| Title of Invention | SULFONYLPYRAZOLE AND SULFONYLPYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS |
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| Abstract | This invention concerns sulfonylpyrazoline carboxamidine derivatives as antagonists of 5-HTs receptors, to methods for the preparation of these Compounds and to novel intermediates usefui for tiieir synthesis. The invention also reiates to the uses of such Compounds and compositions, particuiarly their use in administering them to patients to achieve a therapeutic effect in Parkinson"s disease, Huntington"s Chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epiiepsy, obsessive compuisive disorders, mood disorders, migraine. Aizheimer"s disease, age related cognitive decline, mild cognitive impairment, sieep disorders. eating disorders, anorexia, bulimia, hinge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder. Irritable Bowel Syndrome, obesity and type-2 diabetes. The compounds have the general formula(1): wherein the symbols have the meanings given in the description. |
| Full Text | SULFONYLPYRAZOLE AND SULFONYLPYRAZOUNE CARBCXAMIDINE DERIVATIVES AS S-HTe ANTAGONISTS INDEX page Title of the invention 1 Index 1 Technical field 1 Background art 1 Disciosure 3 Definitions 8 Abbreviations 14 Examplel: Analytical methods 16 Example 2: General aspects of syntheses 17 Example 3: Syntheses of pyrazoline intermediates 19 Example 4: Syntheses of Compounds of the invention 41 Example 5; Formulations used in animal studies 63 Example 6: Pharmacological methods 63 Example 7: Pharmaceutical preparations 65 Bibliography 68 Claims 69 Abstract 77 TECHNICAL FIELD This invention relates to the fields of pharmaceutical and organic chemistry, and provides suifonylpyrazoline carboxamidine derivatives, intemiediates. formulations and methods. BACKGROUND ART Serotonin (5-hydroxytryptannine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide ränge of physiological and pathological functions, mediated through a number of receptor families termed 5-HTi, 5-HT2, S-HTs. 5-HT4.5-HT5. S-HTg and 5-HT7. Although the functions of the latter three are less well understood than those of the others, it is generally accepted that Compounds which selectively interfere with 5-HT-mediated Signal transduction are important novel drug targets. The rat S-HTe receptor was cloned by two different groups (Ruat, 1993; Sebben, 1994), and that of the human, sharing a 89% sequence identity, shortly thereafter (Kohen, 1996). Much of the recent interest in the S-HTe receptor is because several psychotropic agents are high affinity antagonists at the human 5-HTe receptor {Kohe- 1996' Roth 1994). These Compounds include amrtriptyline (K=65 nM) and the arvpica^ aniosycnoiics ctazapine {K=9.5 nM). olanzapine iK=10 nM), and quetiapine iK=53 nM Sor^e inese Xf~Dounds, however. is selective. The first seiective 5-HT5 receptor aniagonis:- are Ri 0-4-6790 ana Ro 63-0563. Their usefuiness is limited by their moderate affinity (K=50 nW and 12 nM, respectively) and poor pharmacokinetics (SIeight, 1998). With the recent deveiopment of the selective 5-HTs receptor antagonists Ro-04-6790 and SB-271046, there have been several reports on the activity of these Compounds in models of cognitive function. SB-271G46 improved Performance in the Morris water maze {Rogers, 1999). These resuits are consistent with the finding that chronic intracerebroventricular administration of antisense oiigonucleotides directed toward the S-HTs receptor sequence led to improvements in some measures of Performance in the Morris water maze (Bentley, 1999'^). Recently, the effect of S-HTg antagonists and S-HTe antisense oiigonucleotides to reduce food intake in rats has been reported {Bentley, 1997; Bentley, 1999^; Woolley, 2001). 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. S-HTg selective ligands have been identified as potentially usefui in the treatment or Prophylaxis of certain disorders of the central nervous system such as Parkinson's disease, Huntington's Chorea and/or Schizophrenie, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), age related cognitive deciine, mild cognitive impairment, neurodegenerative diseases characterized by impaired neuronal growrth, sieep disorders, feeding disorders such as anorexia and bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, and pain, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. S-HTg selective ligands are also expected to be of use in the treatmerf of certain gastrointestinal disorders such as functional bowel disorder and Irritable Bowel Syndrome and in the treatment or Prophylaxis of obesity and type-2 diabetes, to achieve reduction of body weight and of body weight gain. The reduction of body weight and of body weight gain (e.g. treating body-weight disorders) is achieved inter alia by reduction of food intake. The goal of the present invention was to provide potent and selective 5-HTs antagonists chemically unrelated to any of the known S-HTe antagonists, Compounds usefui for the treatment of certain CNS disorders. DISCLOSURE Surprisingly ii was found that certain sulfonylpyrazole 3sr3rx3—derivatives ars 5-HTe receptor antagonists. The invention reiaies to a compojrd r^'t-e genera: formula '1; or a tautomer, stereoisomer, N-oxide, isotopically-labelied analogue, or a pharmacologicaily acceptable salt, hydrate or solvate of any of the foregoing, wherein: R1 represents hydrogen, an unsubstituted alkyl(Ci) group, an alkyl(Ci.4) group substituted with one or more Halogen atoms, or a phenyl group optionally substituted with one or more halogen atoms, R2 and R3 independently represent hydrogen, an unsubstituted alkyl(Cv4) group, an alkyl(Ci) group substituted with one or more halogen atoms, an alky!(Ci.4)-0-alkyl(Ci.4)- phenyl group, optionally substituted with one or more hakten atoms, or a phenyl group, optionally substituted with one or more halogen atoms, or, R1 and R2, together with the carbon atoms marked 'a' and 'b' form a Cs-cycloalkyl ring, or, R2 and R3, together with the carbon atom marked 'b' form a Cycloalkyl ring, or R2 and R3, together with the carbon atom marked 'b' fonm an optionally substituted Cs- heterocycloalkyl ring, or R4 and R5 independently represent hydrogen, an unsubstituted alkyl(C1) group, an alkyl(Ci) group substituted with one or more halogen atoms, an optionally substituted monocyclic aromatic group, an optionally substituted fused-bicyclic aromatic group, an optionally substituted monocyclic hetero-aromatic group, an optionally substituted fused- bicyclic hetero-aromatic group, or, R3 and R4, together with the carbon atoms marked 'b' and 'c' form a C3 -8"Cycloalkyl ring, or R3 and R4, together with the carbon atoms marked 'b' and 'c' form an optionally substituted Cs-s-heterocycloalkyl ring, or Re and Rt independentiy represent a hydrogen atorr. or sn aiicvli.C-: crouD. or an aikyl(Cij) group substituted with one or more haloger std-—s c 2 w-.: ;ai Re and Ry, together with the nitrogen atom to which they are attached, form an optionally substituted Cs^s-heterocycloalkyl group, - Rarepresents an optionally substituted monocyclic aromatic group, an optionally substituted fused-bicyclic aromatic group, an optionally substituted monocyclic hetero-aromatic group, an optionally substituted fused-bicyclic hetero-aromatic group, an -CR9=CRio-aryl group wherein R9 and R10 independentiy represent hydrogen or an alkyl-(Ci.3) group, an -Cnc-aryl group, an optionally substituted piperidinyl group, or a group -NR11R12, wherein Rn and R12 independentiy represent hydrogen, an alkyl-(Ci.3) group oran optionally substituted phenyl or benzyl group, The invention relates to racemates, mixtures of diastereomers as well as the individual stereoisomers of the Compounds having formuia (1). The invention also relates to the E isomer, 2 isomer and E/Z mixtures of Compounds having formuia (1). The invention particularly relates to a Compound of the general formuia (1) or a tautomer, stereoisomer, N-oxide, isotopicaliy-labelied analogue, or a pharmacologically acceptable salt, Hydrate or solvate of any of the foregoing, wherein: - R1 represents hydrogen or R1 and R2, together with the cart)on atoms marked 'a' and 'b' form a cyclohexyl ring, - R2 and R3 independentiy represent hydrogen or an alkyl(Ci.3) group, or R2 and R3, together with the carbon atom marked 'b' form a cyclopentyi or cyclohexyl ring, - R4 and R5 independentiy represent hydrogen, an alkyl(Ci.3) group, or R3 and R4, together with the carbon atoms marked 'b' and 'c' form a Cs-s-cycloalkyl ring, - Rg and Ry independentiy represent a hydrogen atom, or an alkyl(Ci_3) group, or an alkyl(Ci.4) group substituted with one or more halogen atoms; or a methoxy group, or a cyclohexyl group, or a benzyl group, or a 4-piperidinyl group, - Ra has the meanings as given above. Even more particular the invention relates to cornpounds of tr-e generaf formula (1) or a tautomer, stereoisomer, N-oxide. isotopica!iy-iabeli&d anakwue or a c-naacologically accep- table Salt, hydrate or solvate of any of the foregoi-c. and R= represents hydrogen, R2 and R3 independentiy represent an aikyis.C--3i group. or R- and R3. logsiner with the carbon atom marked 'b' form a cyclopentyi. or cyciohexv! ring, Rt re^sresents an alkyKCvs) group, Rs has the meanings as given above. in another embodiment the invention relates to Compounds of formula (1) wherein either one, or both, of the two potentially asymmetric carbon atoms in the pyrazoline ring is the levorotatory or dextrorotatory enantiomer. The Compounds of the invention of formula (1), as well as the pharmacologically acceptabie salts thereof, have S-HTs receptor antagonistic activity. They are usefui in treating disorders involving S-HTe receptors, or treatabie by manipulation of those receptors. For instance in: Parkinson's disease, Huntington's Chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sieep disorders, eatiilg disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdraw/al from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephaius, functional bowel disorder. Irritable Bowel Syndrome, obesity and type-2 diabetes. Other embodiments of the invention include, but are not limited to: pharmaceutical compositions for treating, for example, a disorder or condition treatabie by blocking S-HTg receptors, the composition comprising a Compound of formula(l) or a pharmaceutically acceptabie salt thereof, and a pharmaceutically acceptabie carrier; methods of treating a disorder or condition treatabie by blocking S-HTg receptors, the method comprising administering to a mammal in need of such treating a Compound of formula (1) or a pharmaceutically acceptabie salt thereof; pharmaceutical compositions for treating, for example, a disorder or condition chosen from the disorders listed herein; methods of treating a disorder or condition chosen from the disorders listed herein, the methods comprising administering to a mammal in need of such treating a Compound of formula (1) or a pharmaceutically acceptabie salt thereof; pharmaceutical compositions for treating a disorder or condition chosen from the disorders listed herein, the compositions comprising a Compound of formula(l) or a pharmaceutically acceptabie salt thereof, and a pharmaceutically acceptabie carrier; methods for treatina a disorder or condition ChOScH TTDi tn-e dsorders listed herein, the methods comprising administering to a patient in üeec o 5ücn trsatinc a cxjmpound of formuia (1) or a pharmaceutically acceptabie sait there-of. methods of antagonizing a S-HTs receptor thai compnses adminisienng lo a subject in need thereof, an affective amount of a Compound of formuia (1 The invention also provides the use of a Compound or sait according to formuia (1) for the manufacture of medicament. The invention further relates to combination therapies wherein a Compound of the invention, or a pharmaceutically acceptabie sait thereof, or a pharmaceutical composition or formulation comprising a Compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed. Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the Compounds of the invention. The invention also provides Compounds, pharmaceutical compositions, kits and methods for treating a disorder or condition chosen from the disorders listed herein, the method comprising administering to a patient in need of such treating a Compound of formuia (1) or a pharmaceutically acceptable salt thereof. The Compounds of the invention possess S-HTg receptor antagonizing activity. This activity of the Compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art. The invention also provides methods of preparing the Compounds of the invention and the intermediates used in those methods. Isolation and purification of the Compounds and intermediates described herein can be affected, if desired, by any suitable Separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable Separation and Isolation procedures can be taken from the preparations and exampies. However, other equivalent Separation or Isolation procedures couid, of course, also be used. The Compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, Single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents, the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All of the possible optical isomers and diastereomers, in mixtures and as pure or partially purified Compounds, belong to this invention. The present invention comprehends all such isomeric forms of these Compounds. Formuia (1) shows the structure of the class of Compounds without preferred stereochemistry. The independent syntheses of these diastereomers. or their Chromatographie separattons. ma-j be acrieved as known in the art by appropriate modification of the methodology disacsec tns-ar. 