TW200540142A - New β-ketoamide compounds with MCH receptor antagonistic activity and medicaments comprising them - Google Patents

Abstract

The invention relates to β -ketoamide compounds of general formula (I) wherein the groups and radicals A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b have the designations cited in patent claim 1. The invention also relates to medicaments containing at least one inventive amide. As a result of the MCH receptor antagonistic activity, the inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, especially adipositas, bulimia, anorexia, hyperphagia and diabetes.

Description

200540142 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel β-ketoamine compound, a physiologically acceptable salt thereof, and its use as an MCH antagonist, and its preparation is suitable for prevention and / or Use in a medicinal preparation for the treatment of symptoms and / or diseases caused by MCH or in some other way causally associated with 1 ^ 1 (: 11. The invention further relates to compounds according to the invention for use in influencing mammalian dietary behavior And use for weight loss and / or prevention of weight gain. The present invention also relates to compositions and medicaments containing the compounds according to the present invention and methods of making them. An additional object of the present invention relates to methods for the preparation of compounds according to the present invention. [Previous technology] For all living organisms, food intake and its transformation in the body are an essential part of life. Therefore, deviations in food intake and transformation generally cause problems and diseases. In recent decades, people ( (In industrialized countries in particular) lifestyle and nutritional changes have promoted pathological overweight (also known as obesity or obesity). In the diseased population, obesity directly leads to restricted mobility and reduced quality of life. The additional factor is that obesity often causes other diseases such as diabetes, dyslipidemia, high blood pressure, arteriosclerosis and coronary heart disease. In addition, only high weight will also Applying increased pressure to support and mobile devices can cause chronic pain and disease such as arthritis or osteoarthritis. As a result, obesity is a serious health problem in society. The term obesity means an excess of fatty tissue in the body. In this connection, obesity can basically be regarded as an increased degree of obesity leading to health risks. There is no significant difference between normal individuals and obese patients, but it is inferred that the health associated with obesity is 99336.doc 200540142 The risk continues to increase with the increase in obesity . For the sake of brevity, in the present invention, the body mass index (BMI) (which is defined by dividing the measured weight in kilograms by the square of height (in meters)) is higher than a value of 2 5 and More specifically individuals above 30 are considered obese. Except for changes in physical activity and nutrition, there is currently no convincing effective weight loss Treatment options. However, because obesity is a major risk factor in the progression of serious and even life-threatening diseases, the use of pharmaceutically active substances for the prevention and / or treatment of obesity is even more important. A recently proposed approach For therapeutic use of MCH antagonists (see especially WO01 / 21577, WO 01/82925). Melanin-concentrating hormone (MCH) is a cyclic neuropeptide composed of 19 amino acids. It is mainly under mammals Synthesized in the optic mound and traveled from the hypothalamus to other parts of the brain by projection from the hypothalamus neurons. In humans via two different G_protein_coupling receptors from the rhodopsin-related GPCR family (GPCR) (that is, MCH receptors 1 and 2 (MCH-1R, MCH-2R) regulate its biological activity. Φ Investigation of the function of MCH in animal models has provided good evidence for the role of peptides in regulating energy balance (ie, changes in metabolic activity and food intake [12]). For example, when MCH is administered to rats intraventricularly, the food intake of the rats in this group is increased compared to the animals in the control group. In addition, transgenic rats produced more MCH than control animals when given a high-fat diet in response to a significant increase in body weight compared to animals without experimentally altered MCH content. A positive correlation was also found between the increased anxiety phase and the amount of MCH mRNA in the inferior colliculus of rats. However, experiments with MCH knockout mice are particularly important in 99336.doc 200540142 showing MCH function. Lean animals with loss of neuropeptide leading to reduced fat mass consumed significantly less food than control animals. It is inferred that the anorexia effect of MCH in rodents is regulated by Gas-coupled MCH-1R [3-6], which is different from primates, ferrets, and dogs. So far, no second MCH receptor subtype has been found in rodents. type. Loss of MCH-1R in knockout mice resulted in lower fat mass, increased energy conversion, and did not increase weight when fed a high-fat diet compared to control animals. Another indication of the importance of the MCH system in regulating energy balance is derived from experiments with receptor antagonists (SNAP-7941) [3]. In long-term experiments, antagonist-treated animals lose significant weight. In addition to its anorexia effect, the MCH-1R antagonist SNAP-7941 also achieved additional anxiolytic and anti-suppressive effects in rat behavior experiments [3]. So there are clear signs that the MCH-MCH-1R system involves not only regulating energy balance, but also emotions. References: 1 · Qu, D. Shanren's A role for melanin-concent rating hormone in the central regulation of feeding behaviour. Nature, 1996. 3 (M77) · · pp. 243_7. 2. Shimada, M, Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998 · 396 (6712): 670-4. 3 · Borowsky ^ B · Isobaric Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist · Nat Med, 2002. 8 (8) · · 825-30. 99336.doc 200540142 4 · C / ie ", Γ · et al. Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity · 2002 · 143 (7): 2469_77. 5 Marsh, DJ-specific Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci US Af 2002. 99 (5): 3240-5.

6. Takekawa, S. T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. 2002. 438 (3) · pp. 129-35. Some amine compounds are suggested in the patent literature. As an MCH antagonist. Thus, WO 01/21577 (Takeda) describes compounds of the following formula which are particularly useful as MCH antagonists for the treatment of obesity

Ri

Ar1—X-Ar-YN ^, R2 ® where Ar1 represents a cyclic group, X represents a spacer, Y represents a bond or a spacer, Ar represents an aromatic ring that can be fused with a non-aromatic ring, and R1 and R2 each independently represent Η or Hydrocarbyl, while R1 and R2 together with adjacent N atoms can form N-containing heterocyclic rings and R2 and Ar can also form spiro rings, R together with adjacent N atoms and fluorene can form N-containing heterocyclic rings. In addition, WO 01/82925 (Takeda) also describes compounds of the following formula as MCH antagonists for the treatment of obesity

Ri

Ar1—X-Ar-YN [R2 99336.doc 200540142 where Ar1 represents a cyclic group, X and Y represent spacers, ^ represents a fused polycyclic aromatic ring optionally substituted, R1 and R2 each independently represent a fluorene or a hydrocarbon group, At the same time, R1 and R2 together with adjacent N atoms can form N-containing heterocyclic rings and R2 together with adjacent ν atoms and Υ can form N-containing heterocyclic rings. SUMMARY OF THE INVENTION The object of the present invention is to provide a new ketamine compound, especially a new β-ketamine compound effective as an MCH antagonist. The present invention also sets out to provide new β-ketamine compounds that can be used to influence the dietary habits of mammals and achieve weight loss (especially mammals) and / or prevent weight gain. The present invention further proceeds to provide new pharmaceutical compositions suitable for preventing and / or treating symptoms and / or diseases caused by or associated with MCH. In particular, an object of the present invention is to provide a pharmaceutical composition for treating metabolic disorders such as obesity and / or diabetes and diseases and / or disorders related to obesity and diabetes. Other objects of the present invention relate to demonstrating the advantageous use of the compounds according to the invention. The present invention also sets out to provide a method for preparing the amidine compound according to the present invention. For those skilled in the art, other objects of the present invention will become apparent from the foregoing and subsequent comments. Subject matter of the present invention The present invention relates first to ketoxamine compounds, their tautomers, diastereomers, enantiomers, mixtures and their salts. 99336.doc _ 10- 200540142

Among them, R1 and R2 each independently represent Η, optionally, Ci_8_alkyl or C substituted by radical R11; 3.3.7-cycloalkyl, and the position of 5-, 6-, or 7-membered cycloalkyl The -CH2 · group on 3 or 4 may be substituted with _0-, -S- or -NR1, or phenyl or pyrimidinyl may be mono- or poly-substituted with the group R 2G and / or mono-substituted with nitro , Or R1 and R2 form a C2-8-alkylene bridge, where

-One or two -CH2- groups may be independently replaced by each other or -CH = CH- and / or one or two -ch2_ groups may be independently performed by _〇-, -S ...- s〇 ..._ ( S〇2) _, -C (= CH2)-or -NRn_ are replaced by heteroatoms that are not directly bonded to each other and the group -CO- is not directly bonded to the group ... at the same time as above One or more H atoms in the alkylene bridge as defined may be substituted, and the alkylene bridge as defined above may be substituted with—or two identical or different carbocyclic or heterocyclic groups— such that The bond system between the base bridge and the group Cy is formed in the following manner:-via a single bond or a double bond, _ via a common C atom forming a spiral ring system, a common adjacent C and a common double ring system that opens a singular ring system, and / Or N atom. Two or more C and / or N atoms that form a bridged ring system 99336.doc 200540142 R3 represents H, alkyl, c3-7-cycloalkyl, C3_7-cycloalkyl-Cy-alkyl Or the radical -Ci.3 · alkyl, X represents a C! · 8 · alkylene bridge, in which -CH2-group which is not directly bonded to the group R1r2N- can be replaced by -CH = CH_ or , And / or-is not directly bonded to one or two non-adjacent _CH2- groups on the group rir2N- Each can be independently passed through _0-, -3-,-(80) _,-(8〇2)-,-(: 〇- or 七 114-, in each case two 〇, S or N atoms or 0 and S atoms are not directly replaced by bonding together. At the same time, bridge X can be connected to R1, including bonding to N atoms on R1 and X to form a heterocyclic group. At the same time, bridge X can be additionally connected to R2, including connection. To the N atom on R2 and X to form a heterocyclic group, and at the same time, the two C atoms or C and N atoms of the alkylene bridge can be joined together with an additional ci-4_alkylene bridge, and not directly connected The C atom to the heteroatom may be substituted by rig and / or in each case, or two C atoms may be substituted by one or two of the same or different selected from CN6-alkyl, c2.6-alkenyl, c2 alkynyl Group, c3-7_cycloalkyl, C3 7-cycloalkyl-Cw alkyl, Cy cycloalkenyl and (34 7 · cycloalkenylalkyl substituents, and two alkyl and / or alkenyl groups The substituents can be joined together to form a carbocyclic ring system, and Z represents a single bond or _CR7aR7b-CR7eR7d_, Y has one of the meanings assigned to Cy, and R1 can be connected to Y, including the group X and to Rl & x N atoms on it to form a fused with Y Heterocyclyl, and / or 99336.doc • 12- 200540142 x can be attached to γ to form a cyclocyclyl or heterocyclyl fused with ¥, and A has one of the meanings assigned to Cy, and B has the One of the meanings, b has a value of 0 or 1,

Cy represents a carbocyclic or heterocyclic group selected from one of the following meanings:-saturated 3- to 7-membered carbocyclyl,-unsaturated 4- to 7-membered carbocyclyl,-phenyl,-having as hetero A saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group of N, 0 or s atom,-having two or more ^^ atoms or one or two N as heteroatoms Atoms and-0 or 8 atoms of saturated or unsaturated% to 7-membered heterocyclic groups,-aromatic heterocyclic rings having one or more heteroatoms selected from N, 0 and / or 8 which are the same or different -Or 6-membered group, and the 6- or 7-membered group may be fused with a benzene ring or a tonidine ring through two common adjacent c atoms, and the 5- '6- or 7-membered group described above One or two non-adjacent _CH2 groups in each may be independently replaced by -co ... c (= CH2) _, (s〇) ·, or-(s〇2) _ group, and the above-mentioned saturated 6- or 7- Member groups can also serve as bridge rings with imine, N- (Ci4-alkyl) imine, methylene, alkynyl-methylene, or bis- (Cm-alkyl) -fluorenyl bridges The system exists, and the above-mentioned coating group can be mono- or poly-substituted by R20 on one or more c atoms. Substitution, and / or one or more NH groups may be substituted by R21, 99336.doc -13- 200540142 R4 has one of the meanings given to R17 or represents C3_6-alkenyl or C3-6-alkynyl, R and R each Independently represent H, Cn, xenyl, C3-7-cycloalkyl, C3.7 ·% alkyl, < 111-3-alkyl, € 3,? Or (31, at the same time, 5 and 烧 515 can be bonded together to form a C3-7-cycloalkyl group with the c atom bonded to R5a and R5b, and R7a and R7e each independently represent Η, F, ci, Ci-4-alkyl, or CF3, and R and R each independently represent H, F, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-CN3-alkyl, or cf3 , • At the same time, R7a and R7b, which represent an alkyl group, can be joined together to form a C3-7-cycloalkyl group with the C atom bonded to R7a and R * 7b, and / or R7, which represents an alkyl group, and R7d can be joined. Together, it forms a C3-7-cycloalkyl group with the C atoms bonded to R7e and R7d, or R7b and R7d, which represent an alkyl group, can be joined together to form together with the two C atoms bonded to R7b &C3-7-cycloalkyl; R1G represents hydroxy, hydroxy-Cw alkyl, Ci-4-alkoxy, (Ck alkoxy) -Ci-3-alkyl, carboxy, Ci-4-alkoxycarbonyl, Amine group, Cl_4_alkyl group, # group, di- (Cl · 4 · alkyl) · amino group, cyclic-C3-6-alkyleneimine group, amine-Cw alkyl group, Cw alkyl-amine -Cy alkyl, di- (c1-4 · alkyl) -amino-Cw alkyl, cyclo-C3 · 6-alkyleneimino, amino-Ci- 3-alkoxy, C! · 4-alkyl-amino-Ci · 3-alkoxy, di_ (c1-4-alkyl) -amino-CN3-alkoxy, ring-C3 · 6 · Alkyleneimino-Chr alkoxy, aminocarbonyl, Cn alkyl-aminocarbonyl, di- (Ck alkyl) -aminocarbonyl or ring_C36_alkyleneimino-carbonyl, R represents Ci-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-0-, 99336.doc -14- 200540142 rM-O-Cu-alkyl ... r15-〇-CO- , R15-C0-0-, cyano, R16R17N-, R18R19N-CO- or Cy5 R13 has one of the meanings conferred to R17, R14 represents dentin, Cw alkyl, C2_6-alkenyl, C2_6-alkynyl, R15- 0-, R15-0-C0_, R15-C〇, R15-C0-0 ·, R16R17N-, R18R19N-CO_, R ^ -O-Cw alkyl, rW-O-CO-Cw alkyl, R15-〇 -CO-NH-, R15_S02-NH, rWo-CO-NH-Cw alkyl, Rb-SCVNH-Cn alkyl, rM-CO-Cw alkyl, rM-CO-O-Cw alkyl, RHrPN-Cw _ Alkyl, RUrBN-CO-Cw alkyl or Cy-Cw alkyl-, R15 represents H, Cw alkyl, C3_7 cycloalkyl, C3-7-cycloalkyl-Cw-alkyl, phenyl, phenyl- C ^ -alkyl, pyridyl or pyridyl-C ^ -alkyl, R16 represents H, Cu alkyl, C3-7_cycloalkyl, C3.7_cycloalkyl-Cu-alkyl, C4-7 -Ring thin C4-7-Cyclo-Ci-Ci-Ci-Ci-Ci, C4-Ci-Ci-Ci-Ci-Ci-Ci , Cy alkyl-amino group C 2-6-group,-(C 1.4-group)-group " " C 2-6-alkyl group or soil-C 3-6-ethanyl imino group- C2-6-Chenyl, φ R17 has one of the meanings given to R16, or it represents phenyl, phenyl-Ci-3 · alkyl, pyridyl, dioxolane_2_yl, Ci-4-alkane Carbonyl, hydroxy-carbonyl-Ci-3-alkyl, Ci.4-alkoxycarbonyl, Ci.4-alkoxycarbonyl-Cw-alkyl, Ck alkylcarbonylamino-C2 · 3-alkyl, alkyl Carbonylalkyl) -amino-C2-3-alkyl, Ci.4-alkylsulfonyl, C 1-4 -alkynylamino " C 2-3 -alkynyl or alkyl (Continuous fluorenyl) alkyl) -amino-C2-3-alkyl-, R18 and R19 each independently represent only or 匚 -alkyl '99336.doc -15-200540142 R20 represents halogen, hydroxyl, cyano, Cl-6-alkyl, Cw alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, Cycycloalkyl-Cw-alkyl, hydroxyalkyl, RlCw alkyl or one of the meanings assigned to R22 ' R21 represents Ci-4-alkyl, hydroxy-C2-3-alkyl, Cl-4-alkoxy-C2-6-alkane , Cn alkylamino-C2-6-xyl, bis- (Cy-based) -amino-C2-6-based, cyclic-C3-6-alkyleneimino-C2-6-alkane Phenyl-Ci-3-alkyl, CN4-alkyl-carbonyl, C! -4-alkoxy-carbonyl or Cid-alkylsulfonyl 'R22 represents phenyl-Cw alkoxy, cyclo- C3-6-alkyleneimino-Cw alkyl Ioxy 'Ck alkoxy, Ci.4-alkylthio, carboxyl, Ci-4-alkylcarbonyl, Ci-4-alkoxycarbonyl, amino Carbonyl, Ci-4-alkylaminocarbonyl, di- (CN4-alkyl) -aminocarbonyl, cyclo-c3.6-alkyl-amino-carbonyl, cyclo_C3.6-alkyleneimine -Carbonyl, cyclic-C3-6-alkyleneimino-C2-4-alkyl-aminocarbonyl, phenyl_amino-carbonyl, Ckalkyl-sulfofluorenyl, Ci-4-alkyl -Sulfinamidino, Ci-4-alkyl-sulfoamidoamino, amine, Ci-4-alkylamino, di- (CN4-alkyl) -amino, Ci · 4-carbyl- Isopropyl-amino, cyclic_c3_6-alkylenimine, phenyl-Cw-alkylamino, alkyl) -phenyl-Cw-alkyl-amino, #ethylamino, propyl Amino group, phenylcarbonylamino group, phenylcarbonylmethyl-amino group, hydroxy-Ci · 3-alkylaminocarbonyl group, (4-morpholinyl) · carbonyl group, (^ pyrrolidine ) Carbonyl, (1-piperidinyl) -carbonyl, (hexahydro · 1 · nitrocarbyl) _carbonyl, (4-methylpiperazinyl) -carbonyl, aminocarbonylamino or alkylaminocarbonyl _ Amine group, in the above-mentioned groups and groups, especially in X, ... to feet 4, r10, r ", R to R, in each case one or more c atoms can be additionally subjected to F single or Multiple substitutions and / or two or more c atoms in each case may be additionally independently independently substituted by 01 or Br and / or one or more benzene rings in each case may additionally be independently 99336.doc -16- 200540142 Li contains one, two or three selected from the group F, Cl, Br, I, Cm-alkyl, Ci-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxyl, amine, alkyl Amine group, di- (Cl-3 -alkylamino group, ethyl alcohol group, amino group group, mouse group, difluoromethoxy group, trifluoromethoxy group, amino group-Ci-3-alkyl group, Ci-3 · alkylamino-Cid-alkyl and di- (C ^ talkyl) _amino-Cbs-alkyl substituents and / or may be mono-substituted by nitro, and in each case The fluorene atom of the carboxyl group or the fluorene atom bonded to the N atom can be replaced by a group capable of breaking in vivo. > The compounds according to the present invention, including physiologically acceptable salts, are particularly effective as antagonists of MCH receptors (especially MCH-1 receptors) and show very good affinity in MCH receptor binding studies. In addition, the compounds according to the invention have a high to very high selectivity for MCH receptors. The compounds according to the present invention generally have low toxicity, are well absorbed by the oral route and have good brain transmission, especially brain accessibility. The present invention also relates to individual diastereomers, enantiomers of individual optically isomeric forms of compounds, tautomeric forms and free base forms or corresponding acid additions of pharmacologically safe acids A mixture of conformers or racemates. The subject matter of the present invention also includes compounds according to the present invention (including their salts) 'in which one or more hydrogen atoms are replaced with deuterium. The present invention also includes the physiologically acceptable salts of the amidine compounds according to the third aspect of the present invention as described above and below. A leap month also encompasses a composition containing at least one ketamine compound according to the present invention and / or a salt according to the present invention, optionally with the same or more physiologically acceptable excipients. 99336.doc -17- 200540142 The fx description also covers pharmaceutical compositions containing at least one ketamine compound according to the present invention and / or a salt according to the present invention optionally with one or more inert carriers and / or diluents. The invention also relates to the use of at least one β-amidine compound according to the invention and / or a salt according to the invention for influencing the dietary behavior of mammals. The present invention is also related to the use of at least one ketamine compound according to the present invention and / or a salt according to the present invention for reducing mammal body weight and / or preventing weight gain. I. The present invention also relates to at least one bupropion compound according to the present invention and / or a salt according to the present invention for preparing a pharmaceutical composition having MCH receptor antagonistic activity (especially MCH-1 receptor antagonistic activity) Of its purpose. In addition, the present invention relates to at least one bupropion compound according to the present invention and / or a salt according to the present invention for the preparation and / or treatment of symptoms and / or diseases that are suitable for preventing and / or treating caused by or associated with MCH. Use of pharmaceutical composition. The invention also relates to the use of at least one β-amidine compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition suitable for the prevention and / or treatment of metabolic disorders and / or eating disorders, These disorders are in particular obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa, and binge eating disorder. The invention also relates to the use of at least one ketamine compound according to the invention and / or a salt according to the present invention for the preparation of a pharmaceutical composition suitable for the prevention and / or treatment of diseases and / or disorders related to obesity These diseases and / or disorders are especially diabetes (special type diabetes), diabetes outbreaks 99336.doc -18- 200540142 (including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), insulin resistance, glucose tolerance Perceptual abnormalities, brain hump, inadequate mental function, cardiovascular disease (especially arteriosclerosis and high blood stars), arthritis and knee arthritis. In addition, the present invention relates to at least one β · ammonamine compound according to the present invention and / or a salt according to the present invention for use in the preparation of a cell that is suitable for the prevention and / or treatment of cellulite, fat accumulation, and malignant mast cell proliferation. Disease, systemic mastocytosis, mood disorders, affective disorders, camp depression, _. ,,, sleep disorders, reproductive disorders, sexual dysfunction, memory disorders, epilepsy, various Dementia forms and use of pharmaceutical compositions for hormonal disorders. Another object of the present invention is at least one bupropion compound according to the present invention and / or a salt according to the present invention for use in the preparation of a compound suitable for the prevention and / or treatment of urinary incontinence, frequent urination, urgency, urinary feces and enuresis Use of a pharmaceutical composition for maladjustment disorder. The invention further relates to at least one β-ketophosphonium amine compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition suitable for the prevention and / or treatment of dependence and / or withdrawal symptoms Of its purpose. In addition, the present invention relates to a method for preparing a pharmaceutical composition according to the present invention, which is characterized by non-chemically incorporating at least one stilbene compound according to the present invention and / or a salt according to the present invention into one or more inert substances. Carrier and / or diluent. The present invention further relates to a substance containing a first active substance selected from the group consisting of β-ketamine compounds and / or corresponding salts according to the present invention and an active substance selected from the group consisting of 99336.doc -19-200540142 for the treatment of diabetes. Active substance, active substance for treating obesity (preferably different from MCH antagonist), active substance for treating hypertension, active substance for treating dyslipidemia or south jk lipid (including arteriosclerosis), active substance for treating arthritis 2. A pharmaceutical composition comprising an active substance for treating anxiety state and a second active substance for a group consisting of active substance for treating depression, optionally with the same or more inert carriers and / or diluents. The present invention also relates to a method for preparing a β-ketofluoramine compound of formula I,

R1 \ X-Y—Z, r2 /

Ο Ο R

A ~ Hb wherein A, B, b, X, Υ, Z, R1, R2, R3, R5a and R5b have the meanings given above and below, wherein 'in the presence of at least one base in a solvent or a solvent mixture, Make an amine compound of formula A1,

R1 \ Ν-Χ-Υ—Z

A1 wherein Y, B, 111, 112, and 113 have the meanings given above and below, and the acid compound or the slow acid derivative of formula A2 0 0

