of yellow oil.
• the compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)- 1,4-diazepane-l- carboxylate (0.5 g, 1.23 mmol) and p-tert-butylbenzenethiol (0.2 g, 1.23 mmol).Yield: 0.27 g (44 %) ofthe title compound.
• the compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)- 1,4-diazepane-l- carboxylate (0.5 g, 1.23 mmol) and 4-isopropylbenzenethiol (0.19 g, 1.23 mmol). Yield: 0.27 g (46 %) ofthe title compound that was used in the next step without further purification.
• the compound was prepared from tert-Butyl-4 ⁇ 3-[(4-isopropylphenyl)thio]quinolin-5-yl ⁇ - 1,4-diazepane-l-carboxylate (0.27 g, 0.57mmol).
• INTERMEDIATE 14 4-[7-(3,4-Dichloro-phenylsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert- butyl ester
• EXAMPLE 18 7-(3,4-Dichloro-benzenesulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride A mixture of 4-[7-(3,4-dichloro-phenylsulfanyl)-isoquinolin-l -yl] -piperazine- 1 -carboxylic acid tert-butyl ester (230 mg, 0.47 mmol), H 2 O 2 (30% in water, 0.5 mL), trifluoroacetic acid (1.5 mL) was heated at 50 °C, 2h. The reaction was continued overnight at 35 °C.
• EXAMPLE 20 7-(2,5-Dimethyl-benzenesulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride A mixture of 4-[7-(2,5-dimethyl-phenylsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-butyl ester (380 mg, 0.846 mmol), H 2 O 2 (30% in water, 0.5 mL), trifluoroacetic acid (3 mL) was heated at 50 °C, 2h. The reaction was continued overnight at 35 °C.
• the compound was prepared from tert-butyl (3R)-3-hydroxypyrrolidine-l -carboxylate (3.56 g, 19 mmol) and 4-nitro-l-naphthol (3 g, 15.9 mmol). Yield: 5 g (88 %) ofthe title compound as yellow oil.
• the compound was prepared from tert -butyl (3 S)-3-hydroxypyrrolidine-l -carboxylate (3.56 g, 19 mmol) and 4-nitro-l-naphthol (3 g, 15.9 mmol). Yield: 2.8 g (49 %) ofthe title compound as yellow oil.
• the compound was prepared from tert -butyl (3S)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine- 1-carboxylate (5 g, 14 mmol). Yield: 3.5 g (76 %) ofthe title compound as dark pink solid.
• the compound was prepared from tert -butyl (3R)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine-
• the compound was prepared from tert-butyl (3S)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine- 1 -carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol).
• the compound was prepared from tert-butyl (3R)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine- 1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.4 g (87 %) ofthe title compound.
• the compound was prepared from tert-butyl (3S)-3-[(4- ⁇ [(4- chlorophenyl)sulfonyl]amino ⁇ -l-na ⁇ hthyl)oxy]pyrrolidine-l-carboxylate (0.22 g, 0.44 mmol). Yield: 0.15 g (78 %) ofthe title compound as a yellow solid.
• EXAMPLE 41 and EXAMPLE 42 4-(4-Methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamide hydrochloride and 2-bromo-4-(4-methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-3- sulfonic acid p-tolylamide hydrochloride
• the reaction mixture was heated to 120 °C for 15 h.
• the reaction mixture was poured in a silica plug and eluted with chloroform, to give the crude product.
• the crude product was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 0.21 g ofthe desired product, yield 64%, 90% pure.
• EXAMPLE 83 4-(l,4-Diazepan-l-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridine hydrochloride tert-Butyl 4-(2-phenylsulfonyl)fhieno[3,2-c]pyridin-4-yl)- 1 ,4-diazepane- 1 -carboxylate (0.165 g, 0.348 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 2 h. The solvent was evaporated.
• Trifluoroacetic acid (1 mL) was added slowly to a solution of tert-butyl 4- ⁇ 2-[(4- bromophenyl)thio]thieno[3,2-c]pyridin-4-yl ⁇ -l,4-diazepane-l-carboxylate (26 mg, 0.047 mmol) in CH 2 C1 2 at 0 °C.
• the reaction mixture was allowed to reach room temperature, stirred for 40 min and then concentrated in vacuo.
• the residue was twice re-dissolved in MeOH and concentrated in vacuo.
• the residue was again dissolved in MeOH and an excess of IM HCI in diethyl ether (4 mL) was slowly added to the solution.
• Lithium 4-chlorothieno [3, 2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3- (trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine- 1-carboxylate as described in Method Q. Yield 0.023 g (10 % over two steps). Beige solid.
• Lithium 4-chlorothieno [3, 2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,5- dimethoxybenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine- 1-carboxylate as described in Method Q. Yield 0.02 g (10 % over two steps). Beige solid.

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