'n-eir a2-sc= Cis and trans isomers of the Compound of formula (1), or a pharmaceuticaliy acceptable salt thereof, also belong to the invention, and this also applies to tautomers of the Compounds of formula (1) or a pharmaceuticaliy acceptable salt thereof. Some of the crystalline forms for the Compounds may exist as poiymorphs: as such intended to belong to the invention. In addition, some of the Compounds may form soivates with water (i.e. hydrates), or common organic solvents. Such soivates also fall within the scope of this invention. Isotopically-Iabeied Compound of formula (1) or pharmaceuticaliy acceptable salts thereof, including Compounds of formula (1) isotopically-labeied to be detectable by PET or SPECT, also fall within the scope of the invention. The same applies io Compounds of formula (I) labeied with ["C]-, ["C]-, [H]-, or other isotopically enriched atoms, suitable for receptor binding or metabolism studies. The Compounds of the invention may also be used as reagents or Standards in the biochemical study of neurologicai function, dysfunction and disease. DEFINITIONS General terms used in the description ot their usual meanings. The term alkyl as used herein denores a unlvaien: ssrjraiec zranched or straight hydrocarbon chain. Unless otherwise stated, such chains can contair, frorri 1 to 18 carbon atoms. Representative of such alkyl groups are methyi, ethy!. propyl, isopropyL butyl, isobutyi, sec-butyl, ferf-butyl, pentyl, isopentyl, neopentyl, fert-pentyi, hexyl, isohexyi, hepfyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyi, octadecyl, and the like. When qualified as 'lower', the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term 'alkane', and to derivative terms such as 'alkoxy'. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cx-Cy defines the number of carbon atoms present from the integer "x" to the integer "y" inclusive. 'Alkyl(Ci.3)' for example, means methyi, ethyl, n-propyl or isopropyi, and 'alkyl(Ci)' means 'methyi, ethyl, n-propyl, isopropyi, n-butyl, 2-butyl, isobutyi or 2-methyl-n-propyr. The term 'alkenyl' denotes straight or branched hydrocarbon radicals having one or more carbon- carbon double bonds, such as vinyi, allyl, butenyl, etc., and for example represents (C2- 4)alkenyl. In 'alkynyl' groups the straight or branched hydrocarbon radicals have one or more carbon-carbon triple bonds, such as ethynyl, propargyl, 1-butynyi, 2-butynyi, etc., and for example represent (C2-4)alkynyl. Unless otherwise stated, älkenyl'and 'alkynyl chains can contain from 1 to 18 carbon atoms. The term 'acyl' means alkyl(Ci.3) carbonyl, aryicarbonyl or aryl-alkyl(Ci.3)carbonyl. The term 'aryl' embraces monocyclic or fused bicyciic aromatic or hetero-aromatic groups, inciuding but not limited to furyl, thienyl, pyrroiyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyi, pyrazinyl, 1,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyi, benzo[b]furanyl, 1,2,3,4-tetrahydro-naphtyl, 1,2,3,4-tetrahydroisoquinoiinyl, indanyl, indenyl, benzo[b]thienyl, 2,3- dihydro-1,4-benzodioxin-5-yl, benzimidazolyi, benzothiazoiyf, benzo[1,2,5]thia-diazo(y(, purinyl, quinolinyl, isoquinoünyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, naphthyl, pteridinyi or azuienyl. 'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc. means containing one or more N, O or S atoms. 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus inciuding N-bound O-bound or S- bound alkyl groups. The term 'substituted' means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same. The term 'unsubstituted' means that the specified group bears no substituents. 'Optionally substituted' means that a group may or may not be further substituted by one or more groups seJected from C--s alkyi. alkenyi. C-.., a-yi. f!'joro. chloro, bromo, hydroxyL C^s alkyioxy, Ci^ alkenyioxy, aryicxy. arytexv- amjrc. C-_H sicy^mino. dialkyl(C-.=)- amino, arylamino. thio. C,^ alkylthio. arytthio. alkytsutfory arfsu?^"/:. a^.-s.Jfinyi. aryisulfiny!. cyano, oxo, nitro, acyL amido, Ci_8 aikyiamido, dsiicjhC-.5j3~k:-c or iwo opiionai substituents may together with the carbon atoms to which they are attached form a 5- or 6- membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or suiphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include C1.3 alkyi such as for example methyl, ethyl, and trifluoromethyl, fiuoro, chloro, bromo, hydroxyl, C1.3 alkyioxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino. With reference to substituents, the term 'independently' means that when more than one of such substituents are possible, they may be the same or different from each other. 'C3.g-cycloalkyr means cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl; 'Cj heterocycloalkyl' refers to heteroatom containing rings including but not limited to piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryi, tetrahydropyranyl; 'C5.10 bicycloalkyl group' refers to carbo-bicyclic ring systems including but not limited to bicyclo[2.2.1]heptanyl, bicyclo[3.3.0]octanyl or the bicyclo[3.1.1] heptanyl group; 'Ce-iotricycloalkyl group' refers to carbo-tricyclic ring systems including but not limited to the 1- adamantyl, noradamantyl or the 2-adamantyl group. The abbreviation 'Cs-n tetracycloalkyi group' refers to carbo-tetracyclic ring systems including but not limited to the cubyl, homocubyl or bishomocubyl group. The terms "oxy", "thio" and "carbo" as used herein as part of another group respectively refer to an oxygen atom, a suiphur atom and a carbonyl (C=0) group, serving as linker between two groups, such as for instance hydroxyl, oxyalkyi, thioalkyl, carboxyalkyl, etc. The term "amino" as used herein alone, or as part of another group, refers to a nitrogen atom that may be either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine. The terms "sulfinyl" and "sulfonyl" as used herein as part of another group respectively refer to an -SO- or an - SO2- group. As used herein, the term "leaving group" (L) shall mean a charged or uncharged atom or group that departs during a substitution or displacement reaction. The term refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohoi nucleophile. Such leaving groups are well known in the art. Examples include, but are not limited to, N- hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, Gl, I), triflates, mesylates, tosylates, and the like. N-oxides of the Compounds mentioned above belong to the invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts tc a near quantitative cxjnversicr . N-^xkies rr,ay oe more active than their corresponding tertiary amines. or less active. VYniis S-axkJes can assis be reduced to their corresponding tertiary amines by chemicai mear,s Any Compound metabolized in vivo to provide the bioactive agent (i.e., the Compound of formula (1)) is a prodrug within the scope and spirit of the application. Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass treating the various disorders described with the Compound specificaily disciosed, or with a Compound that not specificaily disciosed, but that converts to the specified Compound in vivo after administration to the patient. Prodrugs are bioreversibie derivatives of drug molecules used to overcome some barriers to the Utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeabiiity, stability, presystemic metabolism and targeting limitations {Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; Järvinen, 2005). Prodrugs, i.e. Compounds that when administered to humans by any known route, are metabolised to Compounds having formula (1), belong to the invention. In particular this relates to Compounds with primary or secondary amino or hydroxy groups. Such Compounds can be reacted with organic acids to yield Compounds having formula (1) wherein an additional group is present that is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an 0-{acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. 'Crystal form' refers to various solid forms of the same Compound, for example polymorphs, solvates and amorphous forms. 'Polymorphs' are crystal structures in which a Compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Polymorphism is a frequently occurring phenomenon, affected by several crystallization conditions such as temperature, level of supersaturation, the presence of impurities, polarity of solvent, rate of cooling. Different polymorphs usually have different X-ray diffraction patterns, solid State NMR spectra, infrared or Raman spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. 'Solvates' are generally a crystal form that contains either stoichiometric or non-stoichiometric amounts of a solvent. Often, during the process of crystallization some Compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystallina solid State, thus forming a solvate. When the solvate is water, 'Hydrates' may be formed. The Compound of formula (1) and pharmaceutically acceptable salts thereof may exist in the form of a hydrate or a solvate, and such a hydrate and solvate are also encompassed in the present invention. Examples thereof irrdude 1.10 hydrate, % hydrate. y2 hydratS: monohydrate, dihydrcx;hio(1de hydrate, dihydrc»3nK>rk:-e airrydrss olrydrochioride 3/2 hydrate. and the like. 'Amorphous" rorms are noncr>'S3ii;ne —stena o-g ränge order. and generally do not give a distinctive powder X-ray drffracüon patierr. Crvs-a; -'orms in generai have been described by Byrn (1995) and Martin (1995) To provide a more concise description, some of the quantitative expressions given herein are not quaiified with the term "about". it is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given vatue, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skili in the art, including approximations due to the experimental and/or measurement conditions for such given value. The terms "selective" and "selectivity" refer to Compounds that display reactivity towards a particular receptor (e.g. a S-HTs receptor) without displaying substantial cross- reactivity towards another receptor (e.g. other 5-HT receptor sub-types). Thus, for example, selective Compounds of the present invention may display reactivity towards S-HTe receptors without displaying substantial cross-reactivity towards other 5-HT receptors. In one embodiment, a Compound of the present invention has at least about l0fold selectivity to the 5- HTe receptor, at least about SOfold selectivity to the S-HTs receptor, at least about lOOfold selectivity to S-HTe receptor, at least about 250fold selectivity to the 5-HTs receptor, or at least about SOOfold selectivity to the desired target. Throughout the deschption and the Claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps. While it may be possible for the Compounds of formula (1) to be administered as the raw chemical, it is preferable to present them as a 'pharmaceutical composition'. According to a further aspect, the present invention provides a pharmaceutical composition comprising a Compound of formula (1), or a pharmaceutically acceptabie salt or solvate thereof, together with one or more pharmaceutically acceptabie carriers thereof, and optionally one or more other therapeutic ingredients. The carrier(s) must be 'acceptabie' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as weil as any product that results, directly or indirectiy, from combining specified Ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectiy, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In generai, pharmaceutical compositions are prepared by unrformty and intimatery bringing the acöve ingredient into association with a liquid carrier or a f.nsty divided sofsd -a—er " DotT: a-c tier-, if necessary. shaping the product into the desired fomuiatio-. ne crar—-.Dsjiion indudes enough of the active object Compound to produce the oesirec efe-ct ^por ne progress or condition of diseases. Accordingly, the pharmaceuticai compositions of the oresent invention encompass any composition made by admixing a Compound of the present invention and a pharmaceuticaiiy acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatibie with the other ingredients of the formulation and not deleterious to the recipient thereof. Within the context of this appiication, the term 'combination preparation' comprises both true combinations, meaning a Compound of formula (1) and one or more other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising a Compound of formula (1)and one or more other medicaments in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component Compounds, e.g. label or drawings. With true combinations, the pharmacotherapy by definition is simultaneous. The Contents of 'kit-of-parts', can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient. The affinity of the Compounds of the invention for S-HTe receptors was determined as described above. From the binding affinity measured for a given Compound of formula (1), one can estimate a theoretical lowest effective dose. At a concentration of the Compound equal to twice the measured K,-value, nearly 100% of the S-HTg receptors likely will be occupied by the Compound. Converting that concentration to mg of Compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailabijity. Pharmacokinetic, pharmaco- dynamic, and other considerations may alter the dose actualiy administered to a higher or lower value. The typical daiiy dose of the active ingredients varies within a wide ränge and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician. In general, total daily dose administration to a patient in Single or individual doses, may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily, and more usually from 0.01 to 1,000 mg per day, of total active ingredients. Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system. animal or human. The effect n-ssy indude for exampie. treating the conditions listed herein. The precise effective amount ^o' a süDec: wL- aepend upon the subject's size and heatth. the narure ana exre^'^: r-e -eing rreated. recommendations of the treating physician i^researcner. vetenranan, —e-ics; aocior or oiher clinician), and the therapeutics, or combination of therapeutics. selected fcr administration. Thus, it is not usefui to specify an exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to those saits that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animais without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well- known in the art. They can be prepared in situ when finally isolating and purifying the Compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids {Berge, 1977). The 'free base' form may be regenerated by contacting the salt with a base or acid, and isolating the parent Compound in the conventional matter. The parent form of the Compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the Compound for the purposes of the present invention. 'Complex' refers to a complex of the Compound of the invention, e.g. formula (1), complexed with a metal ion, where at least one metal atom is chelated or sequestered. Complexes are prepared by methods well known in the art (Dwyer, 1964). The term "treatment" as used herein refers to any treatment of a mammalian, for example human condition or disease, and includes: (1) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease. The term 'inhibit' includes its generally accepted meaning which includes prohibiting, preventing, restraining, alleviating, ameliorating, and siowing, stopping or reversing Progression, severity, or a resultant Symptom. As such, the present method includes both medical therapeutic and/or prophylactic administration, as appropriate. As used herein, the term "medical therapy" intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. 