Wherein A'B, b, 115 & and R5b are as defined above, and the group M represents 0H, CH, Cw alkoxy, Cw alkylthio or Cw alkyl-COO-, 99336.doc -20- 200540142 A reaction occurred. The invention further relates to a method for preparing a β-ketofluorene compound of the formula I, R \ r2 / N-χ-Υ-Z \

A_H] b where eight, 8, 1 ^, 乂, y, 2, 111, 112, and 113 have the meanings given above and below, wherein, in a solvent or solvent mixture, and optionally in the presence of activated nucleophiles Hydrolyzing the propynylamine compound of formula B 1 by adding an acid or a base

Among them, 8 ,, 1 ^, and, y, 2, 111, 112, and 113 are as defined above. The starting materials and intermediates used in the synthesis according to the invention (especially the compounds of the formulae Al, A2 and B1) are also the subject of the invention. [Embodiment]

Unless otherwise specified R5b, R7a, R7b, r7c, R7d, R10 u R to R groups, residues and substituents and the index b have the meanings given above. If groups, residues and / or substituents occur more than once in a compound, they may have the same or different meanings in each case. In accordance with the present invention 'also includes tautomers of phantom compounds, especially enol tautomers in the form of ketones represented by formula I. 99336.doc -21-200540142 If R represents a fluorene atom, the following compounds are included according to the present invention, with Formula 1 (keto) indicating the keto form and Formula 1 (enol) indicating the relevant enol form:

α- [· β A--B 1 (keto) 丨 (enol) ^ In the examples and examples described below, only the ketone form is explicitly mentioned; according to the present invention, it can be easily done by anyone skilled in the art The corresponding enol form obtained here is also included in each case. In each case, a particularly good definition of the group Rh'RU is independently H, F, cm, cf3, methyl, ethyl, especially H, F, methyl, ethyl, and H F, methyl is particularly preferred. According to another preferred embodiment, R5a and R5b, which represent methyl groups, are joined together to form a cyclopropyl group with the C atom to which R and 11515 are bonded. Particularly preferably, R5a and R5b represent H. • The preferred meaning of the substituent R3 is H, C! -4-alkyl, C3.6-cycloalkyl or (: 3.6 · cycloalkyl-Cw-alkyl; especially H4Ci_3-alkyl. R3 is particularly preferred Ground represents H or methyl, especially Η. The substituents R1 and R2 as independent groups may have the meanings given above and below or may be connected to each other as a bridge. For the sake of brevity, the description of the group as an independent group will be described first. The preferred meanings of R1 and R2, and then the better meanings of the groups R1 and R2 which are connected to each other to form a bridge. Therefore, the preferred compounds according to the present invention have the following preferred R1 and R2 as independent groups One of these meanings is 99336.doc • 22- 200540142 and one of the following preferable meanings of Rl & R2 which is a group connected to each other to form a bridge. If 1 and R2 are bonded to each other without an alkylene bridge, Then, R1 and R2 preferably independently represent Ci 8-alkyl or c: 3 · 7 · cycloalkyl, which is mono- or polysubstituted by the group Rll, and the position of 6- or 7-membered cycloalkyl is 3 at the same time. Or the -CH2- group on 4 can be substituted by -0_, _S-i_NR1, or phenyl or pyridyl, optionally, by the group R20 and / or by nitrate Mono-substituted, while one of the groups R1 and R2 may also represent Η. | In the groups R1 and R2, one or more C atoms may be mono- or poly-substituted by f and / or one or two C atoms may each be Independently substituted by C1, or cn. The preferred meaning of the group R11 is alkyl, C2-6-alkenyl, C2-6-alkynyl, R15_〇 ·, cyano, R16R17N-, C3_7-cycloalkane Group, cyclic-C3-6-alkyleneimine group, β-pyridyl group, pyridyl-pyridyl, alkalyl, n ^ Ck alkyl-)-piperidinyl, phenyl, and η-pyridyl At the same time, one or more C atoms in the aforementioned groups and residues may be mono- or poly-substituted by F and / or one or two c atoms may be independently mono-substituted by Cl, Br or CN, and the above-mentioned cyclic group is One or more c atoms Φ may be mono- or poly-substituted by r2G, in the case of a phenyl group may be additionally mono-substituted by a nitro group, and / or one or more NH groups may be substituted by R21. If R11 has one of the meanings of r15_〇_, cyano, R16R17N- or ring < Z: 3 · 6 • arsenimine, the C atom of alkyl or cycloalkyl substituted by R11 is more than Preferably, it is directly attached to a heteroatom, such as the group -N-X. The groups R1 and R2 each preferably independently represent H, Cw alkyl, C3_5-alkenyl, C3-5-alkynyl, C3-7-cycloalkyl, hydroxy-C3.7-cycloalkyl, C3.7- Cycloalkyl-Cw-carbyl, (Cyclo · 03 · 7-Cycloalkynyl) -Ci_3 · Cycloyl, Cryptyl-C2-4-cathyl, 99336.doc -23- 200540142 NC-C2 · 3 · Carbonyl, Ci.4-Carbonoxy-C2 · 4-Carbonyl, Cyanyl_c14-Carbonoxy-C2 · 4 · Carbonyl, Ci · 4-Carbonoxy-Chino-C1 · 4- Alkyl, enyl_c14_alanyl, amine-C2-4-alanyl, Ci-4-alanyl-amino-C2-4-alanyl, di- (Ci 4-alanyl) amino- C2 · 4 · alkyl, cyclic-C3-6 * -alkyleneimino_c2-4_alkyl ,. ratio. Each < -3- group, N- (Ci_4 · alkynyl) -σ ratio 17 each of octyl group, σ specific mouth each _c1-3-carbon group, N- (Ci.4_carbon group) -σ Bilobityl-C1-3-pyridyl, pyridyl_3_yl or _4-yl, N- (Ci-4-pyridyl) -brazilian-based or -4 · yl, lipid-c1 -3_alkenyl, N ^ Ch4-alkyl) -piperidinyl-C3-alkyl, tetrahydropiperan · 3-yl, tetrahydropyran-4-yl, tetrahydrobranyl- Ci · 3 -alkynyl, tetrahydroquinone_3_yl, tetrahydroσfuranyl-Cl · 3 · carbyl, phenyl, phenyl-Cl · 3 · carbyl, tonyl or σ specific bit US_Alkyl, at the same time in the above-mentioned groups and residues, one or more c atoms may be mono- or poly-substituted by F and / or one or two C atoms (especially one c atom) may be independently passed C1 or Br is mono-substituted, and phenyl or pyridyl may be mono- or poly-substituted by the group r20 and / or mono-substituted by nitro. The above-mentioned cycloalkyl group may preferably be selected from the group consisting of mesityl group, mesyl group-Cl · 3 · carbyl group, Cl · 3 · carbyl group, or Cl · 3 · carbyloxy group (especially viayl group, methylol group, methyl group) And methoxy). Defining hydroxy-C 2 -4 -alkynyl and C 1 · 4 -alkoxy-C 2 · 4 -C 2 -4 -alkynyl bridge in the alkynyl group may preferably be additionally passed through hydroxy, hydroxy-C "3 -Alkyl, Ci-3-alkyl or CiT alkoxy (especially hydroxy, methylol, methyl and methoxy) are mono-substituted. Preferred substituents for the above-mentioned phenyl or stildinyl are selected from F, C, Br, I, cyano, Ci-4-alkyl, Ci · 4-alkoxy, difluorofluorenyl, trifluoromethyl, hydroxyl, amine, ^ -pentane, amine, Di-((^-3-alkyl) -amino, acetamido, aminecarbonyl, difluoromethoxy, dioxo, amine-Ci-3-alkyl, Ci-3- Ranylamino-Ci.3_alkyl and di- (Ci-3-alkyl) -amino-Ci-3-alkyl, and the phenyl group can be mono-substituted by Shi Xiao 99336.doc -24 · 200540142 A particularly preferred definition of the group R1 and / or R2 is selected from the group consisting of fluorene, Cw alkyl, C3 · 7 · cycloalkyl, C3.7-cycloalkyl-Cu-alkyl, tetrahydropiperan-3 or -4-yl, tetrahydrobranyl-Ci_3-carbyl, bridging-3-yl or -4-yl, N- (Cl · 4-carbyl) · Pyodo-3 -yl or -4-yl , Bridging group-Ci-3 -alkyl, N- (Ci-4 " · alkyl) -alkyl, -Cw alkyl, phenyl Pyridyl, phenyl-Cw alkyl, pyridyl-Ci-3-alkyl, meridian- € 2-4-alkyl, fluorene 1.4-alkyloxy-〇2-4-alkyl, amino匚 2-4-alkyl, (^ 1.4 " 1-alkyl-amino- € 2-4-alkyl and di-(^ 11-4-alkyl) -amino " ^ 2-4- | The alkyl group may be selected from a methyl group, a methyl group -C 1.3 -alkyl group, a C 1.3-alkyl group, or (^ -3-alkoxy group (especially a hydroxyl group, a methylol group, a methyl group, and (Methoxy) substituents are mono-, di-, or tri-substituted, and define the C2_4-alkyl bridge in hydroxy-C2-4-alkyl and Ci.4-alkoxy-C2-4-alkyl can be additionally passed through a hydroxyl group , Hydroxy-Ci.3-alkyl, CN3-alkyl, or (^ -3_alkoxy (especially hydroxy, hydroxymethyl, methyl, or methoxy) is mono-substituted, and the alkyl group may be mono- or Polysubstituted and / or monosubstituted by C1. A particularly preferred definition of the groups R1 and / or R2 is also selected from the group consisting of fluorene, Cb4 · alkyl, C3-5-alkenyl, C3-5-alkynyl, C3-7- Cycloalkyl, Cw cycloalkyl-Cw alkyl, Cl.4_alkyloxy-C2_3 · alkyl, pyridyl and benzyl, meanwhile alkyl, cycloalkyl or cycloalkyl can be mono- Or di-substituted, mono- or poly-F, or mono-substituted with Br, C1 or CN, and One of the groups Ri and R2 may also represent η. Particularly preferred groups R1 and / or R2 are selected from H, fluorenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Propylene-3-yl, propyne-3-yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylfluorenyl, cyclopentylmethyl, cyclohexylfluorenyl, phenylpyridinyl, phenylfluorene Radical, σ-pyridinylmethyl, tetrahydropiperazine 99336.doc • 25- 200540142 sulfan-4 · yl, tetrahydropyran-4-yl-methyl, sulfan-4-yl, N- (Ci.4 -Rhodium) -piperidin-4-yl, piperidin-4-yl-methyl, N- (Ci-4-alkyl) _piperidin-4-yl-methyl, and the above ethyl, propyl And butyl may be mono-substituted by amine, methylamino or dimethylamino or may be mono- or di-substituted by hydroxy, methoxy or ethoxy, and the above cycloalkyl ring may be substituted by hydroxy, hydroxymethyl Or the methyl group is mono- or di-substituted and the methyl group may be mono- or poly-substituted by fluorine. Examples of particularly preferred definitions of the groups R1 and / or R2 are methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-hydroxy-propyl, 3-hydroxypropyl, 2- Hydroxy | methyl-2-methyl-propyl, 2-methoxyethyl, 3-amino-propyl, propen-3-yl, propyn-3-yl, cyclopropyl, cyclopentyl, cyclo Hexyl, cyclopropylmethyl, cyclopentylfluorenyl, (1-hydroxycyclo-propyl) methyl, phenyl, pyridyl, phenylmethyl, 0pyridylmethyl, tetrahydropyran-4 -Yl, N-methyl-nitro-4-yl, N- (methylcarbonyl) -piperidin-4-yl and N- (third butoxycarbonyl) -piperidin-4-yl, and hydroxyalkane The group may be additionally substituted with a hydroxyl group, and the group R1,! ^ One of them can also represent H. If the substituent R1 has one of the above-mentioned preferred meanings but is not Η, then the substituent R2 particularly preferably represents Η, methyl, ethyl, n-propyl, isopropyl, hydroxyethyl, or 2-methoxy Ethyl. Particularly preferably, at least one of the groups R1, R2 and particularly preferably two groups have a meaning other than Η. If R1 and R2 form an alkylene bridge, this is preferably a (alkylene bridge), in which 〃-Cil2_ group which is not adjacent to the N atom of the WVN- group can be replaced by -CH = CH- , And / or-preferably not adjacent to the N atom of the N12N_ group-(: 112_ group can pass 99336.doc -26-200540142 -0-, -8-,-€ 0-,-(: (= (^ 112)-or seven-foot 13- (youjiajing-0-, -8- or 卞 1113-) are not directly bonded together with heteroatoms and the group -CO- is not directly bonded to the group R ^ R ^ N- substitution, while one or more fluorene atoms in the alkylene bridge defined above may be replaced, and the alkylene bridge defined above may be carbocyclic or heterocyclic The ^ substitution makes the bond system between the alkylene bridge and the group Cy formed in the following manner:-via a single or double bond,-via a common C atom forming a spiro ring system,-via a fused bicyclic ring system via two They are commonly adjacent to C and / or n atoms, or -C and / or n atoms which form a bridged ring system through three or more. R13 preferably represents H, C-6-alkyl, Ck alkylcarbonyl or (^ · 4-alkoxycarbonyl. R13 particularly preferably represents 11 or Cue alkyl, especially η, methyl, ethyl Or propyl. R1 and R2 also preferably form an alkylene bridge so that] ^ 112> | _ means selected from the group consisting of azetidine, σ-pyridine, pyridine, aziridine, 2,5_ Dihydro-1Η-pyridine, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro_1Η • nitrogen, 2,3,6,7_tetrahydro_ιη_ nitrogen A group of exhaled or piperazine, in which the free imine functional group is substituted with Rn, piperidine_4_one, morpholine, and thiomorpholine, especially selected from pyrrolidine, piperidine, piperidine_4-05I, 2, 5. Dihydro_1H_pyrrole, piperazine, in which the free imine functional group is replaced by Ru, morpholine and thiomorpholine. At the same time, according to the general definition of R1 and R2, one or more H atoms can be measured by the ruler " The substitution and / or the above-mentioned groups may be replaced by one or two identical or different carbocyclic groups or hetero 99336.doc -27- 200540142 Yiki Cy in the manner prescribed according to the general definition of R and & 2. Use A particularly preferred group for this purpose is called phenyl, C 3 7 alkyl, azetidinyl ', especially base, C, Tffi JJ. 3.6.% Alkyl, cyclo-C3-5-alkylene Imino group and N-Cl-4_ alkyl group ((aza-Cj TS2 p * «· \ ethylenyl group)-, and the cyclic group Cy can be passed as specified The radical bridge formed by R and 11> (where the -CH2- moieties may be replaced as specified) may be passed through one or two identical or different carbocyclic or heterocyclic groups C y ( It is substituted as described above. If an alkylene bridge is connected to the group Cy via a single bond, Cy is preferably selected from the group consisting of C3 7_cycloalkyl, U-alkylimino, piperazinyl, 1-imidazole, thienyl and phenyl, especially C3-6-cycloalkyl, pyrrolidinyl, piperidinyl and piperazinyl, which may be substituted as specified And, in each case, the N atom may be substituted by Ci 4-alkyl, in particular. If the alkylene bridge is bonded to the group Cy via a common C atom to form a spiro ring system, Cy is preferably selected from the group consisting of: C3 cycloalkyl, aza-Cw cycloalkyl,嗔 -Cw cycloalkenyl, 2,3-dihydro-1H · xantholin _4__, especially cyclopentyl and cyclohexyl, which may be substituted as specified, and in each case the N atom may undergo ¢: ^ 4-alkyl substituted. If the alkylene bridge is bonded to the group Cy via two common adjacent C and / or N atoms to form a fused bicyclic ring system, Cy is preferably selected from the group consisting of: C4_7_cycloalkyl, Aza-C4 · 7-cycloalkynyl, benzyl, fluorenyl, especially phenyl and pyrrolidinyl, which may be substituted as specified, and in each case the N atom may be particularly Cl.4-alkyl To replace. If an alkylene bridge is bonded to the group 99336.doc -28- 200540142 Cy through three or more C and / or N atoms to form a bridged ring system, Cy is preferably C4_8-cycloalkyl or nitrogen. Miscellaneous-〇4-8-Bad Yuanji. Preferably, the group is defined according to one of the following partial formulas: X R—n y

99336.doc -29 · 200540142

99336.doc -30- 200540142

At the same time in the heterocyclic ring formed by the group RiR ^ N-, one or more η atoms may be substituted by R14 and / or fluorene atoms may be substituted by Cy as defined by C3_7-cycloalkyl, and the Cy may be substituted by R2G, In particular, the ring on the heterocyclic ring formed by F, hydroxy, Cw alkyl, CF3, CN3-alkoxy, OCF3 or hydroxy-Cn alkyl group may be one or more The C atom is mono- or poly-substituted by R20, and in the case of a benzene ring, it may be additionally mono-substituted by nitro, and X 'and X " each independently represents a single bond or (^ -3-alkylene, and if the group Y is bonded to X or Xπ via the C atom of (group of Y), then χ ,, X "can also represent -Cw extended alkyl 3_ extended alkyl-NΗ- or -Cw extended alkyl-New Alkyl), and x'f additionally represents -o-Cw-alkyl, _NH-C-alkyl, or -N (Ci-3-alkyl) _Ci-3_alkyl, and if the group Y passes through The C atom (of the group Y) is bonded to XM, then χM also represents -NΗ-, -N (Ci.3_alkyl) _ or _〇-, meanwhile, in the meanings given to x, x " above In each case, ^ may be substituted by R10, preferably hydroxy, ω-hydroxy_Cl_3_alkyl, ω · ((^ _ 4 · alkane 99336.doc -31-200540142 alkyl and / or 4-alkoxy substituted, and / or in each case one or two c atoms may be selected from one or two of the following, which may be the same or different Substituents: C ^ -alkyl, CM-alkenyl, C26_alkynyl, C37_cycloalkyl,

Cycycloalkyl-Cl.3 · alkyl, C: 4 · 7 · cycloalkenyl and C4 · 7 · cycloalkenylalkyl, and two alkyl and / or alkenyl substituents can be joined together to form Carbon ring system, and

In X, X ′, one or more C atoms in each state may be independently independently substituted with F mono or poly and / or one or two C atoms in each state may be independently independently substituted with C1 or Br, and wherein R2, R1g, Ri3 The meaning given below. R14, R18, R2G, R21, and X have the above and X, χ each preferably independently represents a single bond or a sintered group, and if the group Y is bonded to X via a C atom bond, or X ", χ ,, X , May also represent alkylene · 0-, -Ci.3 · alkylene-NH ·, or -Cw alkylene-N (Cw alkyl) ·, and X " additionally may represent -〇_CN3_ Alkylene, -alkylene, or -N (Ci · 3 · alkynyl), and if the group γ is bonded to X via the c atom, X · 'also means -NH-, -ΝΑ "Alkyl)-or _〇. Particularly preferably, X, and X " each independently represent a single bond or a methylene group, and if the group γ is bonded to X, or X ,, via a c atom bond, then X ,, X " also represents _ch2-0_ , _Ch2-nh, or-^^ • ^ ((^-"Baking group 丨 — 'and if the group ya is connected to 乂 via a 匚 atom bond ^ X " also means _NH ·, -NCCw alkyl) or · 0-. In the above-mentioned preferred and particularly preferred meanings of RiR ^ N-, the following definitions of the substituent Ri4 are preferred: F, C, Br, Cm-alkyl, C2.4-alkenyl, c2_4-alkynyl , C3y cycloalkynyl-Cy alkyl, meridian, meridian-Cy alkyl, c1-4-oxy, 99336.doc -32- 200540142 C0- (Ci_4-alkyloxy) -Ci-3_ Ci, Ci-4-alkyl, alkynyl, alkynyl, Cl-4-alkyl, carbonyl, hydroxy-carbonylalkyl, Cbfalkoxy-carbonyl-C ^ -alkyl, Ci-4-alkoxy- Carbonylamino, Cbralkoxy-carbonyl-amino-Cl · 3 · alkyl, amine, Ci-4-alkyl-amino, C3-7-cycloalkyl-amino, N- (C3- 7- ^ alkylalkyl) -amino, di- (Cm-alkyl) -amino, amino-Ci-3-alkyl, C1-4-alkyl-amino_Ci-3-alkyl , C3-7_cycloalkyl-amino-Ci-3-alkyl, ^^-(〇3-7-cycloalkyl) " ^-((^ 1-4- 院) -Amine < 1.3-alkyl, di- (Ci-4-alkyl) -amino-Ci-3_alkyl, cyclic-C3-6-alkylimide-Ci-3_ > Alkyl, aminocarbonyl, C ^ -4-alkyl · amino-carbonyl, C3-7-cycloalkyl-amino-carbonyl, N- (C3-7 · cycloalkylalkyl) -amino- Carbonyl, di-((^. 4-alkyl) -amino-weiyl, σ specific alkyl group · oxy, σ specific alkyl group-amino group, fluorene specific alkyl group-Ci_3_alkyl group-amino group-. In the above meaning of the group R14, one or more C atoms may be mono- or poly-substituted by F and / or one or two C atoms may be independently mono-substituted by C 1 or Br, and the alkyl group may be mono- or poly-substituted by fluorine in particular. Particularly preferred meanings of the substituent R14 are F, Cl, Cbc alkyl, C3.6_ cycloalkyl-C! · 3-alkyl, hydroxy, hydroxy-(^ · 3-alkyl, Ci_4-alkoxy , Cl_4-alkoxy-ci-3_alkyl, amine-Cw alkyl, Cyalkyl-amino-cN3 · alkyl, c3_7-cycloalkyl-amino_Cl 3_alkyl, ^ ((^^ Cycloalkylalkyl) -amino-Cw alkyl, bis- (Cw alkyl) _amino-c ^ 3-alkyl, cyclo-C3-6-alkyleneimino_ Cl 3 -alkyl, aminocarbonyl and pyridylamino. One or more c atoms in the above meaning of the group R14 and An alkyl group which may be substituted by mono- or fluoro. Therefore, a better meaning also includes, for example, -cf3 & -ocf3. If in the heterocyclic ring formed by the group, the H atom may be replaced by Cy (preferably substituted by r20 mono or poly), which represents c_99336.doc -33-200540142 cycloalkyl, then Cy preferably represents a Cw ring Yuan and R2G preferably represents ρ, light group, C 3-3 & group, C 3 V-1-3- alkoxy group, OCF3 or hydroxy-Cl-3-alkyl group, especially F, Jing group, methyl group Beauty, methoxy, CF3, OCF3 or methyl. Cy is particularly preferably ^^ cycloalkyl and 1-light-C3-5-cycloalkyl. Particularly preferably, the group is defined according to one of the following partial formulas.