'Mammals' include animais of economic importance such as bovine, ovine, and porcine animais, especially those that produce meat, as well as domestic animais, sports animais, zoo animais, and humans, the latter being preferred. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, Observation or experiment. As used herein, the term "body weight disorders" -e-ers to me disorders caused by an imbalance between energy intake and energy expe-r>dir_'3. 'Bsumnc - aonormai (e.g., excessive) body weight. Such body weight-disorders •nc;-jc-£ coesc. Sibley. "993: SIeigh, 1995, 1997). 'Obesity' refers to a condition wnersty = persor nas a 5oay Mass index (BMI), caiculated as weight per height squared (km/m^). of at ieast 25.9. Conventionally. those persons with normal weight have a BMI of 19.9 to less than 25.3. Tne obesity herein may be due to any cause, whether genetic of environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's Syndrome, Type-Il diabetes, GH- deficient subjects, normal variant Short stature, Turners Syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g. children with acute tymphoblastic leukemia. ABBREVIATIONS ACE-chloride 1-chloroethyl chloroformate ACN acetonitrile AcOH acetic acid ADD attention deficit disorder ADHD attention deficit hyperactivity disorder API atmospheric pressure Ionisation BMI body mass index n-BuOH n-butanol t-BuOH t-butanol (0-BOC Cfert/a/yj-butoxycarbonyl CHO Chinese Hamster Ovary (cells) CNS central nervous system CUR curtain gas DBU 1,8-diazabicyclo[5.4.0]undec-7-ene (1,2)-DCE (1,2)-dichloroethane DCM dichloromethane DF deflector voltage DIPEA A/,A/-diisopropylethylamine □MAP 4-dimethylaminopyridin DMC 2-chloro-1,3-dimethylimidazolinium Chloride DMF N,N'-dimethylformamide DMSO dimethylsulfoxide EA ethylacetate EP entrance potentia! EtOAc ethylacetate EtOH ethanoi EtzO diethyl ether PCS fetal calf serum PP focusing potential g gram(s) h hour(s) 5-HT 5-hydroxytryptamine, Serotonine KO/Bu potassium fert-butoxide Mal methyl iodide MeOH mettianol mg milligram(s) min minute(s) ml or mL miliiiiter(s) m.p. melting point c.q. melting ränge MsCI methanesulfonyl Chloride (mesyl Chloride) MIBE methyl fert-butylether NaHMDS sodium hexamethyldisilazane NEB nebulizer gas PA Petroleum aether (40-60) p-TsOH paratoluene sulphonic acid Rf retention factor (thin layer chromatography) R, retention time (LC/MS) RT room temperature sex strong cation exchange TBAB tetrabutylammonium bromide TEA triethylamine TEM temperature TFA trifluoroacetic acid THF tetrahydrofuran EXAMPLE 1: ANALYTICAL METHODS Nuclear magnetic resonance spectra {H NMR) were determined in the indicated solvent using a Bruker ARX 400 (^H: 400 MHz) or a Varian VXR200 ('H: 200 MHz) Instrument at 300 K. unless indicated otherwise. The spectra were determined in deuterated Chloroform or DMSO obfained from Cambridge Isotope Laboratories Ltd. Chemical shifts (5) are given in ppm downfield from tetramethylsilane (1H). Coupling constants J are given in Hz. Peakshapes in the NMR spectra are indicatsd with the symbols 'q (Quanet ). 'de idoubie quartetv f (triplet). 'dt' (double tripiet). 'd' (doublet), dd' (double doublstK dcki' oouDie aoLoe o-Du-et 's" (singlet). "bs' (broad singlet) and 'nn' (multipiet;. NH and spgnas e-- mixing the sample with a drop of D2O. Flash chromatography refers to purification using the indicated eiuent and silica gel (Merck silica gel 60: 0.040-0.063 mm). Melting points were recorded on a BQchi B-545 melting point apparatus. All reactions involving Compounds sensitive to moisture and/or oxygen were carried out under an anhydrous nitrogen atmosphere. Reactions were monitored by using thin- layer chromatography (TLC) on silica coated glass plates (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualised by UV light (254 nm) or I2. Liquid Chromatography- Mass Spectrometry (LC-MS): The LC-MS system consisted of 2 Perkin Elmer series 200 micro pumps. The pumps were connected to each other by a 50 pl tee mixer, connected to a Gilson 215 auto sampler. The method was as follows: Step total time flow (pl/min) A(%) B(%) 0 0 2000 95 5 1 1.8 2000 0 100 2 2.5 2000 0 100 3 2.7 2000 95 5 4 3.0 2000 95- 5 A= 100% Water with 0.025% HCOOH and lOmmol NH4HCOO pH= + 3 B= 100% ACN with 0.025% HCOOH The auto sampler had a 2 pl injection ioop, and was connected to a Waters Atlantis C18 30*4.6 mm column with 3 pm particles. The column was thermostated in a Perkin Elmer series 200 column Oven at 40° C. The column was connected to a Perkin Elmer series 200 UV meter with a 2.7 pl flowcel. The wavelength was set to 254 nm. The UV meter was connected to a Sciex AP! 150EX mass spectrometer. The mass spectrometer had the following parameters: Scanrange: 150-900 a.m.u.; polarity: positive; scan mode: prcfile; resolution Q1: UNIT; step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10. The light scattering detector was connected to the Sciex API 150. The light scattering detector was a Sedere Sedex 55 operating at 50° C and 3 bar N2- The complete system was controlied by a G3 powermac. EXAMPLE 2: GENERAL ASPECTS OF SYNTHESES Suitable syntheses of claimed Compounds and intermedian follow routes analogous to those previocsi' disciosed in WD 1H-pyrazole or 4,5-dihydro-3H-pyrazole Duiiding bkZKS H.'zr or prepared as described below. containing pyrazoiine moieties smoieying 4.5-dihydro- Route 1 employs sulfonyl carbamates of general formula (I), which can for instance be prepared by reaction of Sulfonamides with methyl chloroformate or di-fert-butyl dicarbonate in tiie presence of base. Their reaction products with pyrazolines of general formula (II) can subsequently be converted into the chloroimine intermediates of general formula (III) using halogenating agents such as PCI3, POCI3/DMAP or 2-chloro-1,3-dimethylimidazolinium Chloride (DMC), followed by reaction with amines to obtain suifonylpyrazoline carboxamidine derivatives of general formula (IV). Route 2 Route 2 employs N-(bis-alkylsulfanyl-methylene)-sulfonamide structures of general formula (V), which may be prepared from Sulfonamides by reaction with CS2 in the presence of KOH, followed by reaction with an alkyl haiide such as methyl iodide. The two S-alkyl functionalities can subsequently be substituted by amines. preferabhy startirrc wün ths pyrnzoilne building blocks to obtain structures of generai formula ta eod sura-'V'ipy'azo.'r'e caooxamidine derivatives of genera! foimula (IV). Route 3 Route 3 employs alkyl-isothiourea fragments or suitabie salt forms thereof of generai formula (IX), conveniently prepared by reaction of thiourea building blocks with alkyl halides, such as methyi iodide, that can be reacted with pyrazolines in the presence of base to obtain pyrazoline carboxamidine derivatives of generai formula (X). The latter can be reacted vjWh sulfonyl halides (X=Br, Cl, F, preferably Cl) in the presence of base to obtain sulfonylpyrazoline carboxamidine derivatives of generai formula (IV). The selection of the particular synthetic procedures depends on factors known to those skilled in the art such as the compatibility of functional groups with the reagents used, the possibility to use protecting groups, catalysts, activating and coupling reagents and the ultimate structural features present in the final Compound being prepared. Pharmaceutically acceptabie salts may be obtained using Standard procedures well known in the art, for example by mixing a Compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid. EXAMPLE 3: SYNTHESES OF PYRAZOLINE INTERMEDIATES 3-Ethyl-4,5-dihydro-1 H-pyrazoie Hydrazine hydrate (24.55 mL) was dissofveo in MeO-; .5=: - -ze bath. To this Solution, ethyi vinyi ketone (50 mL) was added at sucn a rata thst me te^-r-e-aru-e was Kepi below 10°C. The ice bath was removed and the mixture was stirred fo- 2 h. at room temperature, after which the MeOH was evaporated under reduced pressure. The product was obtained by vacuum distiiiation (70°C, 20 mbar), yielding 7.22 g of a coloriess iiquid. 'H NMR (400 MHz, CDCls) 6 1.15 (t, J = 8 Hz, 3H), 2.34 (q, J = 8 Hz, 2H), 2.59 (t, J = 10 Hz, 2H), 3.10 (brs, 1H), 3.34 (t,J= 10 Hz, 2H). HJNNH, HJO MeOH 3-Methyl-4,5-dihydro-1H-pyrazole Hydrazine hydrate (29.2 mL) was dissolved in MeOH (50 mL). To this Solution, methyl vinyi ketone (50 mL) was added at such a rate that the temperature was kept below 50°C. The mixture was stirred for 2 h. at 50°C, after which the MeOH was evaporated under reduced pressure. The product was obtained by vacuum distiiiation (68-82°C, 20 mbar), yielding 11.8 g of a coloriess liquid. 'H NMR (400 MHz, DMSO-ds) 6 1.88 (s, 3H), 2.47 (t, J = 10 Hz, 2H), 3.15 (t, 10 Hz, 2H), 6.10 (brs, 1H). 4-Ethyl-4,5-dihydro-1 H-pyrazole Hydrazine hydrate (58 mL) was dissolved in MeOH (300 mL) and cooled in an ice bath. To this mixture, a Solution of 2-ethylacrolein (100 g) in MeOH (100 mL) was added at such a rate that the temperature was kept below 10°C. The ice bath was removed and the mixture was stirred overnight at room temperature, after which the MeOH was evaporated under reduced pressure. The product was obtained by vacuum distiiiation (70-80°C, 20 mbar), yielding 54.9 g of a coloriess liquid. ^H NMR (400 MHz, CDGb) 5 0.98 (t, J = 8 Hz, 3H), 1.42-1.70 (m, 2H), 2.89-3.02 (m, 2H), 3.43-3.54 (m, 1H), 6.78 (br s, 1H), NH invisible. 4-Methyl-4,5-dihydro-1 H-pyrazole Hydrazine Hydrate (16.35 mL) was dissoivsd in CH.CS s: -L snd xcted - a- ics bath To this mixture, a Solution of 2-methyiacrolein (24.02 g) in Cn.CN 50 ws accec:. T"-e ice bstr was removed and the mixture was stirred overnight at room temperature. aner which the CHjCN was evaporated under reduced pressure. The product was obtained by vacuui- distiüation (102- 108°C, 250 mbar), yielding 7.0 g of a coiorless liquid. H NMR (400 MHz. CDCb) 5 1.18 (d, J = 7 Hz, 3H), 2.90 (t, J = 9 Hz, 1H), 3.00-3.12 (nn, 1H), 3.51 (t, J= 9 Hz, 1H). 5.48 (br s, 1H), 6.73 (br s, 1H). 5-Ethyl-4,5-dihydro-1 H-pyrazole Hydrazine Hydrate (12.1 mL) was dissolved in MeOH (50 mL) and cooled in an ice batH. To this mixture, a Solution of 2-pentenal (24.4 mL) in MeOH (50 mL) was added at such a rate that the temperature was kept below 10°C. The ice bath was removed and the mixture was stirred for 2.5 h. at room temperature, followed by evaporation under reduced pressure. The product was obtained by vacuum distillation (68-72°C, 25 mbar), yielding 8.25 g of a coiorless liquid./"H NMR (400 MHz, CDCI3) 6 0.92 (t, J = 7.5 Hz, 3H), 1.42-1.61 (m, 2H), 2.36 (ddd, J= 17, 8 and 2 Hz, 1H), 2.76 (ddd, J= 17, 10 and 2 Hz, 1H), 3.51-3.62 (m, 1H), 5.35 (brs, 1H), 6.76 (brs, 1H). NaCIO NHj NHj MeOH/Hp '^N 4,4-Dimethyl-4,5-dihydro-3H-pyrazole 2,2-DimetHyl-1,3-propanediamine (20.0g) was dissolved in H2O (80 mL) and MeOH (20 mL) and cooled in an ice bath. Simultaniously, H2O2 (30%, 120mL) and NaCIO (10%, 350mL) were added dropwise. The reaction mixture was stirred overnight at room temperature, extracted with DCM, the organic layer dried over Na2S04 and the solvent evaporated under reduced pressure. Vacuum distillation (102-105 250 mbar), yielded 11.4 g of a coiorless amorphous oily Compound. ^H NMR (200 MHz, CDCI3) 6 1.05 (s, 6H), 4.13 (s, 4H). Alternatively, this Compound was synthesized as follows: 4,4-Dimethyl-4,5-dihydro-3H-pyrazole 2.2-Dimethyi-1,3-propanediamine i.8.97 g. a-bs dissofvec r --Z if in an bath. Simuitanousiy, H2O2 (30%, 54 mL) and NaCiO .lü'c. wer- sarec aropwise. keeping the temperature below 25='C. Subsequently, the reaction mixture was stin-ed for 1 h. at room temperature, and extracted with DCM (2 x 45 mL). Tne combined organic iayers were extracted with aqueous sodium sulfite (20%, 25 mL), washed with water (2 x 25 mL) dried over Na2S04, and evaporated under reduced pressure (>200 mbar at 50'C) to give 8.89 g of a coiorless fluid (containing some residual DCM). 'H NMR (200 MHz, CDCI3) 6 1.05 (s, 6H), 4.13 (s, 4H). 2,2-Diethyl-malononitrile Malononitrile (15.2 g) was mixed with TBAB (3.0 g, 4 mol%) and ethyl iodide (36.8 mL, 2 equiv.). After stirring for 30 minutes at room temperature, the mixture was cooied in an ice bath, KOtBu (51.6 g, 2 equiv.) was added portionwise, the ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. Extraction with DCM/H2O, drying over Na2S04 and evaporation under reduced pressure gave 40 grams of crude material, which was purified by fiash chromatography eluting with DCM. This yielded 20.4 grams of an orange oil which solidified upon standing. 'H NMR (400 MHz, CDCI3) 5 1.29 (t, J = 7.5 Hz, 6H), 2.00 (q, J = 7.5 Hz, 4H). 2,2-Diethyl-propane-1,3-diamine A suspension of LiAIH4 (4.66 g) in dry EtzO (100 mL) was cooied in an ice bath, and a Solution of 2,2-diethyl-malononitrile (5.0 g) in EtjO (50 mL) was added dropwise at at such a rate that the temperature was kept below 20°C. The mixture was stirred ovemight at rctom temperature, cooied in an ice bath. and quenched by adding H2O (5 mL), 2M aqueous NaOH (10 mL) and again H2O (5 mL). The suspension was filtered, the filter cake was washed with EtjO, and the combined filtrates were evaporated to dryness under reduced pressure to give 5.0 g of a clear, light-yellow liquid. 'H NMR (400 MHz, CDCI3) 5 0.80 (t, J = 8 Hz, 6H), 1.08 (br s, 4H), 1.22 (q, J = 8Hz, 4H), 2.52 (s, 4H). 4,4-Diethyl-4,5-dihydro-3H-pyrazole 2,2-Diethyl-propane-1,3-diamine (5.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooied in an ice bath. Simultaneously, HzOj (24.2 mL of a 30% Solution, 6 equiv.) and NaCIO (54.9 mL of a ^0% Solution, 2.4 equiv.) were added dropwise, the ice bath was removed. and the mixture was stirred 2 h. at room temperature Exirac&on DCM, drying Over Na2S04 and evaporation under reduced pressure yetoec 2,51 3 af a cfea- veüow iiquid containing 77% of the anticipated product and 22-- -- -sr-s-e -a-e-riai Thig material was used in subsequeni steps without further purmcazc--. 'H NM- 0.78 (t, J = 7.5 Hz, 6H), 1.36 (q, J = 7.5 Hz, 4H), 4.14 (s. 4H}. Cyclopentane-1,1-dicarbonitrile Malononitrile (15.0 g) was dissolved in dry DMF (200 mL) and cooled in an ice bath. Subsequentiy, DBU (75 mL, 2.2. equiv.) and 1,4-dibromobutane (29.6 mL, 1.1 equiv.) were added dropwise. The ice bath was removed, an extra 100 mL of dry DMF was added, and the mixture was stirred at 80°C for 2 h. After cooling to ambient temperature, DCM was added and the mixture was washed 5 times with 5% aqueous NaHCOs. The organic phase was dried over Na2S04 and evaporated under reduced pressure to give 40 g of a black oiiy substance. This was purified by flash chromatography eluting with PA:EA 9:1 (Rf = 0.35, visualized with I2) to give 23.4 g of a colorless liquid. ^H NMR (400 MHz, CDCI3) 5 1.94-2.03 (m, 4H), 2.41 (t, J = 7 Hz, 4H). C-(1-Aminomethyl-cyclopentyl)-methylamine A suspension of UAIHA (4.74 g) in dry EtzO (100 mL) was cooled in an ice bath, and a Solution of cyclopentane-1,1-dicarbonitrile (5.0 g) in EtzO (50 mL) was added dropwise at at such a rate that the temperature was kept below 20°C. The mixture was stirred ovemight at room temperature, cooled in an ice bath, and quenched by adding H2O (5 mL), 2M aqueous NaOH (10 mL) and again H2O (5 mL). The suspension was filtered, the Atter cake was washed with Et20, and the combined filtrates were evaporated to dryness under reduced pressure to give 4.95 g of a clear, colorless liquid. 'H NMR (400 MHz, CDCU) 5 1.24 (br s, 4H), 1.22-1.40 (m, 4H), 1.55-1.64 (m, 4H), 2.62 (s, 4H). 2,3-Diaza-spiro[4.4]non-2-ene C-(1-Aminomethyl-cyclopentyl)-methylamine (4.87 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, HzOz (23.9 mL of a 30% Solution, 6 equiv.) and NaClO (54.3 mL of a 10% Solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred 2 h. at room temperature. Extraction with DCM, drying over NBZSOA and evaporation under reduced pressure yielded 3.74 g of a clear, light-yellow liquid containing 90% of the anticipated product and 10% of the diamine starting material. This material was used in subsequent steps without further purification. H NMR (400 MHz, CDOs) 6 1.48-1.57 (m, 4H), 1.62-1.69 (m, 4H), 4.26 (s, 4H). Cyclohexane-1,1 -dicarbonitrile Malononitril (15.0 g) was dissolved in dry DMF (200mL). Subsequently, DBU (75 mL) and 1,5- dibromopentane (34 mL) were added at 0°C (ice bath). The ice bath was removed and the reaction was stirred for 2h at 80°C. After cooling down, the reaction was poured into DCM. The organic layer was washed several times with 5% NaHCOs, the organic layer dried over Na2S04 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with PA:EtOAc (9:1) yielding 25.7g white crystais. ^H NMR (400 MHz, CDCyS 1.48-1.61 (m, 2H), 1.68-1.84 (m, 4H), 2.13 (t, J = 6 Hz, 4H). C-(1-Aminomethyl-cyclohexyl)-methylamine Cyclohexane-1,1-dicarbonitrile (20.0 g) was taken up in dry Et20 (70 mL). This mixture was added dropwise to a suspension of LIAIHA (17.0 g) in dry Et20 (250 mL) cooled in an ice bath. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched by adding H2O (17.0 mL), 2M aqueous NaOH (34.0 mL) and again H2O (17 mL). The suspension was filtered, the filter cake was washed with Et20, and the combined filtrates were evaporated to dryness yielding 20.8 g of a clear, colorless liquid. 'H NMR (400 MHz, CDCI3) 6 1.05-1.55 (m, 14H), 2.61 (s, 4H). 2,3-Diaza-spiro[4.5]dec-2-ene DMF C-(1-Aminomethyl-cyclohexyl)-methylamine (10.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (44.3 mL of a 30% Solution, 6 equiv.) and NaCIO (125.5 mL of a 10% Solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 45 min. at room temperature. Extraction with DCM, drying over NazSÜA and evaporation under reduced pressure, yielded 8.7 g of a clear, light-yellow liquid. . 'H NMR (400 MHz, CDCis) 5 1.24-1.53 (m, 10H), 4.17 (s, 4H). 2-2-Methy|.[1,3ldioxolan-2-yl)-butyric acid ethyl ester Methyl-2-ethyiacetoac8ta1e (100 mL) was laKsn up in toiuene 25: -l* rS-col -46 9 mL, 1.35 equiv.) and a catalytic amount of p-TsOH'HrO we aoaec. are A-as refiuxed overnight under Dean-Stark conditions. After cooling to ambieni temperature. the mixture was washed with 5% aqueous NaHCOs and saturated aqueous NaC.'. the organic Phase was dried over Na2S04 and evaporated under reduced pressure. The residue was purified by repeated vacuum distillation (118-128°C, 15 mbar), yielding 85.5 g of product. 'H NMR (400 MHz, CDCI3) 5 0.90 (t, J = 7 Hz, 3H), 1.28 (t, J = 7 Hz, 3H), 1.40 (s, 3H), 1.59-1.83 (m, 2H), 2.56 (dd, J= 11.5 and 4 Hz, 1H), 3.90-4.06 (m, 4H), 4.18 (m, 2H). 2-(2-Methyi-[1,3]dioxolan-2-yl)-butan-1 –ol 2- {2-Methyl-[1,3]dioxolan-2-yl)-butyric acid ethyl ester (85.5 g) was taksn up in dry EtjO (50 mL). This nnixture was added dropwise to a suspension of LiAIH4 (16.1 g) in dry Et20 (200 mL), cooled in an ice bath. The mixture was refiuxed for 4 h., cooied in an ice bath, and quenched by adding H2O (16.1 mL), 2M aqueous NaOH (32.2 mL) and again H2O (16.1 mL). The suspension was filtered, the filter cake was washed with EtaO, and the combined fiitrates were evaporated to dryness. The residue (49 g) was purified by vacuum distillation (112-125°C, 15 mbar), yielding 43.5 g of a dear, colorless liquid. 'H NMR (400 MHz, CDCI3) 5 0.98 (t, J = 7.5 Hz, 3H), 1.10-1.24 (m, 1H), 1.31 (s, 3H), 1.50-1.75 (m, 2H), 3.12, (br s, 1H), 3.59-3.76 (m, 2H), 3.94-4.02 (m, 4H). 3- Hydroxymethyl-pentan-2-one 2- (2-Methyl-[1,3]dioxolan-2-yl)-butan-1-ol (43.5 g) was taken up in a mixture of H2O (100 mL) and EtOH (10 mL), and concentrated aqueous HCl (1 mL) was added. The mixture was refiuxed for 2 h-, cooled to ambient temperature, neutralized with 2M aqueous NaOH, saturated with ammonium suifate and extracted twice with Et20. The combined organic layers were dried over Na2S04 and evaporated to dryness. The yellowish residue (25.7 g) was purified by vacuum distillation to give 20.7 g of a clear, colorless oil. 'H NMR (400 MHz, CDCI3) S 0.95 (t, J = 7.5 Hz, 3H), 1.49-1.76 (m, 2H), 2.21 (s, 3H), 2.64 (m, 1H), 3.68-3.84 (m, 3H). Acetic acid 2-ethyl-3-oxo-butyl ester 3- Hydroxymethyl-pentan-2-one (20.7 g) was dissolved in CHCI3 (150 mL) and cooled in an ice bath. Acetic anhydride (80 mL) was added, followed by DMAP (2.18 g), and the mixture was stirred overnight at room temperature. After cooling in an ice bath, MeOH (120 mL) was added dropwise, and the mixture was poured into a saturated aqueous NaHCOa Solution. After extraction with DCM twice, the combined organic phases were dried over Na2S04 and evaporated under reduced pressure to give 28.0 g of a light-yellow liquid. ^H NMR (400 MHz, CDCI3) 5 0.93 (t, J = 8 Hz, 3H), 1.46-1.75 (m, 2H), 2.03 (s, 3H), 2.20 (s, 3H), 2.77 (quint., J = 6.5 Hz, 1H), 4.20(d, J=7Hz, 3H). 4- Ethyl-3-methyl-4,5-dihydro-1H-pyrazole Acetic 3cid 2-ethyl-3-oxo-butyl ester (23.0 g) was taken UD in dr>- Tr^F ;75 STR:: DBü (23.9 mL) was added. The mixture W3S stirred et room tenpersr-re '5 —c ic 'orm the intermediate 3-methylene-pentan-2-one. WeOH '75 m was adied "DlbM t-v aroowise addition of hydrazine hydrate (7.75 mL). Tne resufting mDcrurs vvas sirrBc c temperature and evaporated under reduced pressure. The residue was purified by vacuum distillation (94-106°C, 15 mbar), yielding 7.9 g of a clear, coioriess liquid. "'H NMR 2-Dimethylaminomethyl-cyclohexanone To cyciohexanone (259 mL) was added formaldehyde (37.2 mL of a 37% aqueous Solution) and dimethylamine hydrochloride (40.8 g). The stirred mixture was siowly heated and refluxed for 1 h. After cooling to ambient temperature HjO was added, and the mixture was extracted twice with EizO. The aqueous layer was made basic by addition of 50% aqueous NaOH (27.5 mL), and subsequently extracted twice with DCIVI. The combined organic phases were dried over Na2S04 and evaporated under reduced pressure to give 66.6 g of a light-yeilow liquid. ^H NMR (400 MHz, CDCI3) 6 1.34-1.47 (m, 1H), 1.60-1.78 (m, 2H), 1.81-1.92 (m, 1H), 1.98-2.09 (m, 1H), 2.16-2.55 (m, 5H), 2.21 (s, 6H), 2.69 (dd, J = 13 and 6 Hz, 1H). 3,3a,4,5,6,7-Hexahydro-2H-indazole Hydrazine hydrate (28.0 mL) was dissqlved in n-BuOH (200 mL) and cooied in an ice bath. A Solution of 2-dimethylaminomethyl-cyclohexanone (64.0 g) in n-BuOH (50 mL) was added dropwise, the mixture was slowly warmed and refluxed for 20 hours. Het solvent was evaporated under reduced pressure. 4-Ethyl-5-methyl-4,5-dihydro-1H-pyrazole The residue was purified by vacuum distillation (64-67°C, 28 Pa), yielding 24.2 g of a clear, coioriess liquid. This material was used in subsequent steps without further purification. Hydrazine hydrate (12.4 mL) was dissolved in MeOH (10G mL) a-^c coofed in an ice bath. To this mixture, a Solution of 2-ethy{-bu^2-enai (25 g) in MeOH (5C ws a^cea sücr 3 rate -hat the temperature was kept below W'C. Tne tce batr A3S -e-^rve-r s-- -e —ar^re was stirred et room temperature for 2 days. The solvent was evBpo^sä unaer ---u^- oressure. Vacuum distillation (90-100°C, 20 mbar) yieided 16.9 g of a iight-yeibw liquid containing the desired product as a diastereomeric mixture and the hydrazone in approximater/ a 1:2 ratio. This material was used in subsequent steps without further purification. 5-Ethyl-4-methyl-4,5-dihydro-1H-pyrazole Under N2 atmosphere, hydrazine hydrate (63.9 mL, 10 eq) was dissolved in MeOH (100 mL) and cooled in an ice bath. To this mixture, a Solution of 2-methyl-pent-2-enal (15,0 mL) in MeOH (50 mL) was added at such a rate that the temperature was kept below 10°C. The ice bath was removed and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Vacuum distillation (40-45°C, 15 mbar) yieided 9.5 g of a light-yellow liquid containing the desired product as a diastereomeric mixture and the hydrazone in approximately a 1:1 ratio. This material was used in subsequent steps without further purification. 4-Hydroxy-3,3-dimethyl-butan-2-one To 25 mL 3-methyi-butan-2-one was added 7.01 g paraformaidehyde and 36.0 mL trifluoroacetic acid. The mixture was refluxed for 7 hours. After cooling down, 300 mL H2O and 100 g (5 eq) NaHCOs were added. The suspension was filtered and the organic layer was separated. The filter cake was washed two times with DCM, the combined filtrates were dried Over Na2S04 and the solvent was evaporated under reduced pressure to give 23.7 g of an orange liquid. ^H NMR (400 MHz, CDCI3) 6 1.17 (s, 6H), 2.17 (s, 3H), 2.38 (t, J = 7 Hz, 1H), 3.65 (d, J = 7 Hz, 2H). Methanesulfonic acid 2,2-dimethyl-3-oxo-butyl ester 23.7 g 4-Hydroxy-3,3-dimethyl-butan-2-one was dissolved in 150 mL DCM. 49.5 mL (3 eq) Pyridine and 17.5 mL (1.1 eq) mesylchloride were added and the mixture was stirred at room temperature for 20 hours. The suspension was filtered and the filter cake was virashed two times with DCM. The filtrste was washed with 1 M HC' and t^ aqueous iayer was extracted two times with DCM. The cx)mbined fittrates were driec Sa^SC^ a-- —e solvent was evaporated under reduced pressure lo g:ve 41.2 c of = d--^ JC_iC. - SV= iM MHz CDCia) 5 1.24 (s, 6H), 2.20 (s, 3H), 3.03 (s, 3H). 4.21 (8, 2Hi. 3,4,4-Trimethyl-4,5-dihydro-1H-pyrazole 39.2 g Methanesulfonic acid 2,2-dimethyl-3-oxo-butyl ester was dissolved in 200 mL MeOH and cooled in an ice bath. 21.6 mL (2.2 eq) hydrazine hydrate was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, 5 % NaHCOs was added and extracted 3 times with DCM. The combined organic layers were dried Over Na2S04 and the solvent was evaporated under reduced pressure to give 19.5 g of an orange liquid. Vacuum distiliation of 10 g of this liquid yielded 6.4 g light-yellow liquid (76-78°C, 20 mbar). 'H NMR (400 MHz, CDCI3) 5 1.14 (s, 6H), 1.86 (s, 3H), 3.14 (s. 2H), 4.00 (br s, 1H). 3-Dimethylamino-1 -phenyl-propan-1 -one hydrochloride To a Solution of 0.5 mL concentrated aqueous HCl in 40 mL EtOH, acetophenone (30.0 g), paraformaldehyde (10.0 g) and dimethylamine hydrochloride (26.5 g) were added and the mixture was refiuxed for 3 h. The mixture was cooled to room temperature, and the precipitate was filtered, washed with acetone and dried in vacuo to obtain 37.2 g of white crystalline materiai. 'H NMR (200 MHz, DMSO-de) 5 2.84 (s, 6H), 3.38-3.55 (m, 2H), 3.57-3.74 (m, 2H), 7.48-7.73 (m, 3H), 7.97-8.10 (m, 2H). 3-Phenyl-4,5-dihydro-1H-pyrazole Under N2 atmosphere, 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a Solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stin-ed at 50°C. The mixture was refiuxed for 2 hours and evaporated under reduced pressure. Ice water was added to the residue and after stirring for 5 minutes the formed solid was filtered off. The residue was taken up in EtzO, dried over Na2S04, and evaporated to dryness under reduced pressure to give 19.7 g of a yellow oil being 80% pure, which was used in subsequent steps without further purification. 1-(4-Chloro-phenyi)-3-dimethylamino-propan-1-one hydrochloride To EtOH (80 mL), p-chloroacetophenone (77.3 g, 0.50 mol), dimethyiamine hydrocd.loride (52.7 g, 0.65 mol), paraformaldehyde (19.8 g, 0.66 mol) and concentrated aqueous HCl (1 mL) were added and the mixture was refiuxed for 5 h. The mixture was cooled to 40°C, acetone (400 mL) was added, and under stirring the mixture was cooled further to 20°C. The precipitate was filtered, washed with acetone and PA, and air dried to obtain 69.5 g of product which was used without further purification in the subsequent step. 3-(4-Chloro-phenyl)-4,5-dihydro-1H-pyrazole Under Na atmosphere, 1-(4-chloro-phenyl)-3-dimethylamino-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a Solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50°C. The mixture was refiuxed for 2 hours, and evaporated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic phase was washed twice with water, dried and evaporated under reduced pressure, to give 25.0 g of a yellow solid, m.p. 90-100°C. 4-Phenyl-4,5-dihydro-1 H-pyrazole Under N atmosphere, dimethyiamine hydrochloride (7.27g) and forTT.aline (37%) (6.63mL) were added to phenyl acetaldehyde (10 mL) and stirred overnight at room temperature. The reaction mixture was extracted once with diethyl ether, the organic layer was dried over MgS04 and the Solution containing the intermediate 2-phenyl-propenal was taken up in MeOH. Hydrazine hydrate (7.87 mL) was added, and the' reaction mixture was stirred for 2 hours at 50°C (EtzO evaporated). The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and dried over MgS04, followed by evaporation under reduced pressure, yielding 3.12 g of a yellow oil which was used in the subsequent step without further purification. 3-Phenyl-but-3-en-2-one 1-Phenyl-propan-2-one (40.3 g) was dissofved in 2öü mi of MeO- -—aiiie - 9 ^Li. piperidine (4 ml) and HOAc i4 m!) where adaec and de -ea-cDc-- yv3s stirBc S'- The reaction mixture was evaporated to dryness under reduce^d pressu-e r^siu^e ?»=£ ra^.er, üc in diethyl ether, and extracted with water. The organic layer was washed v/ith IM HCL dried Over MgS04 and evaporated under reduced pressure to yield 36,5 g of a yeüow iiqukj. NMR (400 MHz, CDCI3) 5 2.41 (s, 3H), 5.87 (s, 1H), 6.18 (s, 1H), 7.24-7.40 (m, 5H). 3-Methyl-4-phenyl-4,5-dihydro-1H-pyrazole Hydrazine hydrate (12.06 mL) was added to 3-Phenyl-but-3-en-2-one (36.3 g) in MeOH (200 mL). The reaction was stirred overnight at reflux temperature. The solvent was evaporated under reduced pressure. The residue was taken up in diethyl ether and washed with water. The organic phase was dried over Na2S04 and evaporated under reduced pressure. The crude material was purified by flash column chromatography eluting with DCM.MeOH = 98:2 to give 19.7 g of a orange oil, containing 65% of the desired product, which was used in subsequent steps without further purification. 5-Phenyl-4,5-dihydro-1 H-pyrazole Under N2 atmosphere, hydrazine hydrate (9.2 mL) was added to a Solution of cinnamaldehyde (10.0 g) in f-BuOH (20 mL). The mixture was refluxed overnight, followed by concentration under reduced pressure. Water was added to the residue, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure. This gave 10.46 g of a yellow oil containing 85 % of the desired product, which vyas used in subsequent steps without further purification. 'H NMR (200 MHz, CDCI3) 6 2.61-2.80 (m, 1H), 3.04-3.23 (m, 1H), 4.72 (dd, J = 8 and 10 Hz, 1H), 5.60-6.10 (brs, 1H), 6.77-6.87 (m, 1H), 7.18-7.47 (m, 5H). 5-Furan-2-yl-4,5-dihydro-1 H-pyrazole Under N2 atmosphere, hydrazine hydrate (4.0 mL) was added to a Solution of 3-(2-furyl)acrolein (5.0 g) in NBuOH (25 mL). The mixture was refluxed for 2 days, followed by evaporation under reduced pressure. The residue was taken up in DCM and extracted twice with 5% aqueous NaHCOj. The organic phase was dried over Na2S04 and evaporated under reduced pressure. This gave 5.3 g of a yellow oil, containing 45% of the anticipated product and 55% of the hydrazone intermediate that faiied to undergo ring-closure. Addisona; 24 - rBf.ux in n-BuOH gave (after workup) 5.6 g of a brown oii. coniaining 56 '/i of trt5 % of tne hydrazone. This mateiia! was used i.n subseque.n: stacs cation. Characteristic pyrazoline signals in 'H NMR (400 MHz. CDCU-: : 2.£~-3 GE 2- - "1-4.31 (m, 1H), 6.87 (brs, 1H). 3-(3,4-Dihydro-2H-pyrazol-3-yl)-pyridine Under N2 atmosphere, hydrazine hydrate (3.65 mL, 2 equiv.) was added to a Solution of 3-(3- pyridyl)acrolein (5.0 g) in f-BuOH (25 mL). The mixture was refluxed for 3 days, foliowed by evaporation under reduced pressure. The residue was tal 3-Furan-3-yl-propenal 6.08 g (triphenylphosphoranylidene)acetaldehyde was suspended in 10 mL dry DMF, Added was 1.67 mL (1 equiv.) 3-furaldehyde and the mixture was stirred overnight at 80 °C. The mixture was taken up in EA and washed 4 times with 5% aqueous NaHCOa, the organic phase was dried over Na2S04, filtrated and concentrated in vacuo. The residue was suspended in PA, filtrated and concentrated in vacuo to yieid 1.47 g of a light browm oii containing 68 % of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in 'H NMR (400 MHz, CDCI3): 5 6.45 (dd, J = 8 and 16 Hz, 1H), 9.63 (d, J = 8 Hz, 1H). 5-Furan-3-yl-4,5-dihydro-1H-pyrazole 5.84 ml (10 equiv.) hydrazine hydrate was added to 20 mL diethylether. The emulsion was cooled with an ice/NaCI bath to -10 °C. A Solution of 1.47 g 3-furan-3-yl-propenal in 20 mL diethylether was added dropwise. The mixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. 5% aqueous NaHCOs was added and the mixture was extracted 3 times with EA. The combined organic layers were dnec over NaSO- imrBied and concentrated in vacuo. The residue was catched on an SCX ion excnar-ae xsiu—n. wasr—n with MeOH and eluted with IM NH. in MeOH to yiekj S5C tc c- ors-ce o," the desired product after evaporation. This materiai was used ir, sussecue-n stecs w—c_- rurtner purification. 'H NMR (400 MHz. CDCU) a 2.62-2.72 (m, 1H). 2.S7-3.07 (m, 1H), 62-.71 (m. 1H), 5.57-5.74 (br s, 1H), 6.36 (br s, 1H), 6.87 (br s, 1H), 7.35-7.41 (m, 2H). 3-Pyridin-2-yl-propenal 6.08 g (triphenylphosphoranylidene)acetaldehyde was suspended in 10 mL dry DMF. Added was 1.90 mL (1 equiv.) pyridine-2-carbaldehyde and the mixture was stirred overnight at room temperature. The mixture was taken up in EA and washed 4 times with 5% aqueousNaHCOg, the organic phase was dried over Na2S04, filtrated and concentrated in vacuo, The residue was suspended in PA, filtrated and concentrated in vacuo to yieid 1.50 g of a dark yellow oil containing 80 % of the desired product. This materiai was used in subsequent steps without further purification. 'H NMR (400 MHz, CDCI3) 5 7.09 (dd, J = 8 and 16 Hz, 1H), 7.30-7.36 (m, 1H), 7.49-7.59 (m, 2H), 7.77 (dt, J = 8, 8 and 2 Hz, 1H), 8.67-8.74 (m, 1H), 9.81 (d, J = 8 Hz, 1H). 2-(3,4-Dihydro-2H-pyrazol-3-yl)-pyridine 4.56 ml (10 equiv.) hydrazine hydrate was added to 20 mL diethylether. The emuision was cooled with an ice/NaCI bath to -10 °C. A Solution of 1.25 g 3-pyridin-2-yl-propenal in 20 mL diethylether was added dropv;ise. The mixture was stirred ovemight (with »ce bath) and allowed to slowly reach room temperature. 5% aqueous NaHCOs was added and extracted 5 times with EA. The combined organic layers were dried over Na2S04, filtrated and concentrated in vacuo. The residue was catched on an SCX ion exchange column, washed writh MeOH and eluted with 1M NH3 in MeOH to yield 1.28 g of a browm oil containing 90 % of the desired product. This materiai was used in subsequent steps without further purification. ^H NMR (400 MHz, CDCI3) 5 2.84-2.94 (m, 1H), 3.19-3.29 (m, 1H), 4.82-4.90 (m, 1H), 6.83 (br s, 1H), 7.17-7.23 (m, 1H), 7.35-7.40 (m, 1H), 7.69 (dt, J = 7.5, 7.5 and 2 Hz, 1H), 8.53-8.58 (m, 1H). 3- Pyridin-4-yl-propenaI 5.08 g (triphenyiphosphoranylidene)acet3idehyde was suspe-r^ae-c r "iC- ~v DM Added was 1.93 mL (1 equiv.) pyridine^ca.'-t^idehyae s^d ihe .nbct-'e str-ecj ""oorn temperature. The mixture was taken up in EA a.nd vvasnea ^ u—es 5-- 3c_ec_= '••-a—CO; the organic phase was dried over Na2S04, filtrated and concentrated in vacuo. The residue was suspended in PA, filtrated and concentrated in vacuo io yield 1.17 g of a yeiiow oii containing 80 % of the desired product. This material was used in subsequent steps without further purification. 'H NMR (400 MHz, CDCI3) 5 6.85 (dd, J = 8 and 16 Hz, 1H), 7.39-7.47 (m, 3H), 8.70-8.74 (m, 2H), 9.78 {d, J = 8 Hz, 1H). 4- (3,4-Dihydro-2H-pyrazol-3-yl)-pyridine 4.27 ml (10 equiv.) hydrazine hydrate was added to 20 mL diethylether. The emulsion was cooied with an ice/NaCI bath to -10 °C. A Solution of 1.17 g 3-pyrkjin-4-y1-propenal in 20 mL diethylether was added dropwise. The mixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. 5% aqueous NaHCOs was added and extracted 5 times with EA. The combined organic layers were dried over Na2S04, filtrated and concentrated in vacuo. The residue was catched on an SCX ion exchange column, washed with MeOH and eluted with IM NH3 in MeOH to yield 1.23 g of a brown oil containing 90 % of the desired product. This material was used in subsequent steps without further purification. ^H NMR (400 MHz, CDCI3) 5 2.61-2.71 (m, 1H), 3.15-3.25 (m, 1H), 4.68-4.76 (m, 1H), 6.82 (br s, 1H), 7.25-7.30 (m, 2H), 8.55-8.60 (m, 2H). 3-Thiophen-3-yl-propenal 10.0 g (triphenylphosphoranylidene)acetaldehyde was suspended in 10 mL dry DMF. Added was 2.88 mL (1 equiv.) thiophene-3-carbaldehyde and the mixture was stirred overnight at 80 °C. The mixture was taken up in EA and washed 4 times with 5% aqueous NaHCOs, the organic phase was dried over Na2S04, filtrated and concentrated in vacuo. The residue was suspended in PA, filtrated and concentrated in vacuo to yield 4.16 g of an orange oil containing 54 % of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in H NMR (400 MHz, CDCI3): 5 6.54 (dd, J = 8 and 16 Hz, 1H), 9.66 (d, 3 = 8 Hz, 1H). 5-Thiophen-3-yl-4,5-dihydro-1H-pyrazole 14.6 ml (10 equiv.) hydrazine hydrate was added to 50 mL diethylether. The emulsion was cooled with an ice/NaCI bath to -10 °C. A Solution of 4.16 g 3-thiophen-3-yl-propenal in 25 mL diethylether was added dropwise. The mixture was stirred ovemigh: witr i-cs oatr ; anc aiiowed to siowly reach rcx)m temperature. 5% aqueous NaHCO^ was aec anc 5xt3crec 3 ~ with E The combined organic tayers wers dried over Na-SC- nrr=:=c ~ >2CÜO to yieid 4.12 g of an orange oil containing 70 % of the desired procj—.. —=:e~a; _se-Q in subsequent steps without further purification. Characteristic pyrazoline signals IN H NMR (400 MHz, CDCI3): 5 2.78-2.88 (m, 1H), 3.03-3.13 (m. 1H), 4.77-4.86 (m. 1H), 6.86 [m 5. 1H). 3-Thiophen-2-yl-propenai 10.0 g (triphenylphosphoranylidene)acetaldehyde was suspended in 10 mL dry DMF. Added was 3.07 mL (1 equiv.) thiophene-2-carbaldehyde and the mixture was stirred overnight at 80 °C. The mixture was taken up in EA and washed 4 times with 5% aqueous NaHCOs, the organic phase was dried over Na2S04, filtrated and concentrated in vacuo. The residue was suspended in PA, filtrated and concentrated in vacuo to yield 4.27 g of an orange oil containing 50 % of the desired product. This material was used in subsequent steps without further purification. Characteristic signals inH NMR (400 MHz, CDCI3): 5 6.52 (dd, J = 8 and 16 Hz, 1H), 9.63 (d, J = 8 Hz, 1H). 5-Thiophen-2-yl-4,5-dihydro-1H-pyrazoie 15.0 ml (10 equiv.) hydrazine hydrate was added to 50 mL diethylether. The emulsion was cooled with an ice/NaCI bath to -10 °C. A Solution of 4.27 g 3-thiophen-2-yt-propenal in 25 mL diethylether was added dropwise. The rhixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. 5% aqueous NaHCOa was added and extracted 3 times with EA. The combined organic layers were dried over Na2S04, filtrated and concentrated in vacuo to yield 5.58 g of an orange oil containing 70 % of the desired product. This material was used in subsequent steps without further purification. Characteristic pyrazoline signals in ^H NMR (400 MHz, CDCI3): 5 2.77-2.86 (m, 1H), 3.08-3.18 (m, 1H), 4.95-5.03 (m, 1H), 6.88 (br s, 1H). 3-lsopropyl-5-phenyl-4,5-dihydro-1H-pyrazole C.55 mL 3-methyl-2-butanone was dissoived in 10 mL DCM. Aäoec 0 35 ~L n ecL-iv.) bepzaldehyde. foliowed by dropwise addraon of 150 mL ttmc —bcu-e A3S stirred for 1 hour at room temperature. Subsequently'. hydrazine hydrate were added. The mixture was stirred for 30 rr.inüTes s: to— le—r-e-re. and concentrated in vacuo. The residue was taken up in DCM. extracted vvüh 5"': aqueous NaHCOa, and the organic phase was dried over Na2S04, filtrated and concentrated in vacuo to yieid 520 mg of a brown oil containing about 50 % of the desired product, which was used in subsequent steps without further purification. 4-Methyl-5-phenyl-4,5-dihydro-1H-pyrazole 5.22 ml (1 equiv.) hydrazine hydrate was added to 100 mL diethylether. The emulsion was cooled with an ice bath. 15.0 mL 2-Methyl-3-phenyi-propenal was added dropwise, and the mixture was stirred overnight at room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were dried over Na2S04, filtrated and concentrated in vacuo. Vacuum destillation yielded 5.9 g of desired product (mixture of diastereomeric pairs) as a clear fluid (76-82 °C, 0.2-0.3 mbar). ^H NMR (400 MHz, CDCI3) of first diastereomeric pair: 5 0.71 (d, J = 7 Hz), 3H), 3.20-3.31 (m, 1H), 4.77 (d, J = 10 Hz, 1H), 6.73 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 'H NMR (400 MHz, CDCI3) of second diastereomeric pair: 5 1.24 (d, J = 7 Hz), 3H), 2.90-3.11 (m, 1H), 4.22 (d, J = 11 Hz, 1H), 6.71 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 2-Benzylidene-butyraldehyde 30.0 mL Benzaldehyde was dissoived in 150 mL EtOH and cooled v/ith an ice bath. Added was 5.01 mL 45 % KOH (0.2 equiv.), foliowed by dropwise addition of 16.5 mL butyraldehyde. The mixture was stirred for 3 days at room temperature, acidified with IM HCl and extracted with ether. The organic layer was dried over Na2S04, filtrated and concentrated in vacuo. Vacuum destillation yielded 20.4 g of a yellow fluid (78-82 °C, 0.6 mbar) containing 70 % of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in 'H NMR (400 MHz, CDCI3): 8 1.15 (t, J = 7.5 Hz, 3H), 2.57 (q, J = 7.5 Hz, 1H), 7.22 (s, 1H), 9.56 (s, 1H). 4-Ethyl-5-phenyl-4,5-dihydro-1H-pyrazole 62 mi (10 equiv.) hydrazine hydrate was added to 150 nL cooied with an ice/NaCi bath to -10 'C. A soiutior of 20.- c "OC mL ether was added dropwise at -10 'C and siirred ai -IC "'C for 3 -ou-s. --XTU was stirred overnight (with ice bath) and allowed to slowly reach room temperature. H-0 was added, the organic layer was separated and the aqueous layer was extracted 2 times witn diethyiether. The combined organic iayers were dried over Na2S04, filtrated and concentrated in vacuo. Vacuum destillation yielded 6.1 g of a clear fluid (102-106 °C, 0.6 mbar) containing 94 % of the desired product (mixture of diastereomeric pairs). Characteristic signals of the first diastereomeric pair: 'H NMR (400 MHz, CDCb) 6 0.83 (t, J = 6.5 Hz, 3H), 3.03-3.13 (m, 1H), 4.74-4.81 (m, 1H), 6.83 (br s, 1H). Characteristic signals of the second diastereomeric pair: ^H NMR (400 MHz, CDCI3) 5 1.00 (t, J = 7.5 Hz, 3H), 2.84-2.93 (m, 1H), 4.28-4.34 (nn, 1H), 6.76 (br s, 1H), (1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-methanol 15.0 g of 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrobromide was taken up in EA and extracted with 2M NaOH. The organic layer was separated and the aqueous layer again extracted with EA. The combined organic layers were dried over Na2S04, filtrated and concentrated to yield 8.27 g of the free base as a yellow oil (84 %). 6.5 g of LiAIH4 (3.2 equiv.) was suspended in 100 mL dry THF and cooied vh an ice bath. To this was added dropwise a Solution of 8.27 g 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (free base) in 50 mL dry THF. The mixture was stirred for 3 hours at room temperature. The mixture was cooied with an ice bath and 6.5 mL H2O, 13 mL 2 M NaOH and 6.5 mL H2O were added dropwise. The residue was filtered, washed with ether and the filtrate was concentrated in vacuo to yield 6.7 g of a colorless oil. 'H NMR (400 MHz, CDCI3) 5 2.18- 2.26 (m, 2H), 2.36 (s, 3H), 2.49 (t, J = 6 Hz, 2H), 2.92-2.97 (m, 2H), 4.00 (br s, 2H), 5.68 (br s, 1H). 1 -Methy 1-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde 2.88 mL oxalyl Chloride (2.4 equiv.) was dissolved in 20 mL DCM. The mixture was cooied to - 78 "C and a Solution of 3.37 mL DMSO (2.0 equiv.) in 10 mL DCM was added dropwise. The mixture was stirred for 15 minutes at -78 °C. A Solution of 3.0 g (l-Methyi-1,2,5,6-tetrahydro- pyridin-3-yl)-methanol in 10 mL DCM was added dropwise white keeping the temperature below - 65 'C. The mixture was stirred for 15 minutes at -78 'C. 9.81 ml Trsainyvar^ir« .3 0 sqürv. i was added dropwise and subsequentfy the mixture W3S ailowed tc- A3r- tc "oc?- 50 rn^ DCM was added to keep the mixiure stirraDie. "^e mixtu-e w25 s-r-sd " temperature. H2O was added, the organic iayer was separate-- anc —e aga-.extracted with DCM. The combined organic layers were dried over Na-SO^ firtratec and concentrated to yield 3.24 g of an orange oil (85 % pure) which was used withoüt fjrther purification in the subsequent step. 'H NMR (400 MHz, CDCI3) 5 2.43 (s. 3H), 2.48-2.6G (nr;. 4n), 3.11-3.15 (m, 2H), 6.85 (m, 1H), 9.43 (s, 1H). 5-Methyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine 3.2 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde was dissolved in 10 mL n-BuOH. Added were 2 equiv. of hydrazine hydrate, the mixture was refiuxed for 24 hours and subsequently concentrated in vacuo. The residue was tai Benzyl-bis-(2-chloro-ethyl)-amine Bis-(2-chioro-ethyl)-amine hydrochloride was suspended in 150 mL acetonitrile. Added were 34.8 g K2CO3 (3 equiv.) and 10.0 mL benzylbromide (1 equiv.). The mixture was refiuxed overnight. Concentration on silica and purification with flash column chromatography (eiuens PA:ether = 95:5) yielded 4.11 g of a colorless oil. 'H NMR (400 MHz, CDCI3) 6 2.93 (t, J = 7 Hz, 4H), 3.50 (t, J = 7 Hz, 4H), 3.74 (s, 2H), 7.22-7.37 (m, 5H). 1-Benzyl-piperide-4,4-dicarbonitrile 0.57 g Malonitriie was dissolved in 20 mL DMF. Added was 1.31 g K2CO3 (1.1 equiv.) and the mixture was stirred for 2 hours at 65 °C. A Solution of 2.0 g benzyl-bis-(2-chloro-ethyl)-amine (1 equiv.) in 10 mL DMF was added dropwise at 65 °C, and the mixture was stirred for another 3 h. at 65°C. After cooling down, the mixture was diluted with EA and extracted with 5% aqueous NaHCOj. The organic phase was dried over Na;SO-. filtrated and conc^ntrated i- va-ruG to »-veki 2.02 g of an orange oii containing 85% of the antidpated produc: and '5-reihyiramine. This nnaterial was used in the s'Jbse-quent step ^-sro" - \M= (400 MHz, CDCb) 5 2.24 (t, J = 5.5 Hz, 4H). 2.50-2.75 ibr s, 4H), 5.55 2H.. '.ll-'A! -., 5H). C-(4-Aminomethyl-1 -benzyl-piperidin-4-yl)-methylamine 1.50 g of LiAIH4 (3 equiv.) was suspended in 100 mL dry diethylether and cooied with an ice bath. To this was added dropwise a Solution of 2.99 g 1-Benzyl-piperide-4,4-dicarbonitrile in 50 mL dry THF. The mixture was stirred overnight at room temperature. The mixture was cooied with an ice bath and 1.5 mL H2O, 3 mL 2 M NaOH and 1.5 mL H2O were added dropwise. The residue was filtered, washed with THF and the filtrate was concentrated in vacuo to yield 2.63 g of a yellow oil containing about 60 % of the desired product, which was used without further purification in the subsequent step. ^H NMR (400 MHz, CDCI3) 6 1.00-1.60 (br s, 2H), 1.46 (t, J = 5.5 Hz, 4H), 2.40 (t, J = 5.5 Hz, 4H), 2.65 (s, 4H), 3.50 (s, 2H) 7.20-7.36 (m, 5H). 8-Benzyl-2,3,8-triaza-spiro[4.5]dec-2-ene 2.48 g of C-(4-Aminomethyl-1-benzyl-piperidin-4-yl)-methylamine was suspended in 40 mL H2O and 10 mL MeOH and cooied with an ice bath, Simultaniously, 6.7 mL 30 % H2O2 (6 equiv.) and 15.2 mL 10 % NaCIO (2.4 equiv.) were added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was extracted 2 times with DCM, the combined organic layers were dried over Na2S04, filtrated and concentrated to yield 2.20 g of a yellow oil which was used without further purification in the subsequent step. Following route 2, Compound 155 was prepared with this pyrazoline building block. From this, benzyl deprotection (ACE-chioride in 1,2-DCE followed by MeOH) gave Compound 156, which was methylated by reductive alkylation ((CH20)n in the presence of NaBH(0Ac)3 in 1,2-DCE) to gh/e Compound 157. To malonitrile (10.00 g; 151.32 mmol; 2.0 equiv.) was added iodomethane (4.71 ml; 75.66 mmol; 1.0 equiv.) and tetrabutylammonium bromide (0.98 g; 3.03 mmol; 0.04 equiv.). The mixture was stirred at room temperature for 30 minutes. subsequentiy ooc' w)tn an ice Datn. and Doiassium ?e/t-butoxide (8.4S g: 75.66 rr.mol: 1.0 equiv.) ' aodec : 3dcr;it3c- .sca-eo before mixture solidifies). The macture was stirrec for 2 hours added, followed by extraction with DCM twice. Dr/ing over Na^SOi. fifc^rc" 3-r -e-ova r"' —e solvent yielded 10 g of a brown fluid, that was purified by flash-coiumn chromatography wrLh eluens DCM:PA = 1 ;1, 3:1 and DCM to yield 3.25 g of a clear fluid (soiidified upon Standing}. 'H NMR (400 MHz, CDCI3) 5 1.79 (d, J = 7.5 Hz, 3H), 3.79 (q, J = 7.5 Hz, 1H). 2-Benzyloxymethyi-2-methyl-malononitriie ethylmalonitrile (3.22 g; 39.40 mmol; 1.0 equiv.) was dissolved in THF (35 ml). Benzyl chloromethyl ether (7.54 g; 43.35 mmol; 1.1 equiv.) and sodium iodide (0.20 g; 1.33 mmol; 0.03 equiv.) were added. The yellow suspension was cooied with an ice bath and sodium hydride (1.89 g; 47.29 mmol; 1.2 equiv.) was added in small portions. More white precipitate was formed. The mixture was stirred for 30 min at room temperature, diluted with ether, and extracted with 5% aqueous NaHCOs. The organic phase was dried over Na2S04, filtrated and concentrated in vacuo to give 9.6 g of a yellow fluid / oil. Purification by flash column chromatography (eluens EA.PA = 1:4) yielded 6.2 g of a yellow oil. ^H NMR (400 MHz, CDCI3) 0 1.78 (s, 3H), 3.72 (s, 1H), 4.71 (s, 2H), 7.31-7.43 (m, 5H). 2-Benzyloxymethyl-2-methyl-propane-1,3-diamine LiAIH4 (3.22 g; 84.84 mmol; 3.0 equiv.) was suspended in 30 mL dry diethylether and cooied with an ice bath. A Solution of 2-Benzyloxymethyi-2-methyl-malononitrile (5.72 g; 28.28 mmol; 1.0 equiv.) in 20 mL dry diethylether was added dropwise. The suspension was stirred at room temperature for 4 hours, and subsequently cooied with an ice bath. To this was added 3.22 mL H2O, 6.44 mL 2 M NaOH and 3.22 mL H2O. The precipitate was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to yield 5.47 g (84%) of a colorless oil. 'H NMR (400 MHz, CDCI3) 5 0.84 (s, 3H), 2.59-2.69 (m, 4H) 3.29 (s, 2H), 4.49 (s, 2H), 7.24- 7.39 (m, 5H). 4-Benzyloxymethyl-4-methyl-4,5-dihydro-3H-pyrazole .92 g 2-Benzyloxymethyl-2-methyl-propane-1,3-diamine was dissolved in water (40 L) and MeOH (10 mL) and cooied with an ice bath. Simultaneously, 30 % H2O2 (16.1 mL) and 10 % NaCIO (36.5 mL) were added dropwise. The resulting white emulsion was stirred overnight at room temperature. The mixture was extracted with DCM, the organic phase was dried over Na2S04, filtrated and concentrated in vacuo to yield 5.69 g of a pale yellow oil, containing about 70 % of the desired product, which was used without further purification in the subsequent Step. ^H NMR (400 MHz, CDCI3) 5 1.05 (s, 3H), 3.22 (s, 2H), 4.11-4.20 (m, 2H), 4.29-4.38 (m, 2H), 4.48 (s, 2H), 7.24-7.39 (m, 5H). Malononitrile (5.0 g) was dissolved in DMSO (5 mL). Subsequently. bis(2-bromoethyr} einer (9.49 mL) and TBAB (1.22 g) were added, followed by portionwise addition of KOfBu (8.49 g). The mixture was stirred for 4 h. at room temperature, taken up in DCM and extracted 3 times with 5% aqueous NaHCOs. The organic phase was dried over Na2S04 and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting with PA:Et20 65:35 (R; = 0.24, visualized with KMn04) to give 2.49 g (24%) of a solid. 'H NMR (400 iVIHz, CDCb) 5 2.24 (t, 4H), 3.87 (t, 4H). C-(4-Aminomethyl-tetrahydro-pyran-4-yl)-methylamine Tetrahydro-pyran-4,4-dicarbonitrile (1.52 g) was dissolved in dry THF (25 mL) and cooled to - 10°C. To this Solution, BHs-THF (56 mL of an 1M Solution in THF, 5 equiv.) was added dropwise, the mixture was allowed to warm to room temperature, and subsequently stirred at 60°C for 6 h. The mixture was cooled in an ice bath, and HCl (24.2 mL of a 6M aqueous Solution, 13 equiv.) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was neutralized with 2M aqueous NaOH and extracted three times with DCM. The aqueous layer was evaporated do dryness, the residue was stirred with CHCI3, the solids were filtered off and the organic phase was evaporated under reduced pressure to yield 1.0 g (62%) of a yellow oil. H NMR (400 MHz, CDCI3) 5 1.46 (t, 4H), 2.74 (s, 4H). 3.67 (t, 4H). 8-Oxa-2,3-diaza-spiro[4.5]dec-2-ene C-(4-Aminomethyl-tetrahydro-pyran-4-yI)-methy!amine (1.0 g) was taken up in a mixture of H2O (10 mL) and MeOH (2.5 mL), and cooled in an ice bath. Simultaneously, H2O2 (4.8 mL of a 30% Solution, 6 equiv.) and NaCIO (12.4 mL of a 10% Solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred ovemight at room temperature. Extraction with DCM, drying over Na2S04 and evaporation under reduced pressure yielded 380 mg of a clear, light-yellow liquid containing 85% of the anticipated product and 15% of the diamine starting material. This material was used in subsequent steps without further purification. ^H NMR (400 MHz, CDCI3) 6 1.49 (t, 4H), 3.65 (t, 4H), 4.28 (s, 4H). 2,2-B»s-(2,2,2-trifluoro-ethyl)-malononitrile Maiononitril (20.15 mmol) and l-iodo-S.S^S-trrfiuoroproDane !42.55 r were ciss0r»'ac 3-C ml dry THF. and the mixture was cooied with an i.asatt oatr.. :g sa- 3 added portionwise, keeping the temperaiure below 5'C. Tns rea^tio- —xTu-e st:- room temperature for 2 hours and evaporated under reduced pressure. The crude .mar&-i3: was purified by flash chromatography eluting with DCM, yieiding 0.76 grams of an oii. 'H NMR (400 MHz, CDCI3) 5 2.62-2.49 (m, 4H), 2.31-2.24 (m, 4H) 2,2-Bis-(2,2,2-trifluoro-ethyl)-propane-1,3-dianiine 40 mg LiAIH4 (8.95 mmol) was suspended in 15 ml dry Et20 and cooled in an ice bath. A Solution of 760 mg 2,2-Bis-(2,2,2-trifluoro-ethyl)-malononitrile in EtaO was added dropwise at such a rate that the temperature was kept below 20°C. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched byadding H2O (0.35 ml), 2M aqueous NaOH (0.70 ml), and again H2O (0.35 ml). The suspension was fittered, the filtercake was washed with EtjO, and the combined filtrates were evaporated to dryness under reduced pressure to give 0.72 g of an oil. This material was used in the subsequent step without further purification. 4,4-Bis-(2,2,2-trifIuoro-ethyl)-4,5-dihydro-3H-pyrazole ,2-Bis-(2,2,2-trifluoro-ethyl)-propane-1,3-diamine (720 mg) was taken up in a mixture of H2O (3 ml) and MeOH (0.75 ml), and cooled in an ice bath. Simultaneously, H2O2 (1.7 mL of a 30% Solution, 6 equiv.) and NaCIO (3.85 mL of a 10% Solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred overnight at room temperature. The mixture was extracted with DCM, the organic phase was dried over MgSÜA, and evaporation under reduced pressure yielded 0.82 g of an oil containing 50 % of the anticipated product and 50 % of the diamine starting material. This material was used in the subsequent step without further purification. 'H NMR (400 MHz, CDCI3) « 4 25 (s. 2 H). 2.24-1.85 (m, 4 H), 1.85-1.43 (m. 4H). EXAMPLE 4: SYNTHESES OF SPECIFIC COMPOUNDS Route 1 (2-Chloro-benzenesulfonyl)-carbamic acid methyl ester To 25.0 g 2-chloro-benzenesuifonamide was added 75 mL acetonitrile and 45.2 mL (2.5 eq) triethylamine. The mixture was cooled with an ice bath and 15.1 mL methyl chloroformate was lowty added dropwise. The mixture was was stirred ovemight at roa-. lempersturB and concentrated in vacuo. Water was added and de aqueous iayer was A3snec —~ eiher. Acidification of the aqueous layer wüh 2 W HCl ied to fo~=tio" c' = suspension was fiitered, the residue was washed wrth HiO anc anec ir- vacuo x- y-erc IS 1 o r a white solid. 'H NMR (400 MHz, DMSO-ds) 5 3.58 (s. 3H), 7.52-7.61 (m. IHi. 7.52-7.72 2H), 8.10(dd, J = 8 and 1.5 Hz, 1H), 12.42 (br s, 1H). 2-Chloro-N-4-ethyl-4,5-dihydro-pyrazole-1-carbonyl)benzenesulfonamide 8.5 g 4-EthyI-4,5-dihydro-1H-pyrazoie was dissoived in 75 mL toluene. 19.0 g (2-chloro- benzenesulfonyO-carbamic acid methyl ester was added and the mixture was refluxed for 4 hours. After cooling down a precipitate was formed. The suspension was fiitered, the residue was washed with PA and dried in vacuo to yield 20.3 g white crystals. 'H NMR (200 MHz, DMSO-de) S 0.90 (t, J = 7.5 Hz, 3H), 1.30-1.70 (m, 2H), 3.00-3.40 (m, 1H), 3.25 (t, J= 10.5 Hz, 1H), 3.74 (t, J = 10.5 Hz, 1H), 7.08 (s, 1H), 7.40-7.73 (m, 3H), 8.03-8.16 (m, 1H), 10.00 (br s, 1H). 2-Chloro-N-[diethylamino-4-ethyl-4,5-dihydro-pyrazol-1-yl]-methylene]-benzene- sulfonamide (Compound 1) 2.0 g 2-Chloro-N-4-ethyl-4,5-dihydro-pyrazole-1-carbonyl)benzenesulfonamide was dissoived in 10 mL DCE. 1.07 g 2-Chloro-1,3-dimethylimidazolinium Chloride (DMC) and 1.75 mL TEA were added and the mixture was refluxed for 1.5 hours to generate the chloroimine intermediate in situ. Subsequently, 5 mL (excess) diethylamine was added and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and H2O was added. Extraction with DCM (2 times), drying of the combined organic layers over Na2S04, evaporation o dryness and purification with flash chromatography (ettier R-: yeliow oii "H NMR (400 MHz, CDCi.) c 0.95 (t J = 7.5 Hz. 3H.i. «m. 2H;. 3.00-3.10 (m. 1H). 3.48 «q. J = 7 Hz. 4H). 3.7C idd. . = " = Hz. 1H), 5.97 (d. J = 2 Hz, 1H), 7.30-7.41 (m, ZH), 7.45 (dd. . =7.5 7.5 and 2 Hz, 1H). f = 0.35; vtejced 320 ma o a Route 2 N-(Bis-methylsulfanyl-methylene)-2-chloro-benzenesulfonamide To 41.6 g 2-chloro-benzenesulfonamide was added 300 mL DMF and 22 mL carbondisulfide. The mixture was cooled with an ice bath. A Solution of 29 g KOH (15.0 mL) in 100 mL H2O was added dropwise at such a rate that the temperature was kept below 10°C. The mixture was stirred for 30 minutes at 5°C. Subsequently, 32 mL Mel was added dropwise at such a rate that the temperature was kept below 10°C. Then, the mixture was aliowed to warm to room temperature and stirred for another 30 minutes. H2O was added and a precipitate formed. This was filtered off and washed with H2O. The residue was triturated with EtOH, fiitered off and dried in vacuo to yield 42.6 g white crystais. 'H NMR (200 MHz, CDCI3) 6 2.57 (s, 6H), 7.32-7.60 (m, 3H), 8.11-8.27 (br d, J = 7.5 Hz, 1H). 2-Chloro-N-[(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyl-sulfanyl-methylene]benzenesulfon- amide 500 mg 4-Ethyi-4,5-dihydro-1H-pyrazoie was dissolved in 10 mL Pyridine. 1.51 g N-(Bis- methylsuifanyl-methylene)-2-chloro-benzenesulfonamide was added and the mixture was refiuxed overnight. The mixture was concentrated in vacuo and H2O was added, foiiowed by extracion twice with DCM. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The crude product was purified with flash chromatography (gradient DCM:acetone = 100:0 to 95:5) to yield 1.30 g of a yellow oil. ^H NMR (400 MHz, CDCI3) 5 1.02 (t, J = 7.5 Hz, 3H), 1.55-1.77 (m, 2H), 2.28 (s, 3H), 3.27-3.39 (m, 1H), 4.13 (dd, J = 11.5 and 6.5 Hz, 1H), 4.58 (t, J= 11.5 Hz, 1H), 7.16 (d, J = 2 Hz, 1H), 7.39 (dt, J = 7.5 and 2 Hz, 1H), 7.46 (dt, J = 7.5 and 2 Hz, 1H), 7.52 (dd, J = 7.5 and 2 Hz, 1H), 8.17 (dd, J = 7.5 and 2 Hz, 1H). 2-Chloro-N-[ethylamino-(4-ethyl-4,5-dihydro-pyrazoI-1-yl)-methylene]-benzenesulfon- amide (Compound 2) 1.30 g 2-Chloro-N-[{4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyi-sulfanyl-methylene]-benzenesulfon- amide was dissoived in 10 mL MeOH. 5 mL (excess) of a 70 % Solution of ethylamine in H2O was added and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and the crude product was purified by flash chromatography (ether, Rf = 0.33) to yield 1.09 g of a colorless oii. 'H NiVIR (400 MHz, CDCI3) 8 0.95 (t, J = 7.5 Hz, 3H), 1.16 (t, J = 7 Hz, 3H), 1.44-1.69 (m, 2H), 3.03-3.18 (m, 1H), 3.44-3.58 (m, 2H), 3.71 (br dd, J = 11 and 7.5 Hz, 1H), 4.12 (brt, 11 Hz, IH), 6.86 (br s, 1H), 6.94 (d, J = 2 Hz, 1H), 7.35 (dt, J = 7.5 and 2 Hz, IH), 7.40 (dt, J = 7.5 and 2 Hz, 1H), 7.48 (dd, J = 7.5 and 2 Hz, 1H), 8.18 (dd, J = 7.5 and 2 Hz, IH). In an analogous manner, the Compounds in the table below mari Route 3 1 -ethyl-2-m6thyl-isothiourea hydroiodide 20.5 g Ethyl-thiourea was dissoived in 100 mL EtOH. The mixture was cooled with an ice bath and 13.5 mL (1.1 eq) Mel was added dropwise. The mixture was stirred for 1 hour at room temperature and concentrated in vacuo to yield 48.3 g of a light-yeilow oii. 'H NMR (400 MHz, DMSO-de) 5 1.17 (t, J = 7.5 Hz, 3H), 2.61 (s, 3H), 3.34 (q, J= 7.5 Hz, 2H), 9.10 (brs, 2H). 4,N-Diethyi-4,5-dihyclro-pyrazole-1-carboxamidine hydrochioride 19.36 g EthyM.S-dihydrolH-pyrazoie was dissoiVe-d ir, 00 -Erz -I- methyt-isoihiourea hydroiodide and 33.8 mL DiPEA were added and the -ocj-e y,=£ for 48 hours. The mixture was concentrated, 2 M NaOH was added. foilcwed by extraction wlth DCM (three times). The combined organic layers were dried over Na2SGi and the solvent was evaporated in vacuo to yield 32.7 g (99%) of a red oil containing 75% of the desired product according to NMR. The oil was dissolved in EtOH and 194 mL 1 M HCl in EtOH was added dropwise. The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. Crystallization from CHsCNiMTBE = 1:1 gave 11.52 g (29%) of the desired product as a beige solid. 'H NMR (400 MHz, DMSO-ds) 5 0.96 (t, J = 7.5 Hz, 3H), 1.16 (t, J = 7 Hz, 3H), 1.46- 1.72 (m, 2H), 3.32 (q, J = 7 Hz, 2H), 3.35-3.45 (m, 1H), 3.55 (dd, J = 10.5 and 7 Hz, 1H), 3.96 (t, J= 10.5 Hz, 1H), 7,34 (d, J = 2 Hz, 1H), 8.00 (br s, 2H). Benzo[1,2,5] thiadiazole-4-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)- methyleneamide (Compound 78) 300 mg 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 10 mL DCM. 0.53 mL DiPEA and 310 mg benzo[1,2,5]thiadiazole-4-sulfonylchloride were added and the mixture was stirred ovemight at room temperature. The mixture was washed with 5 % NaHCOs and 2 M NaOH, the organic layer dried over Na2S04 and the solvent evaporated in vacuo to yield 410 mg of a red/brown oil. The crude product was purified by fiash chromatography (DCM:aceton = 98:2, Rf = 0.18) to yield 350 mg (65%) of an orange oil. ^H NMR (400 MHz, CDCI3) 5 0.93 (t, J = 7.5 Hz, 3H), 1.16 (brt, J = 7 Hz, 3H). 1.41-1.66 (m, 2H), 3.01-3.16 (m, 1H), 3.39-3.55 (m, 2H), 3.59-3.74 (m, 1H), 3.95-4.15 (m, 1H), 6.94 (brs, 1H), 6.95 (brs, 1H), 7.68 (dd, J = 9 and 7 Hz, 1H), 8.15 (br d, J = 9 Hz, 1H), 8.31 (brd, J = 7Hz, IM). 1 -ethyi-2-methyl-isothiourea hydroiodide 20.0 g Ethyl-thiourea was suspended in 100 mL EtOH, and 30 g (1.1 eq) Mel was added dropwise, during which the mixture became a clear yeilow Solution. Subsequently, the mixture as stirred for 1 hour at room temperature and concentrated in vacuo to yveß ' g of 3 yettow oil. -H NMR (400 MHz. DMSO-ds) ö 1.17 (t. J = 7.5 Hz. 3H ;. 2.61 s. 5- 2- _ = ".5 -x 2H). S.1C .brs. 2H). N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride 12.0 g 4,4-dimethyl-4,5-dihydro-3H-pyrazole was dissolved in 100 mL Pyridine. A Solution of 30.0 g 1-Ethyl-2-methyi-isothiourea hydroiodide in 50 mL Pyridine was added and the mixture was refluxed for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was taken up in DCM (120 mL). The organic phase was extracted with 2N NaOH (2 x 120 mL), washed with water (120 mL), dried over Na2S04 and evaporated under reduced pressure to yield 16,3 g (79%) of an orange oil. The oil (10.0 g) was taken up in EtOAc (50 mL) and heated to 60°C. After removal of the heat source, a 5-6N Solution of HCl in isopropanol (20 mL) was dosed over a period of 4 minutes. After cooling to room temperature, EtOAc (50 mL) was added over a period of 4 minutes, and the mixture was stirred at 20°C for 90 minutes. The formed crystals were colected by filtration and washed with EtOAc (20 mL), followed by drying under reduced pressure at mild heating, to give 6.52 g (54%) of the desired product as a yellow solid. ^H NMR (400 MHz, DMSO-de) 5 1.13 (t, J = 7 Hz, 3H), 1.24 (s, 6H), 3.27-3.34 (m, 2H), 3.64 (s, 2H), 7.26 (s, 1H), 8.03 (brs, 2H), 8.13 (brs, 1H). 3-Chloro-N-[(4,4-dimethyl-4,5-dihydrö-pyrazol-1-yl)-ethylamino-methylene]- benzenesulfonamide (Compound 33) .39 g N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspend- ded in 65 mL DCM. 12.0 mL DiPEA and 3.96 mL 3-chloro-benzenesulfonyl Chloride were added and the suspension was stirred for 20 h. at room temperature, resulting in a dark brown turbid Solution. The mixture was extracted with 2M NaOH (2 x 125 mL) and IM HCl (2 x 125 mL), washed with water (100 mL), and the organic layer was dried over Na2S04 followed by evaporation under reduced presure to yield 7.70 g of a brown oil. The oil (1.0 g) was dissolved n MIBE (3 mL) under refiux. and the Solution was sloqwfy cooied to "Dom temoefaTure- initializing crystailization The suspension was siirred foi" 10 min a: roon- rerro&'sti.rs - S L) was added over a period of 1 minute. Tine resutting suspensio- s::—e-z ZI ~ - room temperature and 50 min. at O'C, and product was coiieaed bv -asr—c hexane (1 mL). Drying under reduced pressure at 40°C yieided 0.85 g of a iignt-brown solid, m.p. 62-67°C. n an analogous manner, the Compounds in the table below marked The Compounds of the invention are new. As indicated in the table above, they have a high affinity (pKj) for S-HTg receptors, and are potent antagonists (pAa). Structuraily the most cioseiy related Compounds disciosed in the literature are some of the sulfonylpyrrolidine derivatives disciosed in WO 02/030881 ; In WO 02/030881, for examples 18 (R = p-CHs), 25 (R = p-CI), 26 (R = H) and 27 (R = 0NO2) no pharmacoiogical data were given, but t^iey are claimed to be modulators of gabapentin binding sites, usefui in the therapy of a number of symptoms and disorders, including pain and migraine. These Compounds are unlikely to have affinity for S-HTe receptors, because during the synthetic explorations around the Compounds of the present invention a series of Compounds was synthesized with ring systems different from the pyrazoline ring (present in ail Compounds of the invention), and all of those were found to be inactive as S-HTg antagonists. The dosest to those disciosed in WO 02/030881 was: This Compound was found to be inactive (pAj ds o* ü-.e invention is crjdal for interaction with 5-HT^ receptors. Tne specific Compounds of which the synthesis is described above sre i-xe~aec iz illustrate the invention in more detail, and therefore are not deemed to restrict the scope of tne invention in any way. Other embodiments of the invention will be apparent to thcse skiiied in tne art from consideration of the specification and practice of the invention disciosed herein, it is thus intended that the specification and exampies be considered as exempiary oniy. EXAMPLE 5: FORMULATIONS USED IN ANIMAL STUDIES For oral (p.o.J administration: to the desired quantity (0.5-5 mg) of the solid Compound of generai formula (1) in a glass tube, some giass beads were added and the solid was miiied by vortexing for 2 minutes. After addition of 1 ml of a Solution of 1% methylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68), the Compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). Remaining particles in the suspension were further suspended by using an ultrasonic bath. For intraperitoneal (i.p.) administration: to the desired quantity (0.5-15 mg) of the solid Compound of generai formula (1) in a giass tube, some glass beads were added and the solid was milied by vortexing for 2 minutes. After addition of 1 ml of a Solution of 1 % methylcellulose and 5% mannitol in water, the Compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7. EXAMPLE 6: PHARMACOLOGICAL METHODS In vitro affinity for human S-HTe receptors Affinity for human S-HTe receptors was measured in a membrane preparation of CHO-celis transfected with human S-HTg receptors by binding studies using [^H]-N-Methyl-Lysergk; seid diethylamide ([^H]-LSD) as ligand. The membrane preparation was prepared from celis supplied by Euroscreen (Brüssels). CHO/Ga16/mtAEQ/h5HT6-A1 cells were grown in T-flasks in CHO- S-SFM II medium (Gibco BRL), supplemented with 1% dialysed FCS, 2 mM L-glutamine, Geneticin 500 ng/ml and Zeocin 200 jig/ml. Cells were harvested using 0.25% Trypsin (1 ml/T175-flask), centrifuged and subsequently suspended in CHO-S-SFM II medium and frozen at -80°C. After thawing cells were centrifuged during 3 minutes at 1500g at 4°C. From the pellet, cell membranes were prepared by two cycles of homogenization (Potter-Elvehjem 10 strokes, 600 rpm) and centrifugation (40,000g for 15 min, 4°C). The assay was established so as to achieve steady State conditions and to optimize specific binding. For the S-HTs receptor. membranes from 5.10" ceiis were incubated with 5.0 nM ["'Hj-LSD at • Nonspecific bincing was determined using 10 ' W Serotonin .Assays were termin= fiftration througn glass fibre filters iGF/3) which hac beer or—psaze-z "T Z 5-- polyethyleneimine. Total and bound radioactivity was determined by iiquic sciirniisro-. w-rir-g. Greater than 80% specific binding was achieved in each of these assays. Compounds were tested at a 4 log concentration ränge; all determinations were performed as triplicates. iCjo values were determined by non-iinear regression analysis using Hill equation curve fitting. The inhibition constants (Kj -values) were caiculated from the Cheng-Preushoff equation; Ki= iCso: (1+L/Kd) wherein L represents the concentration radioligand ([^H]-LSD) in the assay, and Kd the affinrty of the radioligand for the receptor. Results are expressed as pKj-values, means ± SD of at least three separate experiments. In vitro functional activity ((ant)agoni,sm) on human S-HTs receptors The CHO-human-SHTg-Aeqorin assay was bought from Euroscreen, Brüssels (Euroscreen, Technical dossier, Human recombinant Serotonin S-HTg-M receptor, DNA clone and CHO AequoScreen™ recombinant cell line, catalog n°: ES-316-A, February 2003). Human-S-HTg- Aequorin cells express mitochondrial targeted apo-Aequorin. Cells have to be loaded with coelanterazine, in order to reconstitute active Aequorin. After binding of agonists to the human 5- HTg receptor the intracellular calcium concentration increases and binding of calcium to the apo- Aequorin/coelenterazine complex leads to an oxidation reaction of coelenterazine, which results in the production of apo-Aequorin, coelenteramide, CO2 and iight (X^ax 469nm). This iuminescent response is dependent on the agonist concentration. Luminescence is measured using the MicroBeta Jet (Perkin Elmer). Agonistic effects of Compounds are expressed as pECso. Antagonistic effects of Compounds were determined as inhibition of 10"® M a-methylserotonin induced luminescence and the pAz was caiculated according to Cheng-Preushoff equation. Compounds were tested at a 5 log concentration ränge, and 3 independent experiments were performed in duplicate. EXAMPLE 7: PHARMACEUTICAL PREPARATIONS For clnicai use. :x)mpounds of formula (1 - are formülated inic a pharmaceutica' coDosiüQis that are imporTant and novel embodimefits of tne inve-nrlor: because r-reCompounds, more particularly specific Compounds disclosed herein. Types of pharmaceutical compositions that may be used include, but are not limited io, tablets, chewanie tabieis. capsuies (including microcapsuies), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or apparent to a person skilIed in the art from the specification and general Knowledge in the art. The active ingredeient for instance, may also be in the form of an' inclusion complex in cyclodextrins, their ethers or their esters. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer. The pharmaceutical formulation contains at least one Compound of formula (1) in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredients suitably is in the ränge of from about 0.1% (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1% to 25% (w/w). The Compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxillary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxillary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, geiatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, Polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stear/i fumarate and Polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets. A tablet is prepared using the ingredients below: Inqredient Quantitv (mq/tablet) COMPOUND No. 20 10 Cellulose, microcrystalline 200 Silicon dioxide, fumed 10 Stearic acid 10 Total 230 The components are blended and compressed to form tablets each weighing 230 mg. The active ingredients may be separately premixed with the other TOn-acrrve i-g-ecierts. before being mixed to form a foimulation. "Hne active ingredtems -ay aiso be escr other. before betng mixed with the non-actrve ingredients ic fonri a forrr!Uiat>Dr.. Soft gelatin capsules may be prepared with capsuies containing a mixture of ine acuve ingredients of the invention. vegetable eil, fat, or other suitable vehicie for soft geiatin capsules Hard geiatin capsuies may contain granules of the active ingredients. Hard geiatin capsuies may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitoi, potato starch, com starch, amylopectin, celiulose derivatives or geiatin. Hard geiatin capsuies can be prepared using the foiiowing ingredients: Ingredient Quantity (mq/capsuie) COMPOUND No. 20 10 Starch, dried 95 Magnesium stearate 14 Total 120 The above ingredients are mixed and filied into hard geiatin capsuies in 120 mg quantities. Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a geiatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicie for geiatin rectal capsuies; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration. Suppositories, each containing 1 mg of active ingredient, may be made as follows: Ingredient Quantity (mq/suppository) COMPOUND No. 20 20 Saturated fattv acid qlvcerides 2,000 Total 2,020 The active ingredient is passed through a appropriately sized mesh sieve and suspended in the saturated fatty acid glycehdes previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool. Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and Polyethylene glycol. An intravenous formulation may be prepared as follows: Bentley. J. C. et ai. (1999 Br J Pharmacol. Suppl. 126. P66 Bentley. J. C., et ai. /1999=). Br J Pharmaco! 126(7): 1537-42 Berge, S.M.: 'Pna.aceuticai salts", J. Pharmaceuricai Science. 66. 1-15 i157.. Bickel. M.H., : "The pharmacology and Biochemistry of N-oxides", PharmacologicalReviews 21(4), 325 - 355, 1969. ' Bundgaard, H. (editor), "Design ofProdrugs", Elsevier, 1985. Byrn et ai., Pharmaceutical Research, 12(7), 945-954, 1995. Dwyer & Meilor,; "Chelating agents and Metel Chelates", Academic Press, chapter 7, 1964. Ettmayer, P. et al., "Lessons learned from marketed and investigational prodnjgs'. J.Med.Chem., 47, 2393-2404, 2004. Järvinen, T. et al., "Design and Pharmaceutical applications of prodrugs", pages 733-796 in: S.C. Gad (editor): "Drug Discovery Handbool^', John Wiley & Sons Inc., New Jersey, U.S.A.. 2005. King, F.D., (editor), page 215 in: "Medicinal Chemistry: Principles and Practice", 1994, ISBN 0- 85186-494-5. Kohen, R., et al. (1996). J Neurochem 66(1): 47-56 Martin, E.W. (Editor), "Remington: The Science and Practice of Pharmacy", Mack Publishing Company, 19"^ Edition, Easton, Pa, Voi 2., Chapter 83, 1447-1462, 1995. Rogers, D. C., et al. (1999). Br J Phararncol 127(suppl.). 22P Roth, B. L., et al. (1994). J Pharmacol Exp Ther 268(3): 1403-10 Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun. 193: 268-276 Sebben, M. et al. (1994) NeuroReport 5: 2553-2557 Sibley, D.R. et al., Mol. Pharmacol., 1993, 43, 320-327 SIeight, A.J., etal., Neurotransmission, 1995, 11,1-5 SIeight, A.J., et al., Serotonin ID Research Alert, 1997, 2(3), 115-8). SIeight, A. J., et al. (1998). Br J Pharmacol 124(3): 556-62 Stella,J., "Prodmgs as therapeutics", Exoert Qpin. Ther. Patents. 14(3), 277-280, 2004. Wooliey M. L. et al. (2001) Neuropharmacology 41: 210-219 WO 01/070700 and WO 02/030881 COMPOUND No. 20 1 g Arlatone G™ ^00 rr\- EtOH m! Water. sterile 800 ml The Compound is dissolved in the Arlatone G™, EtOH and water, and then the Solution is slowiy diluted with further water. If desired, such liquid preparations may contain coloring agents, flavoring agents, preser\'atives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a Solution of a formulation of the invention in a pharmaceuticaily acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use. Also provided according to the present invention are formulations and 'kits of parts' comprising one or more Containers filied with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for use in treating a condition in which antagonism of S-HTs receptors is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one Compound of formuia (1) to a patient suffering from, or susceptible to, a condition in which antagonism of S-HTe receptors ts required or desired. By way of example and not of limitation, several pharmaceutical compositions are given, comprising preferred active Compounds for systemic use or topical application. Other Compounds of the invention or combinations thereof, may be used in place of (or in addition to) Said Compounds. The concentration of the active ingredient may be varied over a wide ränge as discussed herein. The amounts and types of ingredients that may be included are well known in the art. BIBLIOGRAPHY Bentley, J. C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255 We Claim: 1. A Compound cf fomul (1) or a tautomer, stereoisomer, N-oxide, isotopicaiiy-labeiled anaiogue, or a pharmacologicaiiy acceptable salt, hydrate or solvate of any of tiie foregoing, wiierein: Ri represents hydrogen, an unsubstituted alkyl(Ci.4) group, an alkyi(Ci.4) group substituted with one or more lialogen atoms, R2 and R3 independently represent hydrogen, an unsubstituted alkyl(C14) group, an alkyl- (C1.4) group substituted with one or more haiogen atoms, an phenyl-alkoxy(Ci^)-alkyl{Ci.4) group, optionally substituted witti one or more haiogen atoms, or, Ri and R2, together with the carbon atoms marked 'a' and 'b' form a Cs-cycloaikyl ring, or, R2 and R3, together with the carbon atom marked 'b' form a Cj-cycloalkyl ring, or R2 and R3, together with the carbon atom marked 'b' form an Cj-s-heterocycloalkyl ring, unsubstituted or substituted with one or more substituents Y, chosen from (Ci-3)alkyl, tri- fiuoromethyl, fiuoro, chioro, bromo, hydroxyl, (Ci.3)a!kyloxy, trifluoromethoxy, and amino. or R4 and Rs independently represent hydrogen, an unsubstituted alkyi(Ci^) group, an alkyt- group substituted with one or more haiogen atoms, a monocyclic or a fused-bicycftc aromatic or hetero-aromatic group, which groups are unsubstituted or substituted with one or more substituents Y, as defined above or, R3 and R4. together with the carbon atoms marked 'b' and 'c' form a Cs-cycloalkyl ring, or R3 and R4, together with the carbon atoms marked 'b' and 'c' form an Cs-s-heterocycloalky! ring, which groups are unsubstituted or substituted with one or more substituents Y, as defined above or Rs and R7 independently represent a hydrogen atom, or an alkyl(Ci.4) group, or an alkyl(Ci_4) group substituted with one or more haiogen atoms; or a (Ci.3)alkoxy group, or a dialkyl(Ci.3)- amino-alkyl{C-.3 ' group, or a monocydic or fused bicyclic aromatic or hetero-ararr=t>c or a Cs-s-cycioaikyi or a Cs-s-heterocycloallcyi group, '»vnicr, cydc gnyjps are jns-_b5rt_t5c substituted witn one or more substituents Y. as defined aoove. or a benrproviso that N^43-dimethyl-2-pyriniidinyl)-4,5-dihydro-N-i(4-methytpheny;' phenyl-1H-pyrazoie-1-carboximidamide is exciuded, or Re and R7, together with the nitrogen atom to which they are attached, form an Cs-hetero- cycloalkyl group, unsubstituted or substituted with one or more substituents Y, as defined above, Re represents a monocydic or a fused-bicyciic aromatic or hetero-aromatic group, which groups are unsubstituted or substituted with one or more substituents Y, as defined above or Rs represents an -CR9=CRio-aryl group wherein Rg and R10 independently represent hydrogen or an alkyl-(Ci.3) group, and wherein 'aryl' comprises monocydic or fused bicyclic aromatic or hetero-aromatic groups, or Rg represents an -C=C-aryi group, wherein aryl' has the abovementioned meaning, a piperidinyi group unsubstituted or substituted with one or more substituents Y, as defined above, or a group -NR11R12, wherein R,, and R12 independently represent hydrogen, an unsubstituted alkyl-(Ci_3) group or a phenyl or benzyl group, which phenyl or benzyl groups are unsubstituted or substituted with one or more substituents Y, as defined above. 2. A Compound as claimed in claim 1 of formula (1), or a tautomer, stereoisomer, N-oxide, isotopically-labelied analogue, or a pharmacoiogicaliy acceptable salt, hydrate or solvate of any of the foregoing, wherein: - Ri represents hydrogen or Ri and R2, together with the carbon atoms marked 'a' and u' form a cyclohexyi ring, - R2 and R3 independently represent hydrogen or an alkyKCi.a) group, or R2 and R3, together with the carbon atom marked 'b' form a cyciopentyi or cyclohexyi ring, - R4 and Rs independently represent hydrogen, an alkyl(Ci.3) group, or R3 and R4, together with the carbon atoms marked 'b' and 'c' form a C3_8-cydoalkyl ring, - Rs and R7 independently represent a hydrogen atom, or an alkyl(Ci.3) group, or an alkyl(Ci) group substituted with one or more halogen atoms, or a methoxy group, or a cydohexyl group, or a benzyl group or a 4-piperidinyl group, s has the meanings as given in Claim 1. 3. A comDOund as cuaimed in ciaim 1 of formuia (1 ): R- and R2. toget-er with the carbon atoms marxed a and b forn:- a Cs-yaoa:,- — r- R2 and R3, together with the carbon atom marked b' form a C3_8-cycioali R3 and R4, together with the carbon atoms marked 'b' and 'c' form a Cs-s-cycloalkyl or Cs-heterocycioalkyi ring, unsubstituted or substituted with one or more substituents Y, as defined above, Rs and R7independently represent a hydrogen atom, or an aikyl(Ci-4) group, or an aikyi(Ci) group substituted with one or more haiogen atoms; or a (Ci.3)aikoxy group, or a diaikyi{Ci.3)- amino-alkyl(Ci.3) group, or a monocyclic or fused bicyclic aromatic or hetero-aromatic group, or a Cs-B-cycloalkyl or a Cs-s-heterocycloalkyl group, which cyclic groups are unsubstituted or substituted with one or more substituents Y, as defined above, or a benzyi group, with the proviso that Rs and Ry can not represent Re and R? can not represent N-(4,6-dimethyi-2- pyrimidinyi)-4,5-dihydro-N'-[(4-methyiphenyl)sulfonyi]-5-phenyl-1H-pyrazole-1-carboximid- amide , or e and Rj, together with the nitrogen atom to which they are attached, form a Css-hetero cycloalkyl group unsubstituted or substituted with one or more substituents Y, as defined above, Rg represents a monocyclic or a fused-bicyclic aromatic or hetero-aromatic group, which groups are unsubstituted or substituted with one or more substituents Y, as defined above or an -CR9=CRio-aryi group wherein Rg and R10 independentiy represent hydrogen or an aikyl-{Ci-3) group, and wherein 'aryl' comprises monocyclic or fused bicyclic aromatic or hetero-aromatic groupsor Rs represents an -C=C-aryl group, wherein 'aryl' has the abovementioned meaning, a piperidinyl group unsubstituted or substituted with one or more substituents Y, as defined above, or a group -NR11R12, wherein RH and R12 independentiy represent hydrogen, an alkyl-(Ci.3) group or a phenyl or benzyi group, which phenyi or benzyi groups are unsubstituted or substituted with one or more substituents Y, as defined above. 4. A Compound as claimed in claim I^Vr alsier. stereoisomer. N-oxide. isctcc- labell anaiogue, or a pharmacoiogf^lly ajiRIE saft. hydraie or soK-aie OT' foregoing. whereji the moiety: is closen T'rom: and wherein Rs, Rrand Rshave the meanings as given in claim 1. 5. A Compound as claimed in claim 1 of formula (1), or a tautomer, stereoisomer, N-oxide, isotopically-labelied analogue, or a pharmacologicaily acceptabie salt, hydrate or solvate of any of the foregoing, wherein: Ri, R4, R5 and Re represents hydrogen, R2 and R3 independently represent an alkyl(Ci.3) group, or R2 and R3, together with the carbon atom marked 'b' form a cyclopentyi, or cyclohexyl ring, Ry represents an alkyl(Ci_3) group and Rs has the meanings as given in claim 1. 6. A Compound as claimed in claim 1 of formula (1), selected from those of the formulae: 7. A Compound as claimed in any one of the Claims 1-6, or a tautomer, stereoisomer, N-oxide, isotopically-labelied analogue, or a pharmacologicaily acceptabie salt, hydrate or solvate of any of the foregoing, said Compound being an optically active enantiomer. 8. A medicamnt, comprising a Compound according tc any one of the ciatn-is a pharmacoiogically acceptable sali, hydrate or solvate rhereof. 9. The medicament of daim 8, to treat Parkinson's disease. Huntington's Chorea, schizc- phrenia, anxiety, depression, manic depression, psychoses, epiiepsy, obsessive compuisive disorders, mood disorders, migraine, Aizheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder. Irritable Bowel Syndrome, obesity and type-2 diabetes. 10. The medicament of Claim 8, further comprising: at least one additional therapeutic agent. 11. Combination preparation comprising (i) a Compound as daimed in daim 1 of formula (1), or pharmacologically acceptable salts or hydrates thereof, and (ii) an other medicament, for simultaneous, separate or sequential use in therapy of Parkinson's disease, Huntington's Chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epiiepsy, obsessive compuisive disorders, mood disorders, migraine, Aizheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes. 12. Compounds of the general formula (l'): wherein X represents either halogen or S-alkyifC-.i and the other symbois r-.e tr~ meanings as grver, in Claim 1 and tautomers. stereoisomers and N-oxides merac-" s as pharmacologically acceptable satts, hydrates and sorvates of saiü compDu.^cs (1") and its tautomers. stereo-isomers and N-oxides, such Compounds oeing usefj^ m -e synthesis of Compounds of the general formula (1). 13. Compounds of the general formula (1^): wherein the symbols have the meanings as given in claim 1, and tautomers, stereoisomers and N-oxides thereof, such Compounds being usefui in the synthesis of Compounds of the general formula (1), with the proviso that when Ri, R2, R3, Rsand Re are hydrogen, and R is phenyl, R7 can not be hydrogen or 4,6-dimethylpyrimidin-2-yi; and with the proviso that when R2, R3, Rs, Re and R7 are hydrogen, and Ri is methyl, R4 can not be phenyl, 2- hydroxyphenyl or 4-methylphenyi. 14. Process to prepare Compounds as claimed in Claim 1 of formula (1) wherein R^ is hydrogen, thus having formula (1'), wherein all symbols have the meaning as given in claim 1, comprising the steps of; (i) reacting a Compound of formula (X), obtainable by reacting a Compound of formula (IX) with an alkyl halide, for instance methyliodide, with a pyrazoline in the presence of a base, to yield a Compound of formula (1^), (ii) reacting a Compound of formula (1) with a sulfonyl halide of formula Rs-SOz-X, wherein X is Br, Cl or F, in an aprotic solvent such as dichloromethane, in the presence of a base such as diisopropylethyl-amine. 15. Use of a Compound as claimed in any of the Claims 1-7 for the preparation of a pharmaceutica! composition for the treatment er prophyiaxis of Parkinson's disease, Huntington's ciiorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Aizheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention defrcit hyperactivity disorder, attention deficit disorder, withdrawai from abuse of cocaine, ethanoi, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes. |
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| Patent Number | 278872 | |||||||||||||||||||||
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| Indian Patent Application Number | 2185/CHENP/2009 | |||||||||||||||||||||
| PG Journal Number | 01/2017 | |||||||||||||||||||||
| Publication Date | 06-Jan-2017 | |||||||||||||||||||||
| Grant Date | 02-Jan-2017 | |||||||||||||||||||||
| Date of Filing | 20-Apr-2009 | |||||||||||||||||||||
| Name of Patentee | AbbVie Bahamas Ltd., | |||||||||||||||||||||
| Applicant Address | Sasson House, Shirley Street & Victoria Avenue, New Providence, Nassau, Bahamas; | |||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 231/06 | |||||||||||||||||||||
| PCT International Application Number | PCT/EP2007/59944 | |||||||||||||||||||||
| PCT International Filing date | 2007-09-20 | |||||||||||||||||||||
PCT Conventions:
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