99336.doc -34- 200540142 At the same time, the group R13 has the meaning given above and below, and in the heterocyclic ring formed by the group R1R2N ·,-or more fluorene atoms may be substituted and / or fluorene atoms may be After Cy substitution of 矣 ^^, which represents 0.36 alkyl, the Cy can be passed through p20, A π

R is in particular via F, via radical, Cl_3-alkyl, CF3, Ci3alkoxy, ocfi or via -Cl_3.xyl, particularly preferably via F, hydroxyl, methyl, methoxy, CF3, OCF3 or The methylol group is mono- or poly-substituted, and the ring connected to the heterocyclic ring formed by the group I ^ IIN- may have one or more c

Atoms are mono- or poly-substituted by R2G (preferably mono-substituted), or can be additionally mono-substituted by nitro in the case of a benzene ring, and R independently represents F, c, c ^ alkyl, Cw ring in each case Alkyl-Cw-alkyl, hydroxy, hydroxy-Ci ^ alkyl, 014-alkoxy, alkoxy-Cw-alkyl, pyridylamino or aminocarbonyl, and at the same time in one or more conditions Each C atom, and especially an alkyl group, may be additionally mono- or polysubstituted by f; particularly preferably, R14 represents methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy_ 丨 _methyl · ethyl, 丨 _hydroxycyclopropyl, methoxy, ethoxy, methoxymethyl than pyridylamino or aminocarbonyl; and R13 Is as defined above, which means in particular alkyl. X preferably represents a ^^-alkylene bridge, where the -CH2 group-which is not adjacent to the N atom of the RiR ^ N- group can be replaced by _ch = ch_ or -OC-, and / or-is not adjacent to The -CH2- group of the N atom of the R ^ R ^ N- group can be passed through _〇_, S ·, _CO_, or _NR4- (particularly via -0, -S, or -NR4 ·) to each Under the condition, two 0, S or N atoms or 0 and S atoms are not directly bonded together. 99336.doc -35- 200540142 At the same time, R4 can be connected to γ to form a heterocyclic system with each other, and bridge X can be connected to Ri, including N atoms bonded to Ri and X to form a heterocyclic group, and C atoms that are not directly connected to heteroatoms may be substituted by rig and / or one or two C atoms may each be substituted by one or two The same or different substituents selected from Ci-6 · alkyl, C2-6-alkenyl, C2-6 · alkynyl, C3.7-cycloalkyl, Cw cycloalkyl_Cl ^ Alkyl, C47-cycloalkenyl, and cyclopentenyl

Ci-3_alkenyl 'is especially cN4_alkenyl, while two alkyl and / or alkenyl groups are substituted. The groups can be joined together to form a carbocyclic system, especially cyclopropyl, cyclobutyl or cyclopentyl . In the above definition of bridge X, two C atoms or C and N atoms of the alkylene bridge can be joined together by an additional Ci4-alkylene bridge. In the group X, a group directly adjacent to the group rir2N-2_CH2- is preferably not substituted with -0, -S_,-(S〇) _,-(S〇2) _, -CO- or -NR4_. These groups are preferred if one or two -CH2- groups in group X are each independently replaced by -0,-,-(SO)-, _ (S02)-, -C0_, or -NRt. It is separated from the R1R2N- group by an alkylene bridge with at least 2 C atoms. If the two X112 groups in the group X are each independently replaced by _〇 · ,,-(S〇2)-, -C0 ·, or -NR4-, these groups are preferably substituted by having at least 2 C The atomic alkyl bridges are separated from each other. If the -CH2_ group of the alkylene bridge is replaced in the group X according to the invention, this -CHy group is preferably not directly connected to a heteroatom, double bond or triple bond. The alkylene bridge X, X, or X " is preferably free of imine groups or has at most one imine group. It is preferable to choose the position of the alkylene bridge χ, χ, or X " so that it does not form the aminal functional group with 99336.doc • 36-200540142 amine NWR2 or other adjacent amine groups, or two N atoms Not close to each other. X preferably represents an unbranched (^ _4 · alkylene bridge, and if the group Y is bonded to X via a C atom (of the group Y), then X also represents -CHrCHNCH-, C2 · 4 · Extended Alkoxy or c2.4-alkylene-NR4- 'is especially c2-4-alkylene or c2-4-alkylene_nr4-, and R4 can be connected to γ to form a heterocyclic system, At the same time, the bridge X can be connected to R1, including the N atom on Ri and X from > to form a heterocyclic group, and in X, the C atom can be substituted by R1G and / or in each case one or two The c atom may be substituted with one or two of the same or different substituents selected from the following: Cw alkyl, C2.6-alkenyl, c2-6-alkynyl, C3-7-cycloalkyl, C3.7 -Cycloalkyl-Cw alkyl, (: 4_7_cycloalkenyl and C4-7-cycloalkenyl-Cw alkyl, especially Ci · 4 · alkyl, with two alkyl and / or alkenyl substituents Can be joined together to form a carbocyclic system, and in the above-mentioned groups and groups, one or more C atoms may be mono- or poly-substituted by F and / or one or two C atoms may be independently And R1, R4 and R1G are as defined above. X is particularly preferably -CH2-, -CH2-CH2- or -ch2-ch2-ch2- -CH2-CH = CH-CH2- and if the group Y is bonded to X via a C atom (of the group Y), then X also represents -ch2-ch = ch- > -ch2-c ^ c-- -CH2-CH2-0- '-CH2-CH2-CH2-0- or _ch2-ch2_nr4- or -CH2_CH2-CH2-NR4-, especially -CH2-CH2-0-, -CH2-CH2-CH2-0 -, -CH2-CH2-NR4- or 99336.doc -37- 200540142 -CH2-CH2-CH2-NR, and at the same time R4 can be connected to Y to form a heterocyclic system with each other, and bridge X can be connected to R1, Including the N atom attached to R1 and X to form a heterocyclic group, and in X, the C atom may be substituted by R1G, preferably via a hydroxyl group, ω_hydroxy + alkyl group, oKCw alkyloxy Xu-alkyl group and / Or ^ alkoxy substitution, and / or one or two C atoms may be independently substituted with one or two identical or different C 1-4 alkyl groups while the two alkyl groups may be joined together to form a carbocyclic ring System, and in each case one or more c atoms may be mono- or poly-substituted by F and / or in each case one or two C-atoms may be independently substituted by Ci or mono. If the group Y is (Group of Y) c atom is bonded to X, then χ particularly preferably represents -CH2 ·, -CHrCH2 ·, -CHrCHrCHr, -CH2-CH2_〇-, -CH2 -CH2-CH2-0-, -CH2-CH2-NR4-, or -CH2-CH2-CH2-NR4-, which may be unsubstituted or substituted as described above. R has one of the meanings conferred to R, and it preferably has the meaning conferred to R10.-The substituent R4 particularly preferably means H, Ci · 6-alkyl, and C3-6_alkenyl. R4 particularly preferably represents fluorene, methyl or ethyl. If R, is bonded to γ to form a heterocyclic ring system, R4 is particularly preferably C2 · 6 · alkyl and C2 6-alkenyl. Right-click on y to form a heterocyclic system with each other, γ is preferably a benzyl group and R4 is preferably a C2.6-alkynyl group or a C "· alkenyl group. The preferred heterocyclic system is indole, = hydrogen Indole, quinoline, bisquinoline, tetrahydroquinoline, and stupid oxo 99336.doc • 38- 200540142 The group R4 preferably represents a vinyl group only when R4 is bonded to Y to form a heterocyclic system. R1G preferably represents hydroxy, ω_hydroxy-Ci 3-alkyl, Ci_4-alkoxy or alkoxyalkyl, especially hydroxy, hydroxymethyl or methoxy. Group X preferably does not contain a carbonyl group. Right In X, X 'or X " the c atom is substituted, it is preferred that the substituent is selected from the group consisting of CW alkyl, C2.4-alkenyl, C2-4_alkynyl, c3 7df alkyl, and cyclopentane Alkyl, hydroxy, .hydroxy-Ci3-alkyl, alkoxyhCu-alkyl and Cyalkyl. In addition, in X, X, or X ", the c atom may be disubstituted and / or one or two Each C atom may be mono- or di-substituted, and preferred substituents are selected from the group consisting of Cw alkyl, Cw alkenyl, c21 fastyl, C3_7-cycloalkyl, and C3-7-cycloalkyl-Cw · alkyl, especially Is. ^ Alkyl, and two

Ck alkyl and / or C2-4-alkenyl substituents may also be joined together to form a saturated or monounsaturated carbocyclic ring. To the right one or more c atoms in the group X, X 'or X' 'are substituted with a hydroxyl group and / or Ci 4_ • alkoxy group, the substituted C atom is preferably not next to another heteroatom. Particularly preferred substituents of one or two c atoms in X, X 'or X " are selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, and Two alkyl substituents on the C atom can be joined together to form a carbocyclic ring. In the definitions of the substituents of the bridge X, X, and / or X " and the definitions of the bridge X, X 'and / or XM itself mentioned above and below, in each case one or more C atoms may be additionally It may be mono- or poly-substituted by F and / or in each case one or two c atoms may additionally be independently substituted by C 1 or Br each independently. 99336.doc -39- 200540142 If one or more C atoms are substituted in the group X, X 'or XM as specified above, the particularly preferred meanings of X, X' and X '' are selected from:

If Y represents a fused bicyclic ring system, the preferred definition of the group X is -ch2-, CH2-CH2- and -CH2-CH2-CH2-, especially -CH2- or -CH2-CH2 ·, which may be as described above Regulation replaced. The group Y preferably has a meaning selected from the following divalent ring groups: phenyl, pyridyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydrolinyl, Tetrahydroquinolinyl, isohydrolinyl, dihydroisoquinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, sulfanyl, sulfan-4-one, 99336.doc- 40- 200540142 σ-secenyl, phenyl- °° phenenyl, sigma-stilbyl or stilbene-α-fluoromethyl, and the above cyclic group may be mono- or poly-substituted by r2G on one or more C atoms. It may also be additionally mono-substituted by Schottky, and / or may be substituted by r2 1 on one or more N atoms. As specified above, R1 may be attached to Y and / or X may be attached to γ, and Y preferably represents phenyl. If the group Y represents phenyl or pyridyl, the bridges X and Z are preferably attached to the group Y at the para position. The group Y is particularly preferably selected from the following divalent ring groups:

99336.doc -41 200540142

ο

At the same time, the above cyclic group may be mono- or poly-substituted by R20 on one or more C atoms, and may be additionally mono-substituted by nitro in the case of a benzene ring, and / or one or more NH groups may be substituted by R21. The group Y representing a phenyl group may be bonded to the group X to form a carbocyclic or heterocyclic group fused to γ. A preferred definition of the groups -X-Y- bonded to each other is selected from the group consisting of: 99336.doc -42- 200540142

At the same time, one or more c atoms of the above-mentioned cyclic group may be mono- or poly-substituted by r2G, and in the case of a benzene ring, they may be additionally mono-substituted by a nitro group.

The group Y is preferably unsubstituted or mono- or di-substituted. A particularly preferred substituent RU of the group Y is selected from the group consisting of fluorine, gas, bromine, cyano, nitro, Cw alkyl, c: 2-6 · alkenyl, hydroxyl, hydroxy_Cl_3-alkyl, 〇14-alkane Oxy, diaminomethyl, trifluoromethoxy, C2-4-alkynyl, Cw alkoxycarbonyl, Cm-carboxy-Cw alkyl, Ci-4-carboxy-carbonylamino, amine , CN4-alkyl-amino, di- (CN4-alkyl) -amino, aminocarbonyl, Ci.4-alkyl-amino-carbonyl, and di-((^. 4-alkyl) -amine -Carbonyl. Particularly preferred substituent r2G of group Y is selected from the group consisting of fluorine, gas, bromine, cyano, < ^ · 3, alkyl, Ci.3-alkoxy, C4-alkoxy Carbonyl, trifluoromethyl, trifluoromethyloxy, amine, and also nitro in the case of a benzene ring. Particularly preferably, the group Y represents a substituted phenyl group of the following partial formula:

Among them, L1 has one of the meanings given to r2G above, preferably F, CM, Br, I, 99336.doc -43- 200540142 CH3 'CF3, 0CH3, 0CF3, methoxycarbonyl, ethoxycarbonyl, CN, amine Base or N02, or Η. The substituent L1 is particularly preferably H, Cl or methoxy. The bridge Z represents a single bond or _CR7aR7b_CR7cR7d, wherein R7a, R7b, R7c, and R each preferably independently represent Η, F, CH3, or CF3. Other preferred meanings of bridge Z are selected from:

Bridge Z is particularly well defined as a single bond and _CH2-CHr. Particularly preferred 2 is a single bond. The preferred meaning of the group A is aryl or heteroaryl. The group A is preferably selected from cyclic phenyl, σ-pyridyl, or naphthyl, which may be mono- or poly-substituted by R20 on one or more C atoms, and may be additionally nitro in the case of a benzene ring. Single replacement. If b has a value of 0, the group a is preferably mono-, di- or tri-substituted. If b has the value 1 ', the group a is preferably unsubstituted or mono- or di-substituted. If b has a value of 1 and the group A is mono-substituted, the substituent is preferably located in the ortho position based on the ketamine group. A is particularly preferably one of the following groups: 99336.doc -44- 200540142

These groups may be mono- or poly-substituted by R20 as specified. A particularly preferred substituent r2g of the group A is selected from the group consisting of fluorine, gas, bromine, cyano, Ci4-alkyl, C2.6-alkenyl, hydroxyl, hydroxy-Cw alkyl, Ci-4-alkoxy, Trifluoromethyl, trifluorofluorenyloxy, C2-4-alkynyl, carboxyl, Cl4-alkoxycarbonyl, Cl-4-carboxy-Cl · 3-alkyl, Ci.4-alkoxy-carbonyl Amine group, amine group, Cn alkyl-amine group, di- (Ck alkyl) -amine group, cyclo_c3-6-alkyleneimine group, amino group Ik group, Ci · 4 · alkyl group-amine And a di- (c14-alkyl) -amino-amino group. Particularly preferred substituents of group A are selected from the group consisting of fluorine, gas, bromine, cyano, C! 4-alkyl, C4-alkoxy, trifluoromethyl, trifluoromethoxy, end Group, Cm-alkoxycarbonyl group, Cw alkyl-amino group and di_ (Cl-4_alkyl group) amino group. In the case where b has a value of 0, the group a is particularly preferably defined as the following partial formula Substituted phenyl:

Wherein L2 has one of the meanings given to R2G or represents Η, preferably f, (: Br, I, CH3, CF3, OCH3, 0CF3, CN or N02, L3 has one of the meanings given to R2G or represents H, Preferred are f, ci, Br, I, CF3, OCF3, CN, N02, Cyalkyl, c3.7-cycloalkyl, r_ ^ 3-7 cycloalkyl-Cw alkyl, Cw alkoxy, Cw cycloalkyl-o, c3 7-cycloalkene 99336.doc -45- 200540142 based -Cu • alkoxy, -COO-Cw alkyl or -COOH; particularly preferred are F, CM, Br, Ck alkyl, CF3, methoxy, 0cf3, CN or N02; particularly preferred is Cl, Br, CF3 or N02; q has a value of 0, 1 or 2, with the proviso that at most phenyl can be mono-substituted by ceryl. A is especially the most Preferably it is a substituted phenyl according to the above partial formula, wherein q represents 1 or 2 and / or at least one substituent 12 is positioned between the substituents L3. A particularly preferred definition of the substituent L2 is C1. Φ Substituent L3 Particularly preferred meanings are C1, methoxy, and CF3. If b = 1, then the group A preferably represents an unsubstituted phenyl group or a substituted group. At the same time, L2 is preferably located in the β-ketoamido group Ortho to the group. L2 is as defined above. If b has a value of 1, then The preferred definition of group B is aryl or heteroaryl, which may be substituted as specified. The preferred definition of group B is selected from phenyl, pyridyl, thienyl, and furyl. Group B is particularly preferred Phenyl. The group B as defined may be mono- or poly-substituted by r20, and phenyl may be additionally mono-substituted by nitro. The group is preferably unsubstituted or mono-, di- or tri-substituted, especially It is unsubstituted or mono- or di-substituted. In the case of mono-substitution, the substituent is preferably located in the ortho or para position of the group eight, especially in the para position. The preferred substituent R 2 of the group B is selected. From fluorine, gas, bromine, cyano, nitro, -Cw alkyl, hydroxy, hydroxyalkyl, alkoxy, trifluorofluorenyl, trifluoromethoxy, Cm-alkynyl, carboxyl, Cl-4 _Alkoxycarbonyl, alkoxy-Cw alkyl, alkoxy_carbonylamino, amine, elf alkyl_amine 99336.doc -46- 200540142, di- (Ci_4_alkyl) -amine, Cyclo-C3-6-Chenylimino, Aminocarbenyl, Cl.4-Chenyl-Amino-Epi and Di- (Cb4-alkyl) -Amino-Epi. Group B A particularly preferred substituent r2G is selected from fluorine, gas, bromine, cyano, cf3, C ^ 3-alkyl, Ck alkoxy, trifluoromethoxy and nitro; especially fluorine, gas, bromine, methoxy, CF3 and trifluoromethoxy. Particularly preferred substitutions of group B The group R2G is selected from the group consisting of gas and methoxy. The following are preferred definitions of other substituents according to the present invention: The substituent R13 preferably has one of the meanings given to R16. R13 particularly preferably represents fluorene, Cw alkyl, c3. 7-cycloalkyl, C3-7-cycloalkyl-Cw alkyl, ω-hydroxy-c2.3-alkyl, oKCV4-alkoxy) -C2_3-alkyl. R13 particularly preferably represents η or Ci-4_alkyl. The above-mentioned alkyl group may be mono-substituted or mono- or poly-substituted by f. The preferred meaning of the substituent R15 is H, Cbc alkyl, C3-7-cycloalkyl, C3_7-cycloalkyl, and as defined above, in each case one or more C atoms can be additionally passed through F Mono- or poly-substitutions and / or in each case one or two C-atoms can additionally be independently independently substituted by C1 or parts. r! 5 particularly preferably represents fluorene, methyl, ethyl, propyl or butyl. The substituent R16 preferably represents H, Cw alkyl, C3 cycloalkyl, C37df alkyl, Cw alkyl, ω_hydroxy_Cy alkyl, or ω · ((: ι · 4_alkoxy) _c2_3_ alkyl At the same time, as defined above, 'in each case, one or more c atoms may be additionally substituted with F mono or poly and / or in each case, one or two c atoms may be additionally independently substituted with C1 or Br each independently. Ri6 Particularly preferably, it represents H, Cn3-alkyl, c3_6_ cycloalkyl, or C3-6 · cycloalkyl-Cl_3_alkyl. The substituent R17 preferably has one of the meanings given to Ri0 as a preferred meaning or represents phenyl or benzene. -Cu-alkyl, η-pyridyl, or (^ 14-alkylcarbonyl. Rn 99336.doc -47- 200540142) especially has one of the meanings given to R16 as a preferred meaning. The substituent R2G preferably represents halogen, Hydroxyl, cyano, Ci4-alkyl, alkenyl, Cw-quick, cycloalkyl, q7 · cycloalkyl_Ci_3-alkyl, cyclyl-Cw-alkyl, R22-Cl_3-alkyl or have as One of the meanings given to Han 22 is better meaning, and as defined above, in each case, one or more C atoms may be additionally substituted by F single or poly and / or in each case, one or two c atoms may be additionally Independently via C1 or Br * is mono-substituted. The R20 group is particularly preferably defined as halogen, hydroxy, cyano, CN4-alkyl, q 7 cycloalkyl and Ck alkoxy, and as defined above, in each case one or more The C atom may be additionally mono- or poly-substituted by F and / or in each case, or two C atoms may each additionally be independently substituted by ^ or mono. R 2 0 particularly preferably represents F, C, Br, I, O. H, cyano, methyl, difluoromethyl, tridenylmethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n Propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl or amine. The substituent R22 preferably represents ^ 4-alkoxy, Ci 4-alkylthio, carboxyl, alkylcarbonyl, ^- 4-alkoxycarbonyl, aminocarbonyl, Ci < alkylaminocarbonyl, di- (cN4-alkyl) _aminocarbonyl, Ci · 4-alkyl-sulfonyl, alkyl_sulfinyl, cN4_alkyl-sulfoamidoamino, amine, alkylamino, di- (Cl · 4-alkyl > amino, Cl-4_alkyl-carbonyl-amino, hydroxy ^^ 3- Alkylaminocarbonyl, aminocarbonyl-amino or C1 ^ alkylaminocarbonyl_amino, as above By definition, in each case, one or more C atoms may be additionally substituted with F mono or poly and / or in each case, one or two C atoms may be additionally independently substituted with C1 or Br. 99336.doc • 48 -200540142 The preferred definition of the group R21 is q-4-alkyl, (^ _4-alkylcarbonyl, Cl-4-alkyl luteinyl, _S〇2-NH2, -SOrNH-C ^ alkyl, _S〇2 -N (Ci-3 · alkyl) 2 and cyclic-C3_6-alkyleneimino-sulfofluorenyl, and as defined above, in each case, one or more c atoms may be additionally subjected to F single or multiple Substitutions and / or in each case one or two C atoms may additionally be independently independently substituted by ci or Br. r21 is particularly preferably H, CN4-alkyl, Ck alkylcarbonyl, Cw alkyloxycarbonyl, especially H & C1-3-alkyl.

Cy preferably represents c ^ 7-cycloalkyl (especially cycloalkyl), Cs-7-cycloalkene >, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , C5-7_cycloalkyl or aza-c: benzene ring, aryl or heteroaryl group condensed by 4 · 7-cycloalkyl, while aryl or heteroaryl group preferably means monocyclic or fused A bicyclic system, and the above cyclic group may be mono- or poly-substituted by R20 on one or more c atoms, and may be additionally mono-substituted by nitro in the case of phenyl, and / or one or more NH groups may be subjected to R21 To replace. The term aryl means preferably phenyl or naphthyl, more preferably phenyl. The term heteroaryl preferably includes alpha-pyridinyl, indolyl, quinolinyl, and amidino. Preferred compounds according to the invention are compounds in which one or more of the groups, radicals, substituents and / or indices have one of the preferred meanings defined above. Particularly preferred compounds according to the invention are their compounds, wherein Υ has one of the following meanings:

99336.doc -49- 200540142

At the same time, the above-mentioned cyclic group may be mono- or poly-substituted by R20 on one or more C atoms, and may be additionally mono-substituted by nitro in the case of a benzene ring, and / or A represents phenyl or aziridinyl, which may be substituted by Mono- or poly-substituted and may also be additionally substituted with a nitro-mono, and / or B represents a phenyl group, which may be mono- or poly-substituted with R2G and may additionally be substituted with a nitro-mono, and / or b has a value of 0 or 1. Particularly preferred compounds are those according to the present invention, wherein A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b each independently have one or more of the above-mentioned preferred meaning. Preferred groups of the compounds according to the invention can be described by the following formula (especially I.a, I.b & Lc):

99336.doc -50- 200540142

r1 \ r2 /

I.h

The bridges X appearing simultaneously in the formulae Ia to Ij that represent -CH2-, -CH2-CH2-, and -CH2-CH2-0- may have one or two each independently selected from Ci-3-alkyl 99336.doc- 51-200540142 and 匸 3-5_cycloalkyl substituents, while two alkyl substituents can be joined together to form (: 3.6-cycloalkyl, especially the above-mentioned bridge X-CH2- especially Preferably, it may have one or two methyl substituents, while the methyl substituents may be joined together to form a cyclopropyl group; and

L1, L2, L3, R1, R2, R3, R5a, R51 R2G are as defined above, and the substituents that appear several times may have the same or different meanings; especially R1 and R2 each independently represent Η, Cw alkyl, C3_7-Cycloalkyl, C3-7-Yamakiroyl-C1 · 3-alkyl, tetrahydroα-chenan-3 or _4_yl, tetrahydroσ-botanyl-C1-3-I Piperidin-3-yl or -4-yl, N-CCw alkyl) -piperidin-3-yl or -4-yl, pyridyl-Cy alkyl, N- (Cn4_alkyl) _piperidine Ci_Cl-3_alkyl, phenyl, 0 to 0 aryl, native thiol-pyridyl, β-pyridyl-C1-3yl, thiol-Cyalkyl, Cyyoxy-C2. 4-Alkyl, Amino-C2_4-Alkyl, Ci-4-Alkyl-Amino-C2 · 4 " · Alkyl or Di_ (c1-4-Alkyl) -Amine-C2-4-A And the ring may be substituted by a group selected from hydroxy, hydroxy-Cl · 3-alkyl, cN3-alkyl, or Ci ^ alkoxy (especially hydroxy, methylol, methyl, and methoxy) Radicals are mono-, di-, or tri-substituted, and define the Φ C2 · 4-alkyl bridge in hydroxy-C2-4-alkyl and Ci · 4-alkoxy-c2_4-alkyl groups, which can be additionally passed through hydroxy, hydroxy-C! —3-alkyl, Cyalkyl or Ci · 3-alkoxy (especially hydroxyl, methylol) , Fluorenyl, or methoxy), and the alkyl group may be mono- or poly-substituted by F and / or mono-substituted by C1; R1 and R2 each independently represent methyl, ethyl, n-propyl, isopropyl, 2 -Hydroxyethyl, 2-Ethyl-propyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 2-methoxyethyl, 3-amino-propyl, acrylic-3 -Yl, propan-3-yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, (1-merylcyclo-propyl) methyl, phenyl, ° Bismethyl, phenylmethyl, η bilylmethyl, tetrahydropyranyl, N-99336.doc -52- 200540142 methyl-piperidin-4-yl, N- (methylcarbonyl) -piperyl Pyridin-4-yl or N- (tertiary butyloxy) -piperidin-4-yl, and the hydroxyalkyl group may be additionally substituted with a hydroxyl group, and one of the groups R1 and R2 may also represent H; or R1 , R2 are joined together so that the group is defined according to one of the following partial formulas:

99336.doc -53- 200540142 At the same time in the heterocyclic ring formed by the group WVN-, one or more η atoms may be replaced by R14 and / or fluorene atoms may be represented by (^^ Cycloalkyl substitution, this may Via R2Q, especially via F, hydroxyl, Cl-3_alkyl,%, Ci 3 ^ oxy, OCF3 or hydroxy_CN3-alkyl, particularly preferably via F, hydroxyl, methyl, methoxy, CF3, OCF3 Or methylol mono- or poly-substituted, and the ring attached to the heterocyclic ring formed by the group may be mono- or poly-substituted by R2G on one or more c atoms (preferably mono-substituted), and in the case of a benzene ring It may also be additionally substituted with nitro in the following. I R3 preferably represents fluorene or methyl, and R independently represents F, Cl, CN4-alkyl, C3-6-cycloalkyl-Cw-alkyl, Hydroxy, hydroxy_Ci 3-alkyl, Ci 4-alkoxy, Ci 4_alkoxy-C! · 3 · alkyl, pyridylamino or aminocarbonyl, and at the same time one or more C Atoms may be additionally mono- or polysubstituted by F or, in each case, c-atoms may be mono-substituted by C1. R14 particularly preferably represents methyl, ethyl, propyl, diIL, methyl, methyl, 1 _Ethyl, 2-Ethyl, 1-Ethyl-1-methyl-ethyl , Methoxy, ethoxy, methoxymethyl, pyridylamino or amine Φ; and 13 R represents H, Cm-alkyl, Cm-alkylcarbonyl or Ci.4-alkoxycarbonyl; especially Good means only or ^^ · alkyl; and Q represents CH or N, especially CH, and CH can be replaced by R20, ^, L · 2, L · 3 each independently have the meaning given to R20 in each case '' Preferably represents fluorine, gas, molybdenum, cyano, C1-3 · alkyl, CI · 3-alkyl, trifluorofluorenyl, trifluorofluorenyl or nitro, and P has a value of 0 or 1 , 99336.doc -54- 200540142 r, s each independently have a value of 0, 1, 2 or 3 under each condition, preferably 0, 1 or 2, most preferably 0 or 1, and Z, R5a, R5b and R20 is as defined above, and the substituents appearing more than once may have the same or different meanings, and in detail, Z represents a single bond or · ΟΗ2-(: Η2-, particularly preferably a single bond, and R5a and R5b each independently represent H, F, C, methyl or ethyl, particularly preferably η, R2G each preferably represents fluorine, chlorine, bromine, cyano, Ck alkyl, C2-6 · alkenyl, hydroxyl, hydroxyalkyl, Ci-4- Alkoxy, trifluorofluorenyl, trifluorofluorenyl, C2-4-alkyne , Carboxyl, Cm-alkoxycarbonyl, Cb4-alkoxy-Cw alkyl, CN4-alkoxy-carbonylamino, amine, Ci-4-alkyl-amino, di- (Ci-4-alkane Group) -amino group, cyclic-C3-6-alkyleneimino group, aminocarbonyl group, Cn alkyl-amino group-carbonyl group and dialkyl group) -amino group-carbonyl group, R2G is particularly preferably selected from fluorine, Gas, Mo, Cyanyl, Shishaki, Ci.4 · Carbonyl, Carbo, ω -Ceryl-Ci-3_carbo, Cy Caroxy, Trifluoromethyl, Trifluoromethoxy, c2_4-Alkyn Group, carboxyl group, Cm-alkoxycarbonyl group and CN4-alkoxyalkyl group. The compounds listed in the experimental part according to the invention are preferred. Some particularly preferred compounds are shown below:

99336.doc -55- 200540142 A.2

A.3 A.4

A.5

A.6

99336.doc • 56- 200540142 A.7

A.8 A.9 A.10

A.11 99336.doc -57- 200540142

99336.doc -58- 200540142

A.18

Certain expressions used above and below to describe compounds according to the invention will now be more fully defined. The term halo means an atom selected from F, Cl, Br and 1 (especially F, C1 and B0. The term Ck alkyl where η has a value of 3 to 8 means a saturated branch having 1 to η C atoms or Unbranched hydrocarbon groups. Examples of such groups include methyl, ethyl, n-inyl, isopropyl, butyl, isobutyl, second butyl, third butyl 99336.doc -59- 200540142, N-pentyl, isopentyl, neopentyl, tertiary pentyl, n-hexyl, isohexyl, etc. where the term Ci may have a value of 1 to § Ci n-alkylene means a saturated component having 1 to 匸 atoms Branched or unbranched hydrocarbon bridges. Examples of such groups include methylene (-CH2-), ethylidene (· 〇 (2-(:) 2-), j • methyl-ethylidene (-CH ( CH3) -CH2-), 1,1-dimethyl-ethyl (-C (CH3) 2-CH2-), n-propane-1,3-yl group (CH2-CH2_CH2-), 1-methyl propane q,% group (-CH (CH3) -CH2-CH2-), 2-methylpropane-1,3 · group (-CH2-CH (CH3)-. CH2 ·), etc. and the corresponding mirror-symmetrical form. The term C2-n-alkenyl in which n has a value of 3 to 6 means a branched or unbranched hydrocarbon group having 2 to n C atoms and at least one C = C double bond. Examples of groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-fluorenyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 5-hexenyl, etc. The term in which η has a value of 3 to 6 (: 2 · η-alkynyl means a branch having 2 to η C atoms Φ and at least one CsC triple bond Unbranched hydrocarbon groups. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, ppentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl , 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. The term Ch-alkoxy refers to a Ck alkyl group, where Ci-rr alkyl is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, 99336.doc -60-200540142 three Butoxy, n-pentyl Group, isopentyloxy, neopentyloxy, tertiarypentyloxy, n-hexyloxy, isohexyloxy, etc. The term Ci-η-alkylthio refers to a C1-n • alkyl-S- group, where Ck Alkyl is as defined above. Examples of such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, second butylthio, third Butylthio, n-pentylthio, isopentylthio, neopentylthio, third pentylthio, n-hexylthio, isohexylthio, and the like. The Ck alkyl group at the surgical edge represents a C1-n-alkyl-C (= 0) group, where the Cbn-.alkyl group is as defined above. Examples of such groups include methylcarbonyl, ethylrodonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, second butylcarbonyl, third butylcarbonyl, n- Amylcarbonyl, isopentyl, neopentylcarbonyl, tertiary pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, and the like. The term C3-n-cycloalkyl means a saturated mono-, bi-, tri- or spiro carbocyclic (preferably a monocarbocyclic) group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, modified dodecyl, bicyclo [3 · 2 · 1] octyl Base, spiro [4.5] decyl, protofluorenyl, probornyl, probosyl, adamantine, etc. The term C5-n-cycloalkenyl refers to a monounsaturated mono-, bi-, tri- or spiro carbocyclic group having 5 to 11 c atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and the like. Δδ (3 · η-cycloalkylcarbonyl means a cycloalkyl_c (= 〇) group, where C3-n-cycloalkyl is as defined above. The term aryl means carbocyclic, aromatic ring system , Such as phenyl, biphenyl, 99336.doc -61-200540142 naphthyl, anthracenyl, phenanthryl, fluorenyl, indenyl, fluorenylcyclopentadienyl, benzyl, biphenyl, etc. " One of the most preferred meanings is phenyl. The term cycloalkyleneimine refers to a 4- to 7-membered ring containing 3 to 7 methylene units and an imine group, and is connected to the A bond on the residue of a molecule. The term ring-C3-7-alkyleneimino-carbonyl refers to a ring-C3-7-alkyleneimine as defined above which is bonded to the carbonyl via an imine bond. Basic ring. The term heteroaryl as used in this application means a heterocyclic, aromatic ring system containing one or more heteroatoms selected from N, 0 and / or s in addition to at least one C atom. Examples of such groups are furyl, phenylthio, pyrrolyl, ° oxalyl, fluorenyl 11, miso, isoamyl, isoamyl. Phenyl, ι, 2,3_triazolyl , 1,3,5-triazolyl, piperanyl Pyridyl, daphrazinyl, mouth-biting group, 0 specific group, 1,2,3-trisyl group, 1,2,4-trisyl group, 1,3,5-trisyl group, 1,2, 3 · oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, glutamate, 1,2,3 · thiadiazolyl, 1,2 , 4 · thiadiazolyl, 1,2,5-thiadiazolyl, 丨,% 'thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuran Benzylthiophene (thienylmethyl), indazolyl, benzodiazepine, benzodiazolyl, phenylisothiazolyl, benzoxazolyl, phenylisosialyl, purine , Quinobetaine, quinolinyl, linolinyl, quinolinyl, isoquinolinyl, oxolinyl, 4-pyridyl, pyridinyl, carbazolyl, azyl, diazyl, oxalidine Radicals, etc. The term heteroaryl also includes partially hydrogenated heterocyclic, aromatic ring systems, especially those listed above. An example of such partially hydrogenated ring systems is 2,3-dihydrobenzofuran Group, ° than pyrrolinyl, oxazoline, called 丨, dolynyl, oxazolyl, oxazoline, oxazolyl, etc. Heteroaryl is particularly preferred Aromatic 99336.doc -62- 200540142 Group of mono- or bicyclic systems. Such as ο: 3 ·? · Cycloalkyl-Ck alkyl, aryl_Cl-n_alkyl, heteroaryl_Ci n-alkyl, etc. The term refers to Ci n_alkyl as defined above, which may be substituted by C 3 7_cycloalkyl, aryl or heteroaryl. Many of the terms given above can be used repeatedly in the definition of formula or group 'And in each case each independently has one of the meanings given above. In particular, the term used in the definition of the group Cy, "unsaturated" (for example, "unsaturated carbocyclyl" or "unsaturated" Saturated heterocyclyl " In addition to mono- or polyunsaturated groups, it also contains corresponding fully unsaturated groups, but especially mono- and di-unsaturated groups. The expression used in this application, as appropriate, is substituted "means that the group so designated is unsubstituted or mono- or poly-substituted with the specified substituent. If the group in question is poly-substituted, the substituent may be The same or different. Unless stated otherwise, the patterns used above and below indicate that this substituent can be bonded to any vacant position of a cyclic group carrying a 2 ^ atom, and according to these types, the substituents in the cyclic group are shown. The bond system faces the center of this ring base.

When ss = 1, the substituent may be bonded to any vacant position of the benzene ring with 20; when S = 2, the selected substituent r2 may be differently bonded to different vacant positions of the benzene ring. In any case, the H atom of the carboxyl group or the fluorene atom bonded to the N atom (imino or amine) can be replaced by a group capable of breaking in vivo. 99336.doc -63-200540142 Groups which can be cleaved from an N atom in vivo mean, for example, a hydroxyl group, a fluorenyl group (such as benzyl or pyridino), or a Cmc alkyl group (such as formamyl, acetamyl, Propionyl, butyryl, pentyl, or hexyl), allyloxycarbonyl, alkoxycarbonyl (such as methyloxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy Ik, second butyl Oxoyl, pentyloxy, hexanoxyl, octyloxycarbonyl, nonoxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxy or hexadecyloxy), phenyl- Cn oxyalkyl (such as benzyloxycarbyl, phenylethoxycarbonyl, or phenylpropoxycarbonyl), C1-3-alkylsulfonyloxyalkyl, C ^ -alkoxy-C2 -4_alkoxy-C2 · 4-alkoxycarbonyl or ReC0-0- (RfCRg) -0-C0 · groups, where

Re represents Cn alkyl, C5-7 · cycloalkyl, phenyl or phenyl_Cl3-alkyl,

Rf represents a gas atom, Ci · 3 · carbon, and C5. -Cycloalkyl or phenyl, and

Rg represents an argon atom or a Ci-3-alkyl group, while an imine group is an additional possible amine group, and the above-mentioned ester group can also be used as a group which can be converted into a carboxyl group in vivo. The residues and substituents described above may be mono- or polysubstituted with fluorine as described. The better fluorinated radicals are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred gasified alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. The preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and triIIonylfluorenyl. The compounds of the general formula I according to the invention may have acid groups (mainly retarding groups) and / or base groups (such as amine functional groups). Compounds of general formula I can therefore exist as the following salts: internal salts; and inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid) or organic acids (such as maleic acid, fumaric acid) that can be used pharmaceutically , 99336.doc -64- 200540142 salts of citric acid, tartaric acid or acetic acid; or with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc hydroxide or ammonium hydroxide or organic Salts of amines (especially diethylamine, triethylamine, triethanolamine). The compounds according to the invention can be obtained using synthetic methods known in principle. Preferably, a delta-Hydrochemical compound can be prepared similar to the preparation method described more fully below, and the $ Hydro-chemical method is also an object of the present invention. The abbreviations used below are defined in the introduction to the experimental section, or they are already familiar to those skilled in the art. The starting materials or intermediates listed below on the right contain R1, R2, R3, X, Y, Z, A, or B with amine functional groups. It is preferred to use, for example, a Boc, Fmoc or Cbz protecting group. In a protected form and released at the end of the reaction using standard methods. Synthesis Plan A:

R3 R5a R5b According to the synthesis plan A, the amine of formula A1 is reacted with the carboxylic acid or carboxylic acid derivative of formula A2 by using the amine synthesis method known in the art to obtain the root 99336.doc -65- 200540142 Invention compounds of formula I. In the carboxylic acid derivative A2, the group M preferably has a meaning selected from the group consisting of OH, Cb Cw alkoxy, CN6-alkylthio, Cw alkyl-COO, and the like. The retarded acid compound of formula A2 (M == OH) is preferably reacted with at least one peptide coupling reagent such as TBTU in a solvent or solvent mixture, and then the reaction mixture is further reacted with the amine compound of formula A1, while the acid compound is A minimum amount of one assay was added to the reaction mixture before and / or after reaction with TBTU. Advantageously, peptide coupling reagents such as TBTU are used in equal molar amounts or in excess relative to carboxylic acid A2, preferably from > equal molar to 50 mol% excess. Alternatively, the reaction can be carried out in the presence of an amount of HOBt such as TBTU. Advantageously, the carboxylic acid of formula A2 and TBTU are used and then the acid compound of formula A2 of 1 ± 0 · 25: 1 ± 0.25: 1 ± 0.25: 1 to 4: amine compound of formula A1: TBTU: test Morby uses this reaction mixture with an amine compound of formula A1. It is also possible to use corresponding active carboxylic acid derivatives such as esters, orthoesters, bitrates or anhydrides without using carboxylic acids. Yang Luzhi ’s suitable test is a third amine such as ethylamine or Junin test and a metal test such as potassium carbonate. The reaction takes place in a suitable solvent or solvent mixture, while DMF and / or THF are preferably used. A carboxylic acid or a carboxylic acid derivative (A2) and an amine (A 1) having a molar ratio of L5: 1 to 1: 1 · 5 are preferably used. The reaction is advantageously carried out at a temperature range of 120 ° C (preferably 20 ° C to 80 °) for 1 to 24 hours. If it is necessary to start the carboxylic acid compound A2 (M = OH), it can be advantageously achieved using a mixed anhydride For this purpose, it is preferred to prepare the carboxylic acid in question by reacting an enemy acid having a molar ratio of 丨: 丨 to 1: 丨 · 2 with an excess of alkyl pivalate (preferably isopropyl pivalate). Mixed anhydride of A2. A suitable base is preferably a tertiary amine such as N • fluorenyl 99336.doc -66- 200540142 morpholine, which is used in a molar amount of the alkyl formate in question. The reaction is carried out in a suitable solvent such as THF at a temperature between ° C and 20 ° C (especially -15 to 0 ° C), and the reaction occurs for 10 to 2400 minutes. Preferably, 纟 1 is further purified and The mixed liver thus obtained is reacted with the amine compound '(A1). An amine compound (A1) is used in excess (preferably 5-10 mol% excess) relative to the carboxylic acid derivative (A2) in question. For example, at 0 ° The reaction is carried out at C to 60 ° C for 1 to 4 hours. Synthesis plan B1: R1 \ 〇⑩ R] NX- 丫-Z, person ^^ A ~ f B] b B1 R3: 2Vx—Y_Z person and A.] b, R3 or According to the synthetic plan B1, the compound of the formula I according to the invention can be obtained by hydrolyzing the three φ bond of the propynyl amidoamine of formula B1. The propyne can be carried out by adding an acid or a base and optionally in the presence of an activated nucleophile. Hydrolysis of ammonium acid to form the corresponding β-ketoamidine. The acids suitable for this purpose are especially strong inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, formic acid, oxalic acid, methanesulfonic acid or trifluoromethanesulfonate / Suitable bases are in particular alkali metal hydroxides, carbonates or acetates, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium acetate or potassium carbonate, or such as triethylamine, piperidine, morpholine, Diisopropylethylamine or an aqueous solution of the second or third amine of diethylamine. 99336.doc -67- 200540142 Advantageously, a molar excess of acid or base is used compared to the propargylamine. Details Examples of suitable activation nucleophiles include secondary amines such as triphenylene, morphine, or diethylamine, or thiols such as ethyl mercaptan or benzyl, or phosphines such as triphenylphosphine or tributylphosphine. Ground, at a temperature between 20 and 1201 (preferably in the range of the solvent fortunate temperature) at Suitable solvents or solvent mixtures (possibly in alcohols such as ethanol or acetone, dimethylformamide, trimethylene acetonitrile towels) for reaction, adding a small amount of water in each case, preferably using a solvent Volume meter

Less than or equal to 10% by volume of water. A suitable reaction time is usually in the range of i to 24 hours. Synthesis Plan B2:

Ο HO

Jb B3 R \, 3

/ N—X—Y——Z—N

R2 / 、 H B2

R \

R 2 / N—X—Y-Z N—C-C ~ —C—A-

Jb B1 in the presence of a base such as triethylamine and an activator such as CDI, TBTU, or DCC, in an organic solvent such as DM, TI, dioxane, acetonitrile, or toluene by combining an amine compound of the general formula B2 with The propyne acid compound of formula B3 is reacted to obtain a compound of formula B1. It is also possible to use a carboxylic acid gaseous compound or mixed anhydride of compound B3 without using compound B3. Here, the amidine bonding process described in relation to the synthetic meter A can also be used. 99336.doc -68- 200540142 Synthesis Project B3:

Br

B3 at a temperature of 0 ° C to 150 ° C, such as two. Compounds of general formula B3 can also be prepared by reacting a compound of general formula B5 with a base such as potassium second butoxide, sodium hydroxide or sodium ethoxide in an organic solvent of smolder, ethanol or thf (with or without water). . However, it is also possible for this reaction to be zero. 〇 to 15〇. A compound of the general formula B5 is reacted with pyridine or quinoline at a temperature of 0 °. The general formula B is obtained by brominating a compound of the general formula B4 at a temperature of _2 (rc to 100 C (preferably between 0 ° C and ambient temperature) in a solvent such as tetracarbonized carbon Compounds of 5. For example, the compounds described in the present invention can also be advantageously obtained by the methods described in the following examples, and these methods can also be combined with methods known to those skilled in the literature. They can be separated mainly by conventional methods. A stereoisomeric compound of formula 。. Separation of diastereomers based on their different physico-chemical properties, such as by stepwise crystallization from a suitable solvent, by the use of a palm or preferably non-palm stationary phase Pressurized liquid or column chromatography. For example, 'The chromosomes covered by the general formula 分离 can be separated by HPLC on a suitable palm stationary phase (for example, Chiral AGP, Chiralpak AD). Alternatively, non-99336.doc- 69- 200540142 Enantiomeric optically active salts separate racemates containing basic or acidic functional groups. These active salts are used in conjunction with optically active acids (such as (+) or tartaric acid, (+), or (-) • Diethyl tartaric acid, (+) or (-) _ monomethyl tartaric acid +) _ Camphorsulfonic acid) or optically active base (such as (R)-(+)-l-phenylethylamine, (SH + i · phenylethylamine, or (s) · March's test)) According to the conventional method for separating isomers, a racemate of the compound of the general formula ⑴ is reacted with an equivalent amount of one of the above-mentioned optically active acids or bases in a solvent ', and the obtained crystals are separated by their different solubility. Enantiomers | Optically active salts. This reaction can be carried out in any type of solvent, with the limitation that the solubility of the salts is sufficiently different. Methanol, ethanol or (for example) a volume ratio of 50:50 is preferred The mixture is then dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate or with a suitable acid (for example, dilute hydrochloric acid or aqueous methanesulfonic acid), and the corresponding ( +) Or ㈠ form of the free compound. A single (R) or (S) enantiomer or general formula can also be obtained by carrying out the above synthesis with a suitable (R) or (S) configured reaction component. A mixture of the two optically active diastereomeric compounds covered. As stated The compounds of formula (I) can be converted into their salts, in particular into their physiologically and pharmacologically acceptable salts for medical use. On the one hand these salts can be used as additions with inorganic or organic acids Physiologically and pharmacologically acceptable acid addition salts of compounds of formula ⑴ exist. In addition, under the condition of acidic hydrogen bonding, compounds of formula 亦可 can also be converted into alkali metals or Alkaline earth metal cations as physiologically and musically acceptable salts of counter ions. For example, using hydrochloric acid, nitrous acid, sulfuric acid, 99336.doc -70- 200540142 phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid , Benzenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid can be used to prepare acid addition salts. In addition, a mixture of the aforementioned acids may be used. In order to prepare alkali metal and alkaline earth metal salts of compounds of formula (I) with acidic bonding hydrogen, it is preferred to use metal and earth metal hydroxides and hydrides, as well as metal (especially sodium and potassium) hydrogen. Oxides and hydrides are preferred, and sodium hydroxide and hydroxide are the best. The compounds according to the invention, including physiologically acceptable salts, are effective as antagonists of MCH receptors (especially MCH-1 receptors) and exhibit good affinity in MCH receptor binding studies. A pharmacological test system for MCH-antagonistic properties is described in the following experimental section. As antagonists of MCH receptors, the compounds according to the invention are advantageously suitable as medicinal active substances for the prevention and / or treatment of symptoms and / or diseases caused by MCH or causally linked to MCH in some other way. In general, the compounds according to the present invention are low in toxicity, can be well absorbed via the oral route and have good intra-brain transmission, especially brain accessibility. Therefore, Mch antagonists containing at least one compound according to the invention are particularly suitable for treating and / or preventing mammals (e.g. rats, mice, guinea pigs, rabbit dogs, book fields, sheep, horses, pigs, cattle, monkeys and Human) symptoms and / or diseases caused by mcih or causally linked to MCH. Diseases caused by or associated with MCH are particularly metabolic disorders such as obesity and eating disorders such as bulimia (including bulimia nervosa). Indicative obesity includes exogenous obesity, hyperinsulinic obesity, proliferative obesity, high growth obesity, dysplastic obesity 99336.doc -71-200540142, hypothyroidism obesity, lower vision Mound obesity, symptomatic obesity, infant obesity, upper body obesity, diet obesity, hypogonadal obesity, trunk obesity. The scope of this indicator also includes cachexia, anorexia and bulimia. The compounds according to the invention may be particularly suitable for reducing hunger, suppressing appetite, controlling eating behaviors and / or inducing satiety. In addition, diseases caused by or associated with MCH also include hyperlipidemia, cellulitis, fat accumulation, mast cell hyperplasia, pancreatic mastocytosis, mood disorders, emotional disorders, depression , Anxiety, reproductive disorders, sexual dysfunction, memory disorders, epilepsy, various forms of dementia and hormonal disorders. The compounds according to the invention are also suitable as active substances for the prevention and / or treatment of other diseases and / or disorders, which are especially associated with obesity, such as diabetes (diabetes mellitus ), Especially type II diabetes), hyperglycemia (especially chronic hyperglycemia), diabetic episodes (including diabetic retinopathy, diabetic nephropathy, diabetic nephropathy, etc.), insulin resistance, glucose Abnormal tolerance, cerebral hemorrhage, insufficient cardiac function, cardiovascular disease (especially arteriosclerosis and hypertension), arthritis and knee arthritis. Advantageously, the MCH antagonists and formulations according to the invention can be used in combination with dietary therapy (e.g. dietary diabetes therapy) and exercise. Another range of indications to which compounds according to the invention are advantageously suitable is the prevention and / or treatment of dysuria such as urinary incontinence, frequent urination, urgency, nocturia, and enuresis, with or without urinary frequency and urgency Fat 99336.doc -72- 200540142 related. In general ' The compounds according to the invention are potentially suitable for the prevention and / or treatment of dependence symptoms such as alcohol and / or nicotine dependence and / or withdrawal symptoms such as weight gain in smokers who leave nicotine. "Dependence" here generally means an irresistible desire to ingest addictive substances and / or to perform certain actions, especially to achieve pleasure or eliminate negative emotions. In detail, the term " dependence " as used herein means dependence on an addictive substance. &Quot; Withdrawal symptoms π here generally means that when an addictive substance is self-dependent on one or more of these substances. Symptoms that occur or may occur in patients withdrawing. The compounds according to the present invention are potentially particularly suitable as reducing or stopping tobacco consumption, treating or preventing nicotine dependence and / or treating or preventing symptoms of nicotine withdrawal, reducing Tobacco and / or desired active substance and generally used as a smoking cessation agent. The compounds according to the invention are also suitable for preventing or at least reducing the weight gain that smokers usually see when they leave nicotine. These substances are also Active substances suitable for preventing or at least reducing the craving for addictive substances and / or dependence on the re-establishment of addictive substances. The term addictive substances refers in particular but not exclusively to substances with psychomotor activity , Such as narcotics or drugs, especially alcohol, test, cocaine, amphetamine, opiates, benzodiazepine, and barbiturate. Achieve The required dose for the effect is suitably 0.001 to 30 mg / kg body weight (preferably 0.01 to 5 mg / kg body weight) in the intravenous or subcutaneous route and suitably 0.01 in the oral or nasal route or by inhalation. To 50 mg / kg body weight (preferably from 0.1 to 30 mg / kg body weight), 1 to 3 times a day in each case. To this end, as appropriate, in combination with other active substances described above and a 99336. doc-73- 200540142 or more inert conventional carriers and / or diluents can be formulated with compounds of formula I prepared according to the present invention, such carriers and / or diluents are, for example, corn starch, lactose, glucose, microcrystalline fiber Vegetarian, magnesium stearate, polyethylene bite ketone, citric acid, tartaric acid, peel, Shi / r ^ ^ ^ shuishui / Ethiopia, water / glycerin, water / sorbitol, water // alcohol Alcohol, hexadecyl stearyl alcohol, dimethylcellulose, or a fatty substance such as meniscus or a suitable mixture thereof to produce a conventional galenic preparatin, such as a common or coated spin Agent, capsule, mouth

Lotion, powder, granule, solution, emulsion, syrup, inhalable aerosol, ointment or suppository. In addition to the pharmaceutical composition, the present invention also includes a composition containing at least one amidine compound according to the present invention and / or a salt according to the present invention optionally with one or more physiologically acceptable excipients. These compositions can also be, for example, solid or liquid foods in which the compounds according to the invention are incorporated. The above combinations may be used as additional actives f, especially for them to enhance the therapeutic effect of the MCH antagonists according to the present invention on the above indications and / or to make it possible to reduce the dosage of the anti-adhesive agents according to the present invention. Active substance. One or more additional active substances are preferably selected from:-active substances for the treatment of diabetes,-active substances for the treatment of diarrhea,-active substances f for the treatment of silk obesity, preferably different from mch antagonists,- Active substance for treating hypertension,-Active substance for treating hyperlipidemia (including arteriosclerosis),-Active substance for treating dyslipidemia (including arteriosclerosis), Active substance for treating arthritis 99336.doc -74- 200540142-Treating anxiety Active substance,-active substance for treating depression. The above-mentioned classes of active substances will now be explained in more detail by means of examples. Examples of active substances for the treatment of diabetes are tensilin sensitizers, insulin secretion accelerators, dual veins, insulin, α-glucosidase inhibitors, β 3 adrenal receptor agonists. Tensilin sensitizers include glitazone, especially pioglitazone and its salts (preferably hydrochloride), troglitazone I (troglitazone), rosiglitazone ( rosiglitazone) and its salts (preferably maleate), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702 And GW-1929. Insulin secretion accelerators include sulfonylurea such as tolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramide, and Its recorded salt, glibenclamide (glibenclamide), gliclazide (gliclazide), glimepiride (glimepiride). Other examples of insulin secretion acceleration agents are repaglinide, nateglinide, mitiglinide (KAD-1229), and JTT-608. Double veins include metformin, buformin, and phenformin. Insulin includes insulin obtained from animals, especially cattle or pigs, semi-synthetic human insulin obtained by enzymatic synthesis of insulin obtained from animals, and human insulin obtained by genetic engineering (such as from E. coli or yeast). In addition, the term insulin also includes insulin-terms (containing 0.45 to 0.9% by weight zinc) and 99336.doc • 75- 200540142 protamine-tengdaosu-terms available from zinc chloride, protamine sulfate and insulin. . It can also be obtained from the Tengdaosu fragment or its derivative (such as ins_D. For another example, in terms of the onset time and duration of the effect, insulin can also include different categories ("super-immediate action", "immediate action" "Interaction type", ", two-stage type,", "moderate type", "delayed type, etc.", depending on the pathological condition of the patient, select its type. Alpha-glucosidase inhibitors include acarbose (acarb 〇se), voglibose _ (voglibose), miglitol (migiitol), eglitazone (emiglita ⑷. Β3 adrenal receptor agonists include AJ-9677, BMS-196085, SB_226552, AZ40140. Different Active substances for the treatment of diabetes in the above substances include ergoset, pramlinide, leptin, BAY-27-9955, and liver glucosidase inhibitors, sorbitol dehydrogenase Inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide. # Active substances for the treatment of diabetic dysfunction include, for example, aldose reductase Inhibitor, Glycation inhibitors and protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-2 analogs, and SGLT-2 inhibitors. Glucose reductase inhibitors are, for example, tolrestat, etor Papalrestat, mirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201. Among the inhibitors of glycosylation An example is pimagedine. Protein kinase C inhibitors are, for example, NGF, LY-33353 1. 99336.doc -76- 200540142 DPPIV blockers are, for example, LAF237 (Novartis), MK43 1 (Merck), and 815541, 823093, and 825964 (all GlaxoSmithkline). GLP-1 analogs are, for example, Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin). SGLT-2 Formulations are, for example, AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson).

Active substances different from the above active substances for the treatment of diarrhea include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, twenty Ethyl eicosapentate, memantine, pimagine (ALT-711). Active substances which are preferably different from MCH antagonists for treating obesity include lipase inhibitors and anorectics. One preferred example of a lipase inhibitor is orlistat. Examples of preferred anorectics are phentermine, mazindol, fluoxetine, fluoxetine, sibutramine, baiamine, (S) , SR-141716, NGD-95-1. Active substances other than those mentioned above for treating obesity include lipstatin. In addition, for the purposes of this application, the active substance group of anti-obesity active substances also includes anorectics, which should be emphasized β3 agonist, pseudo-glandular active substance and NPZ antagonist. Can be regarded as a better anti-obesity or reduced diet 99336.doc -77- 200540142 The range of substances to be active is illustrated by way of example by the following additional list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, stimulant Cholecystokinin-A (hereinafter referred to as CCK-A) agonist, monoamine reuptake inhibitor (such as nometin), sympathomimetic active substance, serotonergic active substance (such as dexfenfluramine, fluorine Fenfluramine, 5-HT2C agonists such as BVT.933 or APD3 56, dopamine antagonists (such as bromocriptine or pramipexol), melanocyte hormone-stimulating hormone Agents or analogs, melanocyte-like hormone analogs, cannabinoid receptor antagonists (Rimonabant, ACOMPLIA TM), MCH antagonists, OB protein (hereinafter referred to as leptin), leptin Analogs, fatty acid synthase (FAS) antagonists, leptin receptor agonists, galanine antagonists, GI lipase inhibitors or reducing agents (such as make you cool). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, and urotensin ( ixrocortin) binding protein antagonists, agonists of the glucagon-like peptide-1 receptor (such as exendin, AC 2993, φ CJC-1131, ZP10 or GRT0203Y), DPPIV inhibitors, and ciliary neurotrophy Factors (such as axokine). In this context, mention should be made of therapeutic forms for weight loss by increasing fatty acid oxidation in peripheral tissues, such as inhibitors of acetyl-CoA rebelase. Active substances for treating hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, and angiotensin II antagonists. Angiotensin-converting enzyme inhibitors include captopril, enalapril, alacpril, delapril 99336.doc -78- 200540142 (delapril) (hydrochloride ), IisinopHl, imidapril, benazepril, cilazapril, temocapril, trandolapril, Manidipine (hydrochloride). Examples of gadolinium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.

Unloading channel openers include levcromakalim, L-27152, AL0671, and NIP-121. Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177. Active substances for the treatment of hyperlipidemia (including arteriosclerosis) include HMG-CoA reductase inhibitors and cellulosic compounds. HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, furvastatin, fluvastatin, and rifastatin Lipantil, cerivastatin, ivavastatin, itavastatin, ZD-4522 and their salts. Cellulate compounds include bezaHbrate, clinofibrate, clofibrate and simflbrate. Active substances for treating dyslipidemia (including arteriosclerosis) include, for example, drugs that increase the content of HDL, such as niacin and its derivatives and preparations such as niaspan, and agonists at acid receptors. 99336.doc -79- 200540142 Active substances for treating arthritis include NSAIDs (non-steroidal anti-inflammatory drugs), especially COX2 inhibitors, such as meloxicam or ibuprofen. 〇Activities for treating anxiety Substances include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, diazepam Lorazepam, alprazolam, fludiazepam 〇 | Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine ), Paroxetine, sertraline. The dosage of these active substances is suitably 1/5 of the minimum normal recommended dose to 1/1 of the normal recommended dose. In another embodiment, the invention also relates to the use of at least one amidine compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal. This use is based in particular on the fact that the compounds according to the invention can be suitable for reducing hunger, suppressing food punishment, controlling eating behaviors and / or inducing satiety. Beneficially affects eating behavior to reduce food intake. Therefore, the compounds according to the invention are advantageously used for weight loss. Another use according to the invention is to prevent, for example, gaining weight in people who have previously sought to lose weight and are interested in maintaining their lower weight. According to this embodiment, it is preferably non-therapeutic. This non-therapeutic use can be cosmetic (for example to change appearance) or to improve overall health. The compounds according to the invention are preferably used non-therapeuticly for non-diagnosed eating disorders, obesity, bulimia, diabetes and / or undiagnosed urination without diagnosis of 99336.doc -80- 200540142. Mammals (especially humans) of disorders (especially urinary incontinence). Preferably, the compound according to the invention is suitable for non-therapeutic use in a population whose BMI (Body Mass Index) is below 30, especially below 25. BMI is calculated by dividing its weight in kilograms by its height (In meters). The following examples are provided to illustrate the present invention ... Introduction Example 'The IR, ih_NMr and / or mass spectrum of the compound prepared have been obtained. Unless otherwise stated, Rf values were determined using a ready-made silicone 60 TLC disk F254 (E. Merck, Darmstadt, article number 1.05714) without chamber saturation. Use off-the-shelf alumina 60 TLC disc F254 (E.

Merck, Darmstadt, article number 1.05713) determined the Rf value obtained under the previous Alox. The ratio specified for the eluent is based on the unit volume of the solvent in question. The unit volume specified under NH3 conditions is related to a concentrated solution of NH3 in water. Chromatographic purification was performed using stone gum manufactured by Messrs Millipore (MATREXrM, 35-70 my). Chromatographic purification was performed using Alcox (E. Merck, φ Darmstadt, standardized alumina 90, 63-200 μm, article number: 1.01097.9050). When the Rf value is given, the following abbreviations are used below for the eluent mixture: (A): Silicone, Dioxane / Methanol / Ammonia (9: 1: 0.01) (B): Silicone, Digas, Methane / Methanol / Ammonia ( 5 = 1: 0.01) (C): Silicone, Digasmethane / Methanol (9: 1) (D): Silicone, Digasmethane / Methanol / Ammonia (9: 1: 0.1) (E): Alumina, Dioxane / methanol (30: 1) 99336.doc -81-200540142 Without specific information on configuration, it is not clear whether pure enantiomers exist or whether some or even all racemates have occurred effect. The following abbreviations are used above and below. Abs. Anhydrous

Cbz benzyloxycarbonyl DMF N, N-dimethylformamide EII electron impact ionization ether ether

EtOAc ethyl acetate

EtOH ethanol

Fmoc 9-fluorenylmethoxycarbonyl

MeOH methanol

Ph Phenyl RT Ambient temperature TBTU 2_ (1H_Benzamidinetriazol-1-yl) -1,1,3,3-tetramethylurea rust-tetrafluoroborate THF tetrahydrofuran Preparation of starting compounds: Example 1.1 3-Biphenyl-4_yl_3-oxo-propionic acid

14.7 g (75.0 mmol) of 4-ethylfluorenyl-biphenyl was dissolved in 150 ml of di 99336.doc -82- 200540142 ethyl ester. A total of 6.50 g (150 mmol) of sodium hydride (55%) was added to the oil in batches at 0 ° C in a protective gas. Mix the mixture at 0. It was kept at 0 ° C for 5 minutes, and then stirred at 80 ° C for 2 hours. After cooling, the mixture was poured onto water, extracted with dichloromethane ', the organic phase was washed with water and finally dried over sodium sulfate. The solvent was removed, and the residue was suspended in water and neutralized with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl bond, the organic phase was dried over sodium sulfate and finally the solvent was removed. The residue was finally recrystallized from petroleum ether and the product was dried in vacuo at 50 ° C. Yield: 15.3 g (76% of theory),

Rf value: 0.60 (silicone, petroleum ether / ethyl acetate = 5: 2) M · ρ · 75-77. .

Ci7H16〇3 EII mass spectrum: m / z = 269 [M + H] + Example 11 · 1 3 · (4'_chloro-biphenyl) -3-oxo-propionic acid ethyl ester

4.29 g (32.5 mmol) of monoethyl malonate were dissolved in 100% tetrahydrofuran and 42.3 ml (67.7 mmol) of butyllithium solution was added dropwise at -60 ° C. 6 N in hexanes). The temperature was brought to -15 ° C, and then the mixture was cooled to -65 ° C again, and 3.40 g (13.5 gas-biphenyl-4-carboxylic acid gaseous substance in 30 ml of tetrahydrofuran was added dropwise (see Gazz. Chim. Ital. 1949, 79, 453 ·). The mixture was kept at -65 ° C for 5 minutes, and then heated for 2 hours to ambient temperature. The mixture was poured onto 50 ml of 1 N hydrochloric acid at 300 99336.doc -83 -200540142 ml Ethane extraction 'Wash the organic phase with saturated sodium bicarbonate solution and water, and finally dry over sodium sulfate. Remove the solvent, recrystallize the residue from petroleum ether and dry the product in vacuum. Yield: 3.10 g (theoretical value) 76%),

Rf value: 0.60 (silicone, petroleum ether / ethyl acetate = 5: 2)

Mp 45-50〇C C17H15CIO3 EII mass spectrum · m / z = 303/305 [M + H] + • The following compounds can also be synthesized similar to the above method: (II · 2) 3- (3-Ga-Biphenyl_ 4-yl) _3 • oxo · ethyl propionate (III · 3) 3 · (4-methoxyphenyl) _3_oxo-ethyl propionate Example III.1 3-Ga-4- [2 · (4_methyl · piperidin-1-yl) _ethoxy] -aniline

Ill.la 4- (2-Bromo-ethylfluorenyl) -3-qi-sonylbenzene Dissolve 36.6 ml (416 mmol) of 1,2-dibromoethyl in 200 ml of DMF, and add 11.5 g (83.3 mmol) potassium carbonate. 7.20 g (41.6 111111〇1) of 2-qi_4-nitro-pan in 40 ml of DMF was slowly added dropwise to this mixture. The mixture was stirred at ambient temperature for 3 hours. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with a saturated saline solution. The organic phase was dried over sodium sulfate. The solvent was removed and the residue was purified via a silica gel column with a petroleum ether / ethyl acetate gradient (4: 1 to 99336.doc -84- 200540142 9: 1). Yield: 7.9 g (68% of theory),

Rf value: 0.55 (silicone, petroleum ether / ethyl acetate = 3: 1) C8H7BrClN03 111.1. B 3 · Ga-4- [2- (4-methyl-piperidin-1-yl) · ethoxy] · Nitrobenzene dissolved 7.80 g (27.8 mmol) of 4- (2 · bromo-ethoxy) _3 · qi · nitrobenzene (Ill.la) and 10.1 ml (84.0 mmol) of 4-methyl-triple in 1 〇ml dichloromethane, and stirred at ambient temperature for 12 hours. The mixture was then filtered through 400 g of alumina (activity 2-3) using digas methane / methanol 49: 1 as the eluent. Yield: 6.9 g (83% of theory),

Rf value: 0.50 (alumina, petroleum ether / ethyl acetate = 3: 1) Mass spectrum of C14H19CIN2O3 EII: m / z = 299/301 [M + H] + 111.1. C 3- 氱 _4_ 丨 2- (4 -Methyl- brigade-1 · yl) _ethoxyb aniline # 6.90 g (23.1 mmol) of 3-Ga-4 · [2- (4-methyl-piperidin-1-yl) -ethoxy -Yl] benzene (Ill.lb) is dissolved in 100 ml of tetrahydrofuran, and at a pressure of 20 pSi at ambient temperature, hydrogen and 30 g of raney * nickel as a catalyst Hydrogenated for 8 hours. The catalyst was then filtered off, the solvent was removed, and the residue was purified via a silica gel column using a two-gas methane / methanol gradient (33. · 1 to 9 ·· 1) as the eluent. Yield · 3.66 g (59% of theory),

Rf value: 0.50 (silicone, methane / methanol = 9: 1) 99336.doc -85- 200540142 c14h21cin2o

Eli mass spectrum: m / z = 269/271 [M + H] + The following compounds can also be synthesized similar to the method described above: ) -Ethoxy] -3-methoxy-aniline (III III) 4- [2- (4-methyl-piperidine-1 · yl) -ethoxymethoxy-aniline (III 4) 3 · Ga-4- [2- (morpholin-4-yl) -ethoxy] -aniline (111.5) 3-Ga-4- [2_ (N-methyl-cyclopropylmethylamino) ) _Ethoxybenzidine

(111.6) 3-Ga-4- [2- (4-methoxy · piperidin-1-yl) · ethoxy] -aniline (111.7) 3-Ga-4- [2- (4-methyl -Piperazin-1-yl) -ethoxy] _aniline (111.8) 3 -random 4- [2- (4- (Cyclo-bromo-1 -yl) -ethoxylactyl] -Examples of this amine IV .1 3- 氱 · 4_ (2_Diethylamino-ethoxy) _aniline

IV.la 3 -Ga-4- (2-diethylamino-ethoxy) _mothylbenzene 52.0 g (0.30mol) of 2-Ga-4-nitro-phenol was dissolved in 500 ml of DMF, and Add 165 g (1.20 mol) of potassium carbonate in batches. The mixture was stirred at ambient temperature for 30 minutes. Then 51.6 g (0.30 mol) of 2-diethylamino-ethyl vapor-hydrochloride was added, and the mixture was stirred at ambient temperature for 3 days. After this time, the mixture was filtered off, the solvent was removed, and the residue was dissolved in ethyl acetate and washed with water. The organic phase was filtered over alumina (activity 2 · 3) and concentrated by evaporation. 99336.doc • 86- 200540142 Yield: 41.0 g (50% of theory),

Rf value: 0.60 (silicone, methane / methanol / ammonia = 9: 1: 0.01) C12H17CIN2O3 IV-lb 3-gas-4- (2-diethylamino-ethoxy) -aniline will be 41 · 〇g (l 50 mmol) 3 -chloro-4- (2-diethylamino · ethoxy) -stone benzene (IV.la) was dissolved in 250 ml of methanol and hydrogen was added at 50 psi at ambient temperature and hydrogen. And 4.0 g of Raney Niron as a catalyst for 5 hours. The catalyst was then eliminated and the solvent was removed. The residue was recrystallized from petroleum ether and dried in vacuo. Yield: 33.0 g (91% of theory),

Rf value: 0.40 (silicone, methane / methanol / ammonia = 9: 1: 0.01)

C12H19CIN2O ΕΠ Mass spectrum: m / z = 243/245 [M + H] + The following compounds were also synthesized similar to the above method: (IV.2) 4- (2 • Diethylamino-ethoxy) _aniline (IV. 3) 4- (2-Diethylamino-ethoxy) -3-methoxy-aniline (IV.4) 4- (2-n than pyridin-1-yl-ethoxy) -3 · Trifluoromethyl-benzylamine (ΐν · 5) 4- (3-Diethylamino-propoxy) · Aniline Examples V.1 3 · methoxycarbonyl 4- (2-pyrrolidin-i-yl- Ethoxy) -aniline

99336.doc -87- 200540142 Vla 3-methoxycarbonyl-4- (2- «pyrrolidin-i-yl-ethoxy) _nitrobenzene 3.43 g (29.8 mmol) 2-pyrrolidine-1- Ethyl alcohol was dissolved in 60 ml of toluene and 575 mg (25.0 mmol) of sodium was added in portions. The mixture was heated to 100. And then stirred for an additional 12 hours at 50 ° C. After cooling, 5.00 g (22.5 mmol) of methyl 2-nitro-5-nitro-benzoate were added in portions and the mixture was stirred at ambient temperature for 1 day. Thereafter, the solvent was removed, and the residue was dissolved in digas methane and washed with water. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation. The product was finally purified through a silica gel column with a two-gas methane / methanol / ammonia gradient (8: 2 to 8: 2: 0.1) as the eluent. Yield: 1.65 g (25% of theory),

Rf value: 0.45 (silicone, methane / methanol / ammonia = 0.19) C14Η18N2Ο5 ΕΙΙ Mass spectrum: m / z = 295 [Μ + Η] + Vlb 3-methoxycarbonyl-4- (2 · pyrrolidine _1_yl-ethoxy) _aniline 1.65 g (5.61 mmol) of 3-methoxycarbonyl_4- (2-pyrrolidin-1_yl_ethoxy) -nitrobenzene (Vla) was dissolved in 1 200 ml of methanol and hydrogenated with 200 mg Raney Ni as catalyst and hydrogenated until the reaction is complete. The catalyst was then filtered off and the solvent was removed. Yield: 1.43 g (97% of theory), Heart value: 0 · 15 (silicone, methane / methanol / ammonia = 9: 1: 0.1) C14H20N2O3 EII Mass spectrum: m / z = 265 [M + H] + 99336.doc -88-200540142 Example VI.l 3-Gas 4- (2 · Diethylamino-ethyl) _aniline

VI.1.a (2-Ga-4_pyridyl-phenyl) -acetic acid gas suspension 8.10 g (37.6 mmol) (2-Ga-4-nitro · phenyl) -acetic acid was suspended in 40 ml of sub- Sulfur gas and reflux for 2 hours. The product was further reacted without any further purification. Crude yield: 8.80 g (1000/0 of theory) C8H5Cl2N03

Vl.lb 2- (2- 氱 _4_nitro-phenyl) _ν, N · diethyl-acetamidine 5.67 ml (54.0 mmol) of diethylamine was dissolved in 50 ml of ethyl acetate and 50 ml of ethyl acetate (3.27 7 mmol) (2-gas-4-nitro · benzyl) -acetic acid vapor (VI · 1.a) was slowly added dropwise at C. Then stir the mixture for an additional 2 hours at ambient temperature. Thereafter, some ethyl acetate was added again, and the mixture was washed twice with water and twice with a saturated saline solution. The organic phase was dried over sodium sulfate, the solvent was removed and the residue was dried in vacuo. Yield: 3.70 g (100% of theory)

Rf value: 0.45 (silicone, petroleum ether / ethyl acetate = ι: 1) C12H15CIN2O3 EI1 Mass spectrum: m / z = 271/273 [M + H] + VI.lc 99336.doc -89- 200540142 [2_ (2- Gas_4_nitro-phenyl) -ethyl] -diethyl-amine was added dropwise at ambient temperature 65.0 ml (65.0 mmol) of a 1 M boron-thf solution to 3.70 g (13.7 mmol) ) 2- (2-Chloro-4_nitro-phenyl) _N, N ^ ethyl-acetamidamine (Vl.lb) in a solution of 130 ml of THF, and the mixture was stirred for 4 hours. The reaction mixture was then evaporated and the residue was combined with 15 ml of methanol and 15 ml of dilute hydrochloric acid. The mixture was then stirred for 15 minutes at ιοοπ, cooled with water and diluted. The mixture was then basified with sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases are extracted twice with water and once with a saturated saline solution, and dried over sodium sulfate. Purification was performed by Αχοχ (neutral, active Π-ΐπ) column chromatography using petroleum ether / ethyl acetate (4: 1) as the eluent. Yield: 2.10 g (60% of theory)

Rf value: 0.65 (Α1οχ, petroleum ether / ethyl acetate = 3: 1)

Ci2H17C1N2〇2

Vl.ld 3 -Ga-4_ (2-diethylamino · ethyl) -aniline # 2.00 g (7.79 mmol) [2- (2-Ga-4-nitro-phenyl) -ethyl [Diethyl] -diethyl-amine (VI.lc) was dissolved in 50 ml of THF and hydrogenated with hydrogen and 0.8 g of Raney nickel as a catalyst at a pressure of 25 psi for 2.5 hours at ambient temperature. The catalyst was then filtered off and the solvent was removed. Yield: 1.80 g (100% of theory)

Rf value: 0.45 (Α1οχ, petroleum ether / ethyl acetate = 1: 1) c12h19cin2 EII mass spectrum: m / z = 227/229 [M + H] + 99336.doc -90- 200540142 Similar to the above method and also synthesized The following compounds: (VI.2) 3-Ga-4- [2- (4-methyl-piperidin-1-yl) -ethyl] -aniline (VI.3) 3-Ga-4- [2- (4-methoxypiperidin-1-yl) _ethyl] -aniline (VI.4) 3 • Ga-4_ [2 · (N_methyl-isopropylamine) -ethyl] _aniline (VI .5) 3-Ga-4_ {2- [4- (morpholin-4-yl) -piperidin-1-yl] -ethylbenzidine (VI.6) 3-Ga-4- [2- ( 4-hydroxy · 4-trifluoromethyl-piperidin-1-yl) -ethylbenzidine

(VI.7) 3-Ga-4- [2- (4-Third-butoxycarbonylamino-piperidine-butyl) -ethyl] · aniline (VI.8) 3-Ga-4 · [2 -(N-ethyl-2-hydroxy-ethylamino) -ethyl l.aniline (VI.9) 2-amino-5-(slightly _1-yl-methyl) -σ ratio Example VII .1 5-amino-1- (2 · pyrrolidine · 1 · yl-ethyl) -1

〇 VII.1.a 5-Nitro-1- (2-pyrrolidin-1-yl-ethyl) -1 ug-indole16.2 g (100 mmol) of 5-nitroindole, 35.0 g (206 The reaction mixture in which mmol) l- (2-gas-ethyl each bite-hydrochloride and 51.0 g (369 mmol) of carbonic acid was discharged in 500 ml of DMF was stirred at ambient temperature for 48 hours and then filtered. The filtrate was evaporated, The residue was dissolved in digas methane and dried over sodium sulfate. The desiccant was filtered off and the filtrate was evaporated. Yield: 25 g (96% of theory) 99336.doc -91- 200540142

Rf value: 0.65 (silica gel, methane / methanol / gas = 9: 1: 0.1) C14H17N3O2 EII Mass spectrum: m / z = 260 [M + HJ + VII.lb 5-amino-1- (2-% role Benzyl-ethyl) _1-indole is similar to Example VLl.d from 27.0 g (104 mmol) of 5-nitro-l- (2-pyrrolidin 4-yl-ethylindole) in THF as a solvent (Vn.ia) Preparation. • Yield: 23.2 g (97 / theoretical value)

Rf value: 0.50 (silica gel, methane / methanol / ammonia = 0.19) C14H19N3 EII Mass spectrum: m / z = 230 [M + Η] + The following compounds were synthesized similar to the above method: (VII.2) 5-amino-1- (2-piperidine · ylethyl) -1 //-indole (VII.3) 5-amino-1- (2-azacycloheptane small-ethyl ) -1 ugly-indole (νΐΙ · 4) 5 · amino-1- (2-diisopropylamino-ethylindole) (VII.5) 5-amino-1- {2_ [bis_ ( 2_methoxyethyl) _amino] -ethyl} -1_indole (VII.6) 5-amino-1- [2_ (N-benzylethylamino) -ethyl] -l / ί-indole • (VII.7) 5-Amino-1- (2-diethylamino · ethyl-indole Example VIII.1 2- (Pyrrolidin_1-yl-fluorenyl) _Benzoxazolyl · Amine 99336.doc • 92- 200540142

VIII.l, a 2-Chloromethyl-6-acryl-phenylamine, 12.5 g (77.9 mmol) of 2-amino-4-nitro-phenol and 10.5 ml (77.9 mmol) of 2- The reaction mixture of gas-ΐ · ι · ΐ-trimethoxy · ethane in 110 ml of ethanol was stirred at 80 ° C for 3 hours. The mixture was then poured onto water and the precipitate formed was filtered off. The filtrate was washed with water and at 80 ° C. Dry at 0 ° C. Yield: 14.2 g (86% of theory) C8H5C1N203 EII Mass spectrum: m / z = 213/215 [M + H] + VIII.lb 6-nitro-2-(«pyrridine-1-yl-methyl Benzoxazole: 3.00 g (14.1 mmol) of 2-aminomethyl-6-nitro-benzoxoxazole (VIII.la), 1.50 ml (18.0 mmol) of oral pyrrolidine and 3.90 g (28.2 mmol) of φ The reaction mixture of potassium carbonate in 30 ml DMF was stirred at 50 ° C. for 12 hours. The mixture was then diluted with water and covered with ether. The precipitate formed was filtered off and dried at 80 ° C. Yield: 1.80 g (52% of theory) C12H13N3O3 EII Mass spectrum: m / z = 248 [M + H] + VIII.lc 2_ (0 ratio hemi-1-yl · methyl) -phenylhydrazone βoxamyl · amine 99336 .doc -93- 200540142 '1.80 g (7.28 methyl: benzene benzoxazole (VIII · lb) in methanol, similar to Example vi.ld from methyl 111111〇1 as a solvent) («Bilo bite_1_ 基 _ Jiamei, Xiaobei. Yield: 1.10g (theoretical value of 70 / 〇)

Rf value: 0.60 (alumina, digas methane / ethanol = 20 ^) c12h15n3o EII mass spectrum: m / z = 218 [M + H] + Example IX.l 2- (4-dimethylaminomethyl-benzene ) _Ethylamine

IX-la (4-dimethylaminomethyl-phenyl-acetonitrile) 4.40 g (20.9 mmol) (4-bromomethyl) -acetonitrile (For the preparation method, see Magnet · Reson. Chem · 2000, 38, 129- 134), 1.71 g (21.0 mmol) of difluorenylamine hydrochloride and 9 · 2 g (66.0 mmol) of carbonic acid in 30 ml • The reaction mixture in acetone was stirred at ambient temperature for 4 hours. The mixture was concentrated by evaporation, dissolved in dioxane and washed with water. The organic phase was dried over sodium sulfate and then the solvent was removed. Yield 3.60 g (99% of theory)

CnH14N2 EII mass spectrum: m / z = 175 [M + H] + IX-lb 2- (4 • dimethylaminomethyl-phenyl) · ethylamine 99336.doc • 94- 200540142 3.60 g (20.7 mmol ) (4-dimethylaminomethyl · phenyl-acetonitrile Kl.la) dissolved in 50 ml of methanol ammonia and at a pressure of 3 bar at 50 ° C with hydrogen and 0.45 g of Raney as catalyst Nickel was agitated for 5 hours. The catalyst was then filtered off and the solvent was removed. Yield: 3.60 g (98% of theory)

Rf value: 0 · 20 (silica gel, digas methane / methanol = 9: 1) C1 iHi gN2 EII mass spectrum: m / z = 179 [M + H] + g The following compounds were also synthesized similar to the above method: (Ιχ · 2) 2_ [4- (Solopyridin-1-yl-methyl) -phenyl] -ethylamine (IX · 3) 2 · [4- (3-aza · spiro [5.5] undecane-3 -Yl-methyl) -phenyl] -ethylamine (IX · 4) 2- [4- (4-hydroxy-4-phenyl-piperidin-1-yl-fluorenylphenyl] -ethylamine (IX 5) {1- [4- (2-Amino-ethyl) _benzyl] _α bottom bite-4-yl} -〇 than bite-2-yl-amine

(Ιχ · 6) 2-methyl-2 [[4_ (salrolidin-1-yl-methyl) _phenyl] -propylamine φ Example X can be synthesized using the method already described in International Patent Application WO 01/27081 The following compounds, or at least methods similar to those described therein, can be used to prepare the following compounds: (X · 1) 4- (Travel Lake-1-yl-methylaniline (X · 2) 4- (diethylaminomethyl) Group) _aniline (X.3) 4- (2-diethylamino-ethyl) -aniline (X · 4) 3-Ga-4- (piperidin-1-yl-fluorenyl) _aniline 99336. doc -95- 200540142

(Χ · 5) 3-Ga-4 _ [(cis-3,5-dimethyl-piperidine-butyl) -methyl] -aniline (χ · 6) 4-[(3 · 5-dimethyl -Piperidin-1-yl) -fluorenyl] • aniline (X · 7) 4 _ [(4_methoxy-σ 辰 ido-1-yl) -methyl] -aniline (χ · 8) 4 _ [( 4-methyl-α-Chen-1 · yl) -methyl] aniline (X · 9) 4 _ [(4_methyl-piperazin-1-yl) -methyl] -aniline (χ · 10) 4_ [(N-methyl-cyclopropylmethylamino) -methyl] _aniline (X · 11) 4-[(2,6-dimethyl-pyridin-1-yl) -methyl]- Aniline (X · 12) 4- (η than pyrrolidin- ^ yl-methylaniline (X · 13) 4- (morpholin-4-yl-methyl) _aniline (χ · 14) 4-[(4 -Hydroxy-piperidin-4-yl) -methyl] -aniline example X 1.1. N-methyl-4- (2-dihexylamino-ethoxy) -aniline

Η

XI.1.a N-methoxycarbonyl-4- (2-diethylamino-ethoxy) -aniline 76.4 g (0.367 mol) 4- (2-diethylamino-ethoxy) · aniline (Compound IV.2) and 102 μm1 (.733 mol) of triethylamine were dissolved in 400 ml of THF and 49.2 g (0.367 mol) of dimethyl pyrocarbonate in 200 ml of THF were added at ambient temperature over 45 minutes. vinegar. The mixture was stirred for an additional 2 hours at ambient temperature. After this time the solvent was evaporated, the residue was dissolved in ethyl acetate and water and the organic phase was washed twice with water. The solvent was removed and the residue was purified via an alumina column using petroleum ether / ethyl acetate (3: 1) as the eluent. 99336.doc -96- 200540142 Yield: 63.3 g (65% of theory),

Rf value: 0.60 (alumina, petroleum ether / ethyl acetate = 1: 3)

Ci4H22N2〇3 EII mass spectrum: m / z = 267 [M + H] +

Xl.lb N-methyl-4- (2-diethylamino-ethoxy) _aniline Place 10.7 g (280 mmol) of lithium aluminum hydride in 600 ml of THF and carefully dropwise at 0 ° C 30.0 g (113 mmol) of N-methoxycarbonyl-4- (2-diethylamino-ethoxy) -aniline (compound XIla) in 300 ml of THF were added. The mixture was stirred at ambient temperature for 12 hours. Thereafter an additional 7.00 g (183 mmol) of lithium aluminum hydride was added and the mixture was stirred at ambient temperature for an additional 24 hours. It was then carefully neutralized with sodium hydroxide solution. The mixture was filtered, the filtrate was dried over sodium sulfate, and the solvent was finally removed. Yield · 24.7 g (99.theoretical value),

Rf value: 0.45 (silicone, methane / methanol / ammonia = 9: 1: 0.1)

C13H22N2O EII mass spectrum: m / z = 223 [M + H] + The following compounds can also be synthesized similar to the above preparation method: (XI.2) N_methyl_4_ (propidinylmethyl) _aniline example XII. 1 3 · biphenyl-4-yl-propynic acid_ [3-fluoren-4- (2-diethylamino-ethoxy) _phenyl] -fluorenamine 99336.doc • 97- 200540142

0.48 g (2.0 mmol) of biphenyl-4-yl-propynic acid chloride (see Bioorg Med Chem. 1996, 4, 851 for the preparation method) was dissolved in 15 ml of toluene and dropped dropwise at ambient temperature. 0.58 g (2 4 mm〇1) [2_ (2-Ga-4-amino-phenoxy) -ethyl] • diethyl-amine (eluent Iv · 丨) in 10 ml of toluene was added. The mixture was stirred at ambient temperature for 8 hours, the solvent was removed, the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, the solvent was removed and the residue was purified via a ♦ gel tube using a turbulent methyl alcohol / methanol / gas (9 ·· 1: 0 · 01) as the eluent. Yield 0.28 g (31% of theory)

Μ · ρ ·: 105-108〇C

Rf value: 0.50 (silicone, methane / methanol / ammonia = 9: 1: 03) C27H27CIN2O2 EII mass spectrum: m / z = 447/449 [M + H] + The following compounds were also synthesized similar to the above method. (XII. 2) 3- (2-Ga-4_trifluoromethyl-phenyl-)-propynic acid_ [3 · Ga-4_ (2 · Diethylamino-ethoxy) -phenyl] • fluoramine (XII · 3) 3- (3-Mo · biphenyl-4-yl) _propionic acid- {3_lact-4- [2- (4-methylpiperidin-1-ylethyl) -benzene }}-Fluorenamine to prepare the end-point compound: 99336.doc -98 · 200540142 Example 1.0 3 -Biphenyl-4-yl-N- {3 -Ga-4- [2- (4-methyl-tripe-1- ) · Ethoxy J_phenyl} -3 _oxo-propylamine

300 mg (1.0 mmol) of 3-biphenyl-4-yl-3-oxopropionate (isolating agent 1.1) and 269 mg (1.0 mmol) of 3-gas- 4- [2 · (4-methyl-piperidin-1-yl) · ethoxy] • aniline (isolating agent ΙΙΙ.1) was dissolved in 5 ml of toluene and stirred in an open test tube at 120 ° C For 8 hours, ethanol was distilled off at the same time. After cooling, petroleum ether was added, and the formed precipitate was suction filtered and dried at 80 ° C in vacuo. Yield: 300 mg (61% of theory),

Rf value: 0.60 (silicone, methane / methanol / ammonia = 9: 1: 0.1)

M.p. 135-139〇C C29H31ClN2〇3

Eli mass spectrum: m / z = 491/493 [M + H] + Preparation of the compound of the following general formula "Isolation engraving" similar to Example 1.0 is shown in the heading, "Isolator" 99336.doc • 99- 200540142

B Example r! R2nx Ll L2 B Mass spectrometer MpfC] RHi * 1.1 -Cl -H Weng 1 II. 1 IV. 1 499/501/503 [M + H] + 175-180 0.50 (A) 1.2 Et2N ~ ~, -H -H AO " Il rv.2 431 [M + H] + 140-142 0.40 ㈧ 1.3 Et2N ~~, -och3 -H 1.1 rv.3 461 [M + H] + 108-110 0.60 (B ) 1.4 Et2N ~ 0 / -Cl -Cl < rH Π.2 IV.l 499/501/503 [M + H] + 108-111 0.40 (C) 1.5 Et2N ~~, -H -Cl II.2 IV .2 465/467 [M + H] + 108-112 0.40 (A) 1.6 Et2N ~ 〇〆-och3 -Cl ^ 〇rH II.2 IV.3 495/497 [M + H] + 157-160 0.70 (B) 1.7 CN to cy -cf3 -H 1.1 IV.4 497 [M + H] + 130-135 0.45 (D) 1.8 Et2S '-H -H 1.1 IV.5 445 [M + H] + 152-157 0.45 (D ) 1.9 CN ～ cy -COO- ch3 -H ACT Il Vl 487 [M + H] + 131-135 0.45 (D) 1.10 Et ~ -Cl -H aCth 1.1 VI. 1 449/451 [M + H] + 118- 122 0.20 ㈧ 1.11 Et ~ -Cl -Cl ^ 〇rH II.2 VI. 1 483/485/487 [M + H] + 132-136 0.20 (A) 1.12 CN ^ -H -H ^ 〇rH Il Xl 413 [M + H] + 157-160 0:50 (A) 1.13 H3C ^ NO < " h3c ″ -H -H 1.1 X.2 401 [M + H] + 126-130 0.60 ㈧ 1.14 w -H -Cl 11.2 Xl 447/449 [M + H] + 72-75 0.50 (A) 99336.doc -100- 200540142

1.15 H3C ^ N ^ < " h3c '' -H -Cl ^ rH II.2 X.2 435/437 [M + H] + 155-160 0.50 (A) 1.16 -H -H II. 1 Xl 447 / 449 [M + H] + 202-204 0.40 (A) 1.17 HX H3CJ, -H -H LI X.3 415 [M + H] + 144-148 0.50 (D) 1.18 H3CV ^ p1 ~ v h3c -och3- H ^ 〇rH 1.1 m.2 501 [M + H] + 224-228 0.60 (〇) 1.19 h3c〇 ~ 9 -och3 -H 1.1 III.3 487 [M + H] + 106-110 0.60 (D) 1.20 Cr < -Cl -H Λ〇α II. 1 X.4 482 [M + H] + 175-177 0.45 (c) 1.21 H3CV ^ h3c -Cl -HA〇 ^ cl Π.1 X.5 509/511 / 513 [M + H] + 174-177 0.80 (C) 1.22 H3C • H -HW Π.1 X.6 475/477 [M + H] + 175-178 0.45 (D) 1.23 MeO ^ O ^^ -H- H a〇ci Π.1 X.7 477/479 [M + H] + 178-181 0.50 (C) 1.24 H3c〇 ^ -H -HA〇 ^ cl Π.1 X.8 461/463 [M + H] + 168-170 0.35 (C) 1.25 h3c-nGn ^ -H -H ^ ra II. 1 X.9 462/464 [M + H] + 176-178 0.30 (〇) 1.26 H3C -H -H ^ r 'II. 1 X.10 447/449 [M + H] + 167-170 0.50 (C) 1.27 ch3 dblower ch3 -H -H II. 1 X.ll 475/477 [M + H] + 168-171 0.45 (C) 1.28 CN ^ -H -H λΟ " II. 1 X.12 433/435 [M + H] + 187-189 0.35 (C) 1.29 h3c'n less than h3cj -H -H λΟ " 1 II. 1 X.2 43 5/437 [M + H] + 175-178 0.35 (C)

ocm /; rW 200540142

1.30 -H -HA〇c, II. 1 X.13 449/451 [Μ + Η] + 188-190 0.45 (C) 1.31 -H -H < rci II. 1 X.14 463/465 [Μ + Η] + 146-149 0.30 (C) 1.32 CN ~ \ -Cl -H 1.1 m.4 479/481 [Μ + Η] + 120-126 0.70 (D) 1.33 h3c 'Human-Cl -H Ι · 1 ΠΙ .5 477/479 [Μ + Η] + 130-132 0.40 (C) 1.34 Me0 ^ 0N ～ 0, '• Cl -H 1.1 ΙΙΙ.6 507/509 [Μ + Η] + 120-125 0.40 (C) 1.35 h3c-〇 ~ 〇 / -Cl -H λΟ " 1.1 m.7 492/494 [Μ + Η] + 130-135 0.30 (C) 1.36 Η〇ο ~ 〇, -Cl -H λΟ " 1.1 ΙΠ. 8 493/495 [Μ + Η] + 115-118 0.30 (C) 1.37 H3Cv 〇Nn ^ -Cl -H λ0 ^ η 1.1 VI.2 475/477 [Μ + Η] + 227-232 0.44 (C) 1.38 MeO Q ♦ -Cl -H λΟη 1.1 VI.3 491/493 [Μ + Η] + > 130 0.53 (C) 1.39 HC PH3 H3Vn ^ h3c into -Cl • H 1.1 VI.4 449/451 [Μ + Η ] + 81-85 0.32 (C) 1.40 Ώ Q · -Cl -H λ0 ^ η 1.1 VI.5 546/548 [Μ + Η] + 171-175 0.24 (C) 1.41 HO F3Ct ^ -Cl -H λ0 ^ η 1.1 VI.6 545/547 [Μ + Η] + 187-191 0.38 (C) 1.42 ch3 H3C HN 0, -Cl -H 1.1 VI.7 576/578 [Μ + Η] + 157-159 0.42 (C ) 99336.doc 102- 200540142

h3c) ho ^ -n, example 2 -Cl -H 1.1 VI.8

Example of the eluent used for the compound of formula n-1 in L3 column fJr2nx L1 L2 L3 Eluent mass spectrum Mp [° C] Rf value * 2.0 Ε, Ν ~ 0 / • Cl -Η • och3 II.3 IV.l 419 / 421 [M + H] + 120- 122 0.40 ㈧ Example 3

The following compound of formula III-l was prepared similarly to Example 1.0, and the eluent used was shown in the line entitled "Eluent": Example RlR2NX L2 Β Eluent Mass Spectrum M · ρ · [° C] RHi * 3.0 0- Cl Π · 2 νπ · ι 419/421 [Μ + Η] + 120-122 0.40 (A) 3.1 Ον ΝΌ < Η-Η λ € τΗ 1.1 νπ · ι 452 [Μ + Η] + 135-142 0.50 (A ) 3.2 Q -Η λζΤΗ 1.1 VII.2 466 [Μ + Η] + 60-65 0.50 (D) 3.3 Q -Η Ι · 1 ΥΠ.3 480 [Μ + Η] + 127-129 0.50 (D) 99336. doc -103- 200540142 3.4 ㈠3. ) —Ch3 h3c ^ -H Il VII.4 482 [M + H] + 139-144 0.65 (D) 3.5 OMe MeO -H Λ〇 ^ Η Il Vn.5 514 [M + H] + 83-86 0.60 ( D) 3.6 q η ～ ν… -H ^ 〇rH Il Vn. 6 516 [M + H] + 85-90 0.70 (D) 3.7 h3c H3C 』... -H 1.1 ΥΠ.7 454 [M + H] + 99 -104 0.55 (D) Example 4 The compound of the following formula IV-1 was prepared similarly to Example 1. The separating agent used is shown in the line titled "π separating agent": R \

(ιν · ι) Example RlR2NX L2 B Mass spectrometer MpfC] Rfjjl. * 4.0 CN ^ -H Il VIIL1 440 [M + H] + 135-138 0.55 (D) Example 5 Similar to Example 1 For compounds of formula V_ 丨, the eluent used is shown in the heading "Eluent," in the line:

(V-1) 99336.doc -104- 200540142 Example rWnx R7a / R7b Beta eluent mass spectrum M.ρ. [t:] RHi * 5.0 h3c ^ nV h3c ″ -Η Ι · 1 Γχ.1 401 [Μ + Η ] + 120-125 0.40 (D) 5.1 CN ^ -Η 1.1 Ιχ. 2 427 [Μ + Η] + 121-125 0.55 (D) 5.2 〇CN ^ -Η AO " 1.1 Ιχ.3 509 [Μ + Η] + 107-111 0.40 (D) 5.3-翁 1.1 1.1 IX. 4 533 [Μ + Η] + 98-103 0.40 (D) 5.4 Qn-Η 1.1 IX. 5 533 [Μ + Η] + 109-112 0.30 ( D) 5.5 -ch3 λ0 ^ η 1.1 Ε. 6 455 [Μ + Η] + 100-106 0.40 (D) Example 6 The compound of the following formula VI-1 was prepared similarly to Example 1.0. The eluent used is shown in the title During the "isolating agent" trip:

(VI-1) Example RlR2NX L1 L2 B Mass spectrometer Mp [° C] Rf value * 6.0 Et2N ~ 〇〆-H -H Il XI. 1 445 [M + H] + 108-112 0.50 (D) 6.1 〇 Parent-H -H Il XI.2 427 [M + H] + 175 0.70 (A) Example 7.0 3 -Biphenyl-4 -yl-N- [3-Ga · 4- (2-diethylamino-ethyl) (Gasyl) -phenyl] -3 -oxo-propanamidin-105 99336.doc 200540142

0.16 g (0.3 6 mmol) of 3-biphenyl-4-yl-propynic acid- [3-gas-4 · (2-diethylamino · ethoxy) · phenyl] -fluorenamine (isolating agent XII · 1) was dissolved in 10 ml of aqueous ethanol and 0.10 ml (1.0 mmol) of piperidine was added. The mixture was stirred at reflux temperature for 8 hours. After cooling, the solvent was removed and the residue was suspended in ether and filtered off. The residue was dried in vacuo at 50 ° C. Yield · 75 mg (45% of theory),

Rf value: 0 · 40 (silicone, methane / methanol / ammonia = 9: 1: 0.01)

Mp 148-151〇C C27H29CIN2O3 EII mass spectrum: m / z = 465/467 [M + H] + The compound of the following general formula νπ-1 was prepared similarly to Example 7 · 0. The eluent used is shown in the title "Eluent" On a trip:

R1, 0 12. 1 t (VII-1) Example Clip 2 L × L1 L2 L3 Mass spectrometer Mp rc] RHt * 7.1 Et ^ ~ 〇, 〆-Cl -Cl -cf3 χΠ.2 491/493/495 [M + H ] + nb 0.40 (E) 7.2 h3c ^ π -Cl Br XII.3 553/555/557 [M + H] + 139- 144 0.48 (C) Example 8.0 99336.doc -106- 200540142

(Oxy) -benzoic acid

mmol) 5- (3 · bibenzyl-4-yl-3 · oxo-propionamine'yl-ethoxy) _methyl benzoate (compound 丨 .9) was dissolved in 0.25 g (0.51 mm Based) -2- (2-% σ each bit _1_based_ 20 ml of methanol was added with 2 () ml 丨 N sodium hydroxide solution and the mixture was stirred at 50 t for 3 hours and at ambient temperature 12 hours. Thereafter, an additional 1.0 ml of a 1 N sodium hydroxide solution was added and the mixture was then stirred at 500 Ct for an additional 3 hours. After cooling, 3.0 ml of 1 N hydrochloric acid was added and then the mixture was stirred at ambient temperature 1 Hr. The solvent was evaporated, the residue was dissolved in a small amount of methanol 'and the resulting precipitate was filtered with suction and dried at 80 ° C under vacuum. Yield 240 mg (100% of theory),

Rf value: 0 · 20 (silica gel, digas methane / methanol / ammonia = 9: 1 ·· 0 · 1) Mp 236-240〇C C28H28N205 05 mass spectrum: m / z = 473 [M + H] + Example 9.0 Ν · {4_ [2- (4-Amine-slightly bit-l-yl) -ethyl] -3-Ga · phenyl} -3-biphenyl-4-yl-3-oxo-propionamidine Amine-107- 99336.doc 200540142

0.19 g (0.33 mmol) of N- {4- [2- (4-third butoxycarbonylamino-piperidine-1, -yl) -ethyl] · 3-lactate-phenyl} -3 -Biphenyl-4-yl-3-oxo-propanamide (Compound 1.41) was dissolved in 7 ml of digas methylbenzene, 500 mi of trifluoroacetic acid was added and the mixture was stirred at ambient temperature for 12 hours . Thereafter, a saturated sodium bicarbonate solution was added and the formed sinker was suctioned through the urn. The residue was dried over sodium hydroxide in vacuo. Yield: 160 mg (100% of theory),

Rf value: 0.10 (silica gel, digas methane / methanol = 9: 1) M · ρ. 144 ° C or higher (decomposition) c28h30cin3o2 EII mass spectrum: m / z = 476/478 [M + H] + Example 10

Compounds of the following formula VIII-1 were prepared similarly to Example 1 · 0. The eluent used was shown in the line entitled "Isolation Qi": _ Example r! R2nx L1 L2 L3 Eluent Mass Spectrum M · ρ · [ ° C] R plant value * 10.0 C / N under-H -H 1.1 VI.9 414 [Μ + Η r 178-182 0.4 plant (A) The following compounds can be prepared similar to the previous examples: 99336.doc -108 -200540142

Example r! R2nx L1 L2 B 11 h3c-〇N ^ ° ^ / -Cl -H < yH 12 H3Cs ^ p1 ~ 9 H3C -Cl -H λζΤΗ 13 CF3f N ~ 〇HO, -Cl -H Λ〇η 14 H ^ Y〇 ^ 0 / 〇-Cl -H 〇rH 15 H〇o ~~ -Cl -H ^ 〇rH 16 HO Gn ~ 〇 / -Cl -H ^ 〇rH 17 H3cfN ~. HO ^ / -Cl -H 18 ch3 ύ ~ ch3 -Cl -H ^ 〇rH 19 GN ~ \ -Cl -H Λ〇 ^ Η 20 ～ cy HO -Cl -H λ〇ή 21 Q ~ cy HO -Cl- H λΟη 22 ch3 ~ H3 with CH3, -Cl -H λΟ "

QcniA rU '200540142 23 Η 穴 -Cl -H 24 Q, -Cl -H ^ 〇rH 25 〇Ν, -Cl -H ^ 〇rH 26 Η3〇ΡΝ ^ ν h3c -Cl -H λΟη 27 ~ HrCr ^ 0- Cl H λΟη 28 HCT〇N ~ Γ -Cl -H ^ rH 29 HO -Cl -H ^ yH 30 CN 乂 -Cl -H ^ 〇rH 31 h3c-n〇N ^ ° T -Cl -H λ € Γ 32 -Cl -H λΟη 33 '' ch3 ch3 -Cl -H aC ^ h 34 -Cl -H 35 C ^ r HO -Cl -H λ〇ή 36 Q ^ v HO -Cl -H λΟ ^ η 37 ch3 H3C ^ N ^ H3C ^ CH3 -Cl -H ^ αΗ Ηπη -110- 200540142

38 h3C \ i -Cl -H ACT 39 H 勹 〆 '-Cl -H ACT 40 CN, V -Cl -H ^ CrH 41 CN ^ v -Cl -H < yH 42 ch3 H3C ^ CH3 -Cl -H λ 〇 ^ η 43 H3C ^ CH3 -Cl -H 44 H3CX, H3VN ^ r h3c -Cl H 〇rH 45 ch3 h3V ~ h3c -Cl • H 46 HN ^ \ > • Cl -H ^ 〇rH 47 Q · -Cl -Cl -cf3 48 On, -Cl -Cl cf3 49 h3c〇, • Cl -Cl -cf3 50 h3c -Cl -Cl -cf3 51 cf3 ^ n-〇 ^ -Cl -Cl -cf3 99336.doc -Ill-200540142

52 〇-Cl -Cl -cf3 53 ηο ^ 〇Ν ^ ° Γ -Cl -Cl -cf3 54 ΗΟ 〇1, -Cl -Cl -cf3 55 C ~ -Cl -Cl cf3 56 Η3 [Ν0Ν ^ ν -Cl -Cl -cf3 57 h3c〇 ^ v -Cl -Cl -cf3 58 ch3 CH3 • Cl -Cl -cf3 59 -Cl -Cl -cf3 60 C ^ r ΗΟ -Cl -Cl -cf3 61 CN ^ v ΗΟ -Cl -Cl- cf3 62 ch3 Η3 ° N-κ ^ H3C ^ CH3 -Cl -Cl -cf3 63 H3C, -Cl -Cl -cf3 64 h3c 〆, -Cl -Cl -cf3 65 CN, V -Cl -Cl -cf3 66 CN ^ v -Cl -Cl -cf3 67 ch3 H3C CH3 -Cl -Cl -cf3 200540142 68 h3c 乂 ch3 -Cl -Cl -cf3 69 h3C \, h3c ^ N ^ h3c -Cl -Cl -cf3 70 CH- h3c -Cl- Cl -cf3 71 '-Cl -Cl -cf3 72 H3C> ^ v h3c -Cl -H aC ^ h 73 -Cl -H λΟη 74 -Cl -H λζΤ 75 HO, H3C- ^ CN ^ V HO, -Cl- H ACT 76 H0V HO -Cl -H λΟ " 77 H3C octa / Ns ^ h3c -Cl -H λ0 ^ η Some test methods for measuring MCH receptor antagonistic activity will now be described. In addition, other testing methods known to the skilled person can be used, such as Hoogduijn Μ et al. In `` Melanin-concentrating hormone and its receptor are expressed and functional in human skin11, Biochem. Biophys. Res Commun. 296 (2002) 698-701 The MCH receptor regulates the inhibitory effect by inhibiting cAMP production, and such as KarlssonOP and Lofas S. in `` Flow-Mediated On-Surface Reconstitution of G-Protein 99336.doc -113- 200540142

Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors 11, Anal. Biochem. 300 (2002), 132-138 described the biosensory measurement of MCH and MCH receptor binding capacity by plasma resonance in the presence of antagonists. Other methods of testing the antagonistic activity against MCH receptors are included in the references and patent literature mentioned above, and a description of the test methods used is therefore incorporated into this application. MCH-1 receptor binding test method ... MCH binds to hMCH-lR transfected cells Species: Human test cells: Stably transfected into CHO / Galpha 16 cells of hMCH_lR Result: IC5 0 value using a syringe (needle The membrane from CHO / Galpha 16 cells stably transfected with human hMCH-1R was resuspended and tested in test buffer (50 mM HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1; % Bovine serum albumin (without protease), 0.021% subtilisin, 1 pg / ml antiprotease, 1 pg / ml leupeptin and 1 μΜ phosphorramidone) diluted to 5 to 15 pg / The concentration of ml. 200 μl of this membrane fraction (containing 1 to 3 pg of protein) was incubated at ambient temperature with 100 pM of 125I-tyrosine hydrazone melanin-concentrated hormones (125 I · M (: Η) available from NEN on the market) —cultivated from 60 Minutes, while increasing the concentration of the test compound in a final volume of 250 microliters. After incubation, the reaction was filtered with a cell harvester through a 0.5% PEI-treated glass wool screen (GF / B, Unifilter Packard). The scintillation was then added Agent (Packard Microscint 20) was then measured in a measuring device (TopCount of Packard) 99336.doc -114- 200540142 Membrane-bound radioactivity determined to remain on the screening program. Non-specific binding force was defined as during incubation Binding radioactivity in the presence of 1 micromolar MCH. Assuming a receptor binding site, analysis of concentration binding curves is performed. Criteria: Unlabeled MCH competes with labeled 125I-MCH with IC50 values between 0.06 and 0.15 nM KD value of the radioligand is 0.156 nM.

Activity test method for Ca2 + coupled to MCH-1 receptor. Calcium activity test using human MCH (FLIPR384). Species: human test cells: CHO / Galpha 16 cells stably transfected with hMCH-lR. Results: First Measurement: Percent of irritation of reference substance (MCH 1 (Γ6M) Second measurement: ρΚΒ value reagent:

HBSS (10x) (GIBCO) HEPES buffer (1 M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Probenecid (Sigma) MCH ( Bachem) Bovine Serum Albumin (Protease Free) (Serva) DMSO (Serva) Ham's F12 (BioWhittaker) FCS (BioWhittaker) L-Glutamic Acid (GIBCO) Picotomycin B (GIBCO) PENStrep (BioWhittaker) Zixin (Zeocin) (Invitrogen) 99336.doc -115- 200540142 Pure CHO / Galpha 16 hMCH-R1 cells were cultured in Ham's F12 cell culture medium (with L-glutamic acid; BioWhittaker; catalog number: BE12-615F). Each 500 ml contains 10% FCS, 1% PENStrep, 5 ml L · face brewed amino acid (200 mM stock solution), 3 ml potent oxytetracycline B (50 mg / ml in PBS), and 1.25 ml qixin ( 100 pg / ml stock solution). The day before the experiment, cells were coated on a 384-well microtiter plate (made by Costai: black wall with transparent bottom) at a density of 2500 cells per well at 37 ° C, 5% C02, and 95% relative humidity The cells were cultured overnight in the above medium. On the day of the experiment, cells were incubated for 45 minutes at 37 ° C in a cell culture medium supplemented with 2 mM Fluo-4 and 4.6 mM probenecid. Cells were washed four times with Hanks buffer solution (1 X HBSS, 20 mM HEPES) combined with 0.07% propranexol after being fed with fluorescent dye. The test substance was diluted in a Hanks buffer solution combined with 2.5% DMS0. After 5 minutes of the final washing step, unstimulated cells were measured in a FLIPR384 device (Molecular Devices; excitation wavelength: 488 nm; emission wavelength: bandpass 510 to 570 nm) in the presence of the substance in a 384-well microtiter plate. Background fluorescent. To stimulate cells, MCH was diluted in Hanks buffer with 0.1% BSA, pipetted into a 384-well cell culture plate 35 minutes after the final wash step, and then the fluorescence from the stimulation was measured in a FLIPR384 device. Data analysis: First measurement: Ca2 + activity was measured when the relative fluorescence of the background was subtracted to the maximum, and its expression was the percentage of the maximum signal of the reference (MCH 10 · 6M). This measurement is used to determine any possible stimulating effect of the test substance. Second measurement: Measure the cell Ca2 + when the relative fluorescence of the background is subtracted to the maximum 99336.doc -116- 200540142 'and its expression is a reference (MCh i0_6m, the signal is normalized to 100 ^) The percentage of the maximum signal. The eC50 value of the MCH dose activity curve with or without the test substance (defined concentration) is graphically determined by the GraphPad Prism 2.01 curve-program. In the graph plotted the antagonist caused the MCH stimulation curve to shift to the right. The inhibitory effect is expressed as a pKB value: pKB log (EC50 (test substance f + MCH) / EC50 (MCH) -1) -10 gc (test substance) The compound according to the present invention (including its salt) in the above test ) Display MCH φ receptor antagonistic activity. Antagonistic activity was obtained by using the above-mentioned MCH-1 receptor binding test in a dose in the range of about 10.10 to 10.5 M, especially 10-9 to 10.6 M. Structure of the IC50 value using the example number according to the above compound 5.1 cnn 0 0 63.7 nM 7.1 34.8 ηM Some examples of formulations are described below, in which the term, active substance, represents one or more compounds according to the invention, including Its salt. In the case of having one or more of the combinations of said active substances, the term •, active substance, also includes additional active substances. 99336.doc -117- 200540142

Example A Powder inhalation capsule composition containing 1 mg of active substance: 1 powder inhalation capsule contains: Active substance 1.0 mg lactose 20.0 mg Hard gelatin capsule 50.0 mg 71.0 mg Preparation method: Grind the active substance to the level required for inhalation granularity. Milled activity

The substance is evenly mixed with lactose. The mixture was enclosed in a hard gelatin capsule. Example B Inhalable solution composition containing 1 active substance for Respimat®: 1 spray contains: 1.0 mg 0.002 mg 0.0075 mg 15.0 μΐ active substance gas benzyl ammonium ethylene monoamine tetraacetic acid di-na supplementary pure Method for preparing water: Dissolve the tongue substance and ammonium benzyl ammonium in water and seal it in a Respimat (R) cartridge.

Example C Hegu used in a nebulizer, & l ^ _ < Inhalable solution of 1 mg active substance 99336.doc 200540142 Composition: 1 ： Contains: 0.1 g of active substance 0.18 g of sodium carbamide 0.002 g of ammonium hydroxide supplemented with pure water Preparation method: 20.0 ml

Dissolve the active substance, sodium gas and benzyl ammonium in water. Example D Propellant fixed-dose aerosol containing 1 mg of active substance Composition: 1 spray contains: Active substance 1.0 mg lecithin 0.1% supplementary propellant gas 50.0 μΐ Preparation method:

The micron-sized active substance is evenly suspended in a mixture of lecithin and propellant gas. Use a metering valve to transfer the suspension into a pressurized container. Example E Nasal spray composition containing 1 mg of active substance: 1.0 mg of active substance 0.9 mg of vaporized sodium 0.9 mg of benzalkonium 0.025 mg 99336.doc -119- 200540142 diethylene diamine tetraacetate 0.05 mg supplement Pure water 0.1 ml Preparation method: Dissolve the active substance and excipients in water and transfer into the corresponding container.

Example F Injectable solution composition containing 5 mg of active substance per 5 ml: Active substance 5 mg glucose 250 mg human serum albumin 10 mg polyethylene glycol tetrahydrofuran methyl ether 250 mg supplemented with 5 ml water for injection :

Dissolve polyethylene glycol tetrahydrofuran methyl ether and glucose in water for injection (wn); add human serum albumin; heat to dissolve the active ingredients; use wfI to reach a specific volume; transfer to an ampoule under nitrogen.

Example G Injectable solution composition containing 100 mg of active substance per 20 ml: 100 mg of active substance potassium dihydrogenate = KH2P04 12 mg disodium hydrogen phosphate = Na2HP04.2H20 2 mg sodium vaporized 180 mg human serum white Protein 50mg 99336.doc 200540142 polysorbate 80 20 mg supplemented with water for injection ^^ Preparation: Polysorbate 80, sodium gasification, potassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in Zhuangshe water ( Wfl); adding human ash albumin; heating to dissolve the active ingredients; using Wfl to reach a specific volume; transferring into an ampoule under nitrogen. Example 冻 Lyophilized powder composition containing 10 mg of active substance: 10 mg of active substance mannose 300 mg of human serum albumin 20 mg Preparation: Dissolving mannitol in water for injection (WfI); adding human serum albumin ,, Heat to dissolve the active ingredients; use Wfl to reach a specific volume; transfer into a bottle; freeze dry. 20 mg 200 mg 10 ml Solvent for lyophilized powder: t Sorbitol S = 80 = Tween 80 Mannitol supplemented with water for injection preparation: Polysorbate 80 and mannitol are dissolved in water for injection (WfI ); Transfer to ampoules.

Example I 99336.doc -121-200540142 Suspicious agent composition containing 20 mg of active substance: Active substance 20 mg lactose 120 mg corn starch 40 mg magnesium stearate 2 mg polyvinylpyrrolidone K 25 18 mg Preparation: The active substance , Lactose and corn starch are uniformly mixed; granulated with an aqueous solution of polyvinylpyrrolidone; mixed with magnesium stearate; extruded in a tablet making machine; the weight of the agent is 200 mg.

Example J Capsule composition containing 20 mg of active substance: 20 mg of active substance 80 mg of corn starch 80 mg of highly dispersed silicon dioxide 5 mg of magnesium stearate 2.5 mg Preparation: uniformly mix the active substance, corn starch and stone dioxide; Combining this with stearic acid 'encapsulates the mixture in a capsule filler into a size 3 hard gelatin capsule.

Example K Suppository 99336.doc -122- 200540142 containing 50 mg of active substance Composition: 50 mg 1700 mg of active substance supplemented with Adeps solidus Preparation: Melt stearin at about 38 ° C; The ground active substance is dispersed uniformly in molten stearin; cooled to about 35. Afterwards, it was poured into a cold mold.

Example L Injectable solution containing 10 active substances per 1 ml

Composition: Active substance 10mg mannitol 50 mg human serum albumin 10 mg supplemented with water for injection 1 mi Preparation: Dissolve mannitol in water for injection (WfI); add human serum albumin; heat to dissolve active ingredients; use wfI to achieve Specific volume; transfer to ampoule under nitrogen. '99336.doc -123 ·

Claims (1)

200540142 10. Scope of patent application: 1. A β-ketofluorene compound of general formula I, its tautomers, diastereomers, enantiomers, mixtures and salts thereof, R \ R2 / NXY - Z, R3 R5a R A-fBL Wherein R and R2 each independently represent H; optionally, a single or multiple substituted group or a Cw ring alkyl group through the group rii, and -CH at the position 3 or 4 of the 5-, 6_, or 7-membered ring alkyl group. : The r group may be replaced by -0-, -S ^ -NRi3_; or optionally mono- or poly-substituted by the group R2G and / or phenyl or e-substituted by nitro, or R1 and R2 Forms a C2-8-extended radical bridge, where -one or two -CH2 · groups can be independently replaced by _CH == N- or -CH = CH-, and / or -one or two -CH2- The groups may each independently pass -0-, -S ... -so_, _ (S〇2)-, _C (= CH2) _, or · NR13- are not directly joined together by heteroatoms and the group -C0_ is not directly Bonding to the group R1R2 is replaced by Qin, and at the same time one or more fluorene atoms in the alkylene bridge defined above may be replaced by R14, and the alkylene bridge defined above may be replaced by one or two The same or different rabbit ring or heterocyclic group Cy is substituted, so that the bond system between the alkylene bridge and the group Cy is formed in the following manner: 99336.doc 200540142-via a single or double bond,-via a spiro The common c atom of the ring system,-via the formation of a fused bicyclic ring The two systems in common are adjacent to c and / or N atoms, or '-via three or more C and / or n atoms forming a bridged ring system, R represents H, Cle6 • alkyl, C3-7_ ring Alkyl, a · Cycloalkyl_Ci4-alkyl or phenyl-Cw · alkyl, _X represents a Cw fluorenyl bridge, where-is not directly bonded to the -CH2- group on the group R1R2N- Can be -CH = CH- or substituted, and / or-is not directly bonded to one or two non-adjacent -CHr groups on the RiR2N- group can be independently managed, each, _ (s〇) _, _ (§〇2) _, _CO- or -NR4- are replaced in such a way that two 0, s or n atoms or 0 and S atoms are not directly bonded together, and the bridge X can be connected to R1, including Bonded to the N atom # on Ri and X to form a heterocyclyl group. At the same time, the bridge X can be additionally connected to R2, including the N atom on R2 and X to form a heterocyclyl group. The two C atoms or C and N atoms of the bridge can be joined together by an additional Cl-4-extrinsic bridge, and the C atoms that are not directly connected to the heteroatom can be replaced by R1G and / or under each condition Or two C atoms can be via one or two same or different Selected from Cw alkyl, C2.6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3 · 7 · cycloalkyl- (1; 1.3-alkyl, [4-7-cyclo Diluted group and € 4-7-cyclodiluted group- (111-3- 99336.doc 200540142 alkyl group substituted with two alkyl and / or alkenyl substituents together to form a carbocyclic system, And Z represents a single bond or -CR7aR7b-CR7cR7d-, Y has one of the meanings assigned to Cy, and R1 can be connected to Y, including the group X and the N atom to form a heterocyclic group fused with γ, And / or X may be connected to Y to form a carbocyclic or heterocyclic group fused to γ, and A has one of the meanings assigned to Cy, B has one of the meanings assigned to Cy, and b has a value of 0 or 1, Cy represents a carbocyclic or heterocyclic group selected from one of the following meanings: • 3- to 7-membered saturated carbocyclyl, -4- to 7-membered unsaturated carbocyclyl, -phenyl, -has N 4- to 7-membered saturated heterocyclyl or 5- to 7-membered unsaturated heterocyclyl of 0, 0 or S heteroatoms,-having two or more N heteroatoms or one or two ^^ heteroatoms and one 5 · to 7-membered saturated or unsaturated heterocyclic group of 0 or S hetero atom,-having one or more The same or different 5- or 6-membered aromatic heterocyclic group selected from N, 0 and / or s heteroatoms, and the above 4-, 5-, 6- or 7-membered groups may be adjacent to each other through two The C atom is fused with a benzene ring or a pyridine ring, and one or two non-adjacent _CH2 groups in the above 5-, 6-, or 7-membered groups can each independently pass -CO ·, _C (= CH2)- , _ (S0)-or-(S02)-group 99336.doc 200540142, and the 6- or 7-membered saturated group may also have an imine group, n_ (Ck alkyl) -imine group, The methyl 'Ci4 channel-methylene or bis (Cn alkyl) -methylene bridged bridge ring system is presented, and one or more c atoms in the above-mentioned ring group may be mono- or poly-substituted by r2O ( In the case of phenyl, it can be additionally substituted by nitro alone), and / or one or more NH groups may be substituted by R21, R4 has the meaning given to Ri7—or C36 • alkenyl or € 36_ | alkyne R, R5b each independently represents H, Cw alkyl, c3_7-cycloalkyl, C3-7 · cycloalkyl-Cw alkyl, CF3, F or C1, and R5a and R5b can be bonded to each other when it is an alkyl group. Together, and together with the c atom bonded to R5a & R5b to form a C3-7-cycloalkyl, R7a, R7e each independently represents Η, f, CM, Cw alkyl or CF3, and R7b and R7d each independently represent Η, f, Cm-alkyl, C3_7 · cycloalkyl, C3-7-cycloalkyl-c! .3- When alkyl or CF3, φ is alkyl, 117 & and R7b can be joined together, and together with the C atom to which r71 is bonded, it forms c3-7 · cycloalkyl, and / or R7 which is an alkyl group. And R7d can be joined together with R7. Together with the bonded C atom to form a C3-7-cycloalkyl group, or R7b and R7d which are alkyl groups can be bonded together, and together with R7b and the two C atoms bonded to form a c3_7-cycloalkyl group; R1G represents hydroxyl, hydroxy-Cw alkyl, Cw alkoxy, (c1-4-alkoxyalkyl, carboxyl, d.4-alkoxycarbonyl, amino, Ci.4- 99336.doc • 4-200540142 Carbo-amino, bis- (Ci-4-carbo) _amino, cyclic-C3-6-carboimino, amino-Ci-3 · carbo, Cy-carbo-amino- Ci-3-Alkyl, Mono- (Ci-4-Alkyl) -Amino-C1-3-Alkyl, Cyclic-C3_6-Ethylimino-Cl · 3 · Alkyl, Amine-Ci_3 -Alkoxy, Cy-Cycyl-Amino_Ci-3-Cydoxy, Di- (Ck alkyl) -amino-Cw alkoxy, Cyclo-C3-6-alkyleneimino-Cw Alkoxy, aminocarbonyl, Q-4-alkyl-aminocarbonyl, di- (Ci.4-alkyl) -aminocarbonyl or cyclic-C3-6-alkyleneimino-carbonyl 'R11 Cw alkyl, C2.6-alkenyl, C2-6-alkynyl, R15-〇-, rH-OC ^ alkynyl_, r15-o-co, r15_co_o_, cyano, R16R17N-, R18R19N- CO- or Cy, R13 has one of the meanings given to R17, R14 represents halogen, Cw alkane Group, C2-6-alkenyl, C2-6-alkynyl, R15_〇_, R15-〇_CO_, R15-CO, R15-C0_0_, R16R17N_, R18R19N-CO-, rU-O-Cm-alkyl , RU-O-CO-Cy alkyl, R15-0-C0_NH ·, R15-S〇2-NH, r15-〇-co-nh_cN3-alkyl, R15_S02-NH_C 3-alkyl, r15-C〇 -Ci-3 · alkyl, rM-CO-O-Cw alkyl, RUrPN-Cw alkyl, rWrBN-CO-Cw alkyl, or Cy-Cw alkyl-, R15 represents H, Ci.4-alkyl, C3-7-cycloalkyl, c3-7-cycloalkyl-Cw alkyl, benzyl, phenyl-Cu-alkyl, pyridyl or pyridyl-Ci-3 · alkyl, R16 represents fluorene, Cn Radical, C3.7-cycloalkenyl, C3-7 · cycloalkenyl-Ci-3-alkyl, Cy cycloalkenyl, C4-7-cycloalkenyl eCl · 3-alkyl, hydroxy-C2 · 3- Alkyl, Cw alkoxy-C2.3-alkyl, amino-C2 · 6-alkyl, Cl-4-99336.doc 200540142 alkyl-amino-C2-6-alkyl, di- (Ci 4-Alkylamino-C2-6-alkyl or cyclic-C3-6_alkyleneimino-c2_6-alkyl, R17 has one of the meanings given to R16, or represents phenyl, phenyl- Ci.3-Alkyl, fluorenyl, dioxolyl, Ci-4-alkylcarbonyl, hydroxy_carbonyl_CN3-alkyl, CN4-alkoxycarbonyl, CN4-alkoxycarbonyl-Chy alkane Group, CN4-alkylcarbonylamino-c2-3-alkyl, N- (Ci-4_alkyl) -N- (Ci.4_alkyl) -amino group < 2-3-alkyl, C1-4-Alkyl-based amino group, Ci-4 · Alkyl-based amino group-C2-3-Alkyl or N- (C 1-4- & alkylsulfonylalkyl) -amino group -C2-3-alkyl-, R18 and R19 each independently represent fluorene or Cw alkyl, R2G represents halogen, hydroxyl, cyano, Cw alkyl, C2-6-alkenyl, C2-6-alkynyl, C3- 7-cycloalkyl, C3-7-cycloalkyl-Ci-3-alkyl, mesityl-Cw alkyl 'rU-Cw alkyl or one of the meanings assigned to R22, 1121 means (111-4-alkyl Base, meridian- € 2-3-alkyl, fluorenyl1-4-alkyloxy-fluorene 2-6-alkyl, Cm-alkylamino _ (: 2.6-alkyl, di- (Cm-alkane ) _Amino group-C2-6-alkyl group, cyclic-C3-6-alkylene group < 2-6-alkyl group, phenylchun_Ci_3_alkyl group, Ci · 4 · alkyl group- Isopropyl, Ci-4-alkyloxy-Ichiyl, or Ci · 4 · alkylsulfonyl, R22 represents phenyl-C ^ -3-alkoxy, cyclo-C3-6-alkyleneimino -C2-4-alkyloxy, Ci-4-alkyloxy, Ci_4-alkylthio, carboxyl, C1-4-alkylamino, Ci.4-alkyloxyalkyl, aminoamino, C1- 4-alkylamino dream carbon, di- (Ci-4-carbon ) -Aminoalkyl, cyclic-C3-6-Cyno-amino-carbonyl, cyclic-C3-6-alkyleneimino_carbonyl, ring-c3_6 • alkyleneimino-C2-4 -Alkyl_aminocarbonyl, phenyl_amino-carbonyl, cle4-alkyl 99336.doc 200540142-sulfonyl, Ck alkyl · sulfinyl, Ci.4-alkyl-sulfonylamino , Amine, Ci-4 · Alkylamino, Di_ (Ci-4-Alkyl) _amino, Ci-4_Alkyl-carbonyl-amino, Cyclic-C3.6-alkyleneimine Group, phenyl-Cbr alkylamino group, n-cCk alkyl group) -phenyl-c ^ -alkyl-amino group, ethylamino group, propylamino group, phenylcarbonylamino group, phenyl group Carbonylmethyl-amino, hydroxy-Cw alkylaminocarbonyl, (4-morpholinyl) -carbonyl, (1-pyrrolidinyl) -k, (1-pyridyl) _jiki, ( Hexazine-1-puff group)-naphthyl, (4-methyl-1-piperazinyl)-carbonyl, aminocarbonylamino or Ck alkylamino > carbonyl-amino In groups and radicals, especially in X, Ri to R4, R10 to R22, in each case one or more C atoms may be additionally substituted with F single or poly and / or in each case one or two C atoms Can be independently additional via C1 or B r monosubstituted and / or in each case one or more benzene rings may each additionally independently contain one, two or three selected from the group F, Cl, Br, I, Cn4 · alkyl, C! .4 · alkane Oxy, difluoromethyl, trifluoromethyl, hydroxyl, amine, Ci γ alkylamino, di_ (c1-3 • alkyl) _amino, acetamidoamino, amineaminocarbonyl, fluorene Group, difluorofluorenyloxy group, trifluoromethoxyl group, amino-Cw alkyl group, Cw alkylamino-Cy alkyl group and dialkyl group) -amino-Ci · 3 · alkyl substituent and / Or it may be mono-substituted by a nitro group, and the fluorene atom of the carboxyl group or the H atom bonded to the N atom under each condition may be replaced by a group capable of being broken in vivo. 2. The β-ketoaminium compound according to claim 1, characterized in that R1 and R2 each independently represent H, Cle6-alkyl, C3-5 · alkenyl, C3-5_alkynyl, C3y cycloalkyl, Hydroxy-C3 · 7 · cycloalkyl, C: 3 · 7 · cycloalkyl_Ci · 3 · alkyl, (hydroxy- ^ ·? · Ring 99336.doc 200540142 alkyl) -Ci_3_alkyl, meridian -C2-4-Carbonyl, NC-C2-3-Carbonyl, C 1-4 ** Alkoxy-〇2-4_Carbonyl, Methyl- (31.4-Carbooxy " ^ 2-4 -Carbonyl, (^ 4 < ^ oxy-I-yl-Cl · 4 · alkynyl, alkyl-Ci_4-alkynyl, amino- (1; 2.4-alkyl, Cw alkyl-amino-C2. 4 · alkyl, di- (Cm · alkyl) -amino-c2.4 ,; ^ group, cyclo-C3 · 6-alkyleneimino-C2 · 4-alkyl, pyrrolidine_3- Group, N- (Ci.4 · calcined group)-° ratio σ each fluorenyl group, σbirocyl group-Ci.3-octyl group, N-ff alkenyl group) _σbiloxyl-Ci.3-carbon group Group, stilbene-3-yl or -4-yl, Njq alkyl) _piperidin-3-yl or -4-yl, piperidinyl-Cw alkyl, N- (CK4_g group)-tripodyl_ Ci · 3 · Alkyl, Tetrahydrobranthyl-3 · Base, Tetrahydrolamine_4_yl, Tetrahydroalanyl-Cw alkenyl, Tetrahydrocranyl_3_yl, Tetrahydrocranyl i Dagger 3, alkyl, phenyl, phenyl -Cn alkynyl, ° yodo or 11 yodo-C ^ .3 · alkynyl, and in the above groups and residues, one or more C atoms may be mono- or poly-substituted by F and / or Or two C atoms (especially one C atom) may be independently mono-substituted by C1 or Br, and phenyl or pyridyl may be mono- or poly-substituted by the group R2G as defined in claim 1 and / or nitrated 3. The mono-substituting of β. Ketoamine compound according to claim 1, characterized in that Ri & R2 forms an alkylene bridge as claimed in claim 1, so that I ^ I ^ N- forms a group selected from azetidine ,% Pyridine, piperidine, aziridine cycloheptane, 2,5-dihydro-1pyridine-pyrrole, 1,2,3,6, tetrahydro-pyridine, 2,3,4,7-tetraargon-1pyridine -Nitrogen, 2,3,6,7-tetrahydro-1H-nitrogen, pyrazine, in which the free imine functional group is substituted with Rl3, piperidone, morpholine and thiomorpholine. In claim 1, one or more of the fluorene atoms may be replaced by R14, and / or the radical bridge may be replaced by one or two identical or different carbocyclyl or heterocyclyl Cys in the manner described in claim 1. , 99336.doc 200540142 At the same time R13, R14 and Cy are defined as described in claim 1. 4. Amides requested item β- keto compound according to any one of 1, 2 or 3, wherein the group: X y 99336.doc -9- 200540142 99336.doc -10- 200540142 Wherein one or more Η atoms of the heterocyclic ring formed by the group Γ ^ Ι ^ N · may be replaced by R14, and the ring connected to the heterocyclic ring formed by the group Rir2N- may be on one or more C atoms Mono- or poly-substituted by R20 'and in the case of a benzene ring can also be additionally mono-substituted by nitro, and X', X " each independently represents a single bond or an alkylene group, and is bonded to the group Y via a C atom bond In the case of X, or X ,, X ,, X " may also represent -Cw-alkylene_〇-, -Cl.3_-alkylene-NH- or -Cw-alkylene-NCCw alkyl) -, And X "additionally represents -O-Cw-alkylene, -NH-Cw-alkylene, or -N (Ci-3_alkyl) -Ci-3-alkylene, and the group Y via C atom is bonded to X ", then X " also means -NH-, _N (Ci-3-alkyl)-or _〇-, and meanwhile, in the meaning given to X ', X " The lower C atom may be substituted by R1G, preferably via a hydroxyl group, a (〇-hydroxy_C13_ 院 99336.doc-11 · 200540142 group, a C0- (Ci-4-alkyloxy) -Ci-3_alkyl group and / Or 匸 ^ 4 ·, substituted by alkoxy, and / or one or two C atoms in each case may be selected from Ci-6 · by one or two of the same or different , C2-6_alkenyl, C2-6-alkynyl, C3.7-cycloalkyl, C3-7-cycloalkyl-Cu-alkyl, c4_7-% dilute and C4_7_i dilute-C1 · 3-Alkenyl substituent substitution, while two alkyl and / or alkenyl substituents can be joined together to form a carbocyclic system, and in X1, X ", in each case one or more c atoms may be Each is independently mono- or poly-substituted by F and / or in each case one or two c atoms may be independently mono-substituted by C1 or Br, and wherein R2, R10, R13, R14, R2O, and X have claim 1 The meaning given in 5. 5. The β-ketoxamine compound according to any one of claims 2 or 3, characterized in that X represents a Ci4-alkylene bridge without branching, and is in the group Y In the case of bonding to X via a C atom, X also represents CH2 CH-CH_, _CH2-CsC-, C2-4 · alkylene or c2_4-alkylene-NR4-, and the bridge X can be connected to On rule 1, it includes a heterocyclic group connected to the N atom on R1 & x, and the bridge X may be additionally connected to R2, including a heterocyclic group connected to the N atom on R2 and X, and in X , C atom may be substituted by Han 1 () and / or in each In addition, the next or two c atoms may be selected from the group consisting of c16_alkyl, 02-6_alkenyl, c2-6-alkynyl, c3.7_cycloalkyl, 〇3 · through one or two of the same or different 7. · Cycloalkylalkyl, c4_7_ 99336.doc -12-200540142 Substituted by cycloalkyl and C4 · 7 · cyclofluorenyl-C1-3-alkynyl with two alkyl and / or alkenyl substituted The groups may be joined together to form a carbocyclic ring system, and in the above-mentioned groups and groups, one or more C atoms may be mono- or poly-substituted by F and / or one or two C atoms may each independently be Ci or ^ Substitute and Ri, R2, r4 and Ri0 are as defined in the request. , As in the β-ketofluorene compound of claim 5, characterized in that X represents _Ch2_, -CH2-CH2-, -CH2-CH2-CH2, or -CH2-CH = CH-CH2-, and The group Y is bonded to X via a C atom bond, and χ also represents CH2_CH = CH_, _CH2-CsC_, -CH2-CH2-O- -CH2-CH2-CH2-0-, -CHrCHrNR4-, or -CH2-CH2- CH2-NR4-, at the same time, the bridge X can be connected to R1, including the N atom on Ri and x to form a heterocyclic group, and in χ, the c atom can be replaced by r1g, preferably via hydroxyl, hydroxyl_Cw Alkyl, alkoxy)-(:!. 3_alkyl and alkoxy substitutions, and / or one or two C atoms may be independently independently via one or two identical or different < ^. 4_alkanes Group substitution, while two alkyl groups can be joined together to form a carbocyclic system, and in each case one or more C atoms can be substituted! ^ Single or multiple substitutions and / or in each case one or two c The atoms may each be independently substituted by 〇1 or Br, and R1, R4, and R10 have one of the meanings given in the claim item! • If you explicitly seek any one of the items 1, 2, or 3 An amine compound characterized in that the group Y is selected from the following divalent ring groups: phenyl ^ Pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydrolinyl, isoxaline, dihydroisoline , Tetrazine · isalinyl 99336.doc -13 · 200540142 and stupid β-oxalinyl, and the above-mentioned ring group may be mono- or poly-substituted by R20 on one or more C atoms. It may be additionally mono-substituted by nitro, and / or may be substituted by R 21 on one or more N atoms, may be connected to γ and / or X may be connected to Y as described in M seeking item 1, and RR and ruler 21 has the meaning given in claim 1. 8. An amine compound, characterized in that it is selected from the group consisting of 99336.doc -14- 200540142 ， Renren J s At the same time, the above-mentioned ring group may be mono- or poly-substituted on one or more C atoms, and may be additionally mono-substituted by nitro in the case of phenyl, and / or more than one • The NH group may be substituted by R21, wherein R20 and R21 are as defined in the claims. , For example, the β-ketoamine compound according to any one of claims 1, 2 or 3, characterized in that the group A represents a phenyl group, an η-pyridyl group or a naphthyl group, and the above-mentioned cyclic group may have one or more The atom c is mono- or poly-substituted by rule 2 (), and may be additionally mono-substituted by nitro in the case of a benzene ring, and R and R 21 may have the meanings given in claim 1. For example, the ketamine compound of any one of the items 1, 2, or 3 is characterized in that the dagger has a value of 0. 11. The ketamine compound according to any one of items 2 or 3, wherein 苴 has a value of 1 and B has a meaning selected from the group consisting of benzyl decanyl, fluorenyl, and b: The cyclic group may be mono- or poly-substituted on one or more C atoms, and may be additionally mono-substituted on a nitro group under the condition of R, and R has the meaning given in claim 1. 12. The ketamic acid amine compound according to any one of the term i, 2 or 3, characterized by 99336.doc • 15- 200540142 z represents a single bond or -CH2-CH2-. The ketamine compound according to any one of i, 2 or 3, wherein R3 represents H or methyl. 14. The ketamine compound according to any one of items 2 or 3, which is characterized by: Υ means Α indicates At the same time, the cyclic groups related to γ, A, and B described above may each be independently substituted on the one or more C atoms by the same or different R20 mono- or poly- ', and in the case of phenyl, it may be additionally Mono substituted with nitro and b has the value 0 or 1. 15. The β-ketamine compound according to claim 14, characterized in that R1 and R2 are as defined in claim 2 or 3, and X is as defined in claim 5. 16. If it is called β-ketohydrazine compound of any one of terms 1, 2 or 3, it is characterized in that r20 represents _ prime, hydroxyl, cyano, alkyl, C2-4-alkenyl, C2-4 -Block, Cw cycloalkyl, c3.7_cycloalkyl-Cw alkyl, hydroxy 99336.doc -16 · 200540142-CiT alkyl, Rlc ^ -alkyl or one of the meanings assigned to R22, and R22 CN4-alkoxy, Ci-4-alkylthio, carboxyl, Ci.4-alkylcarbonyl, Ci-4-alkoxycarbonyl, aminocarbonyl, Ci.4-alkylaminocarbonyl, di- ( Ci_4 · Aromatic group) -Amino group, Ci.4 · Aroyl group-Amino group, Ci-4-Aroyl group-Stone yellow Aromatic group, Ci-4 -Aroyl group-continuous base amino group, Amine group Ci-4_ alkylamino-, di- (C1-4-alkyl) -amino, Cl.4-alkyl-quinyl ", amino, hydroxy-C1-3-alkylaminocarbonyl , Aminocarbonylamino or Ci-4-alkylaminoamino * " Amine 'is also in the definition provided by R2G and R22. In each case, one or more C atoms can be additionally treated by F single or multiple Substitutions and / or in each case one or two C atoms may additionally be independently independently substituted by C1 or Br. 17. A physiologically acceptable salt of a β-ketamine compound as claimed in one or more of claims 1 to 16. 18. A composition comprising at least one β-ketofluoramine compound as claimed in one or more of claims 1 to 16 and / or as required, mixed with one or more physiologically acceptable excipients The salt of item 17. 19. A pharmaceutical composition comprising at least one β-ketamine compound as claimed in one or more of claims 1 to 16 and / or as claimed in claim 17, optionally mixed with one or more inert carriers and / or diluents. Of salt. 20. Use of at least one ketamine compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 for the manufacture of a medicament for influencing the eating behavior of a mammal. 21 · — at least one ketamine compound as claimed in one or more of claims 1 to 16 99336.doc • 17- 200540142 22. 23. 24. 25. 26. Use of a substance and / or the salt as claimed in claim 17 'which is used to manufacture a medicament for reducing the weight of a lactating animal and / or preventing weight gain. A use of at least one β-ketohydrazine compound according to one or more of claims 1 to 16 and / or a salt according to claim 17, which is used for preparing a pharmaceutical composition having a receptor antagonistic activity. A use of at least one β-ketamine compound as claimed in one or more of claims 1 to 16 and / or a salt as claimed in claim 17 for the preparation for the prevention and / or treatment of a disease caused by or associated with MCH MCH is a pharmaceutical composition with causal symptoms and / or diseases. Use of at least one ketamine compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 for the preparation of a substance suitable for the prevention and / or treatment of metabolic disorders and / or diet Pharmaceutical compositions for disorders, particularly obesity, bulimia, bulimia, cachexia, anorexia, anorexia nervosa, and bulimia. Use of at least one ketamine compound according to one or more of claims 1 to 16 and / or a salt according to claim 17 for the preparation and / or treatment of diseases related to obesity and Pharmaceutical composition of / or disorders, especially these diseases and / or disorders: diabetes, especially type 11 diabetes; diabetes onset, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy; insulin resistance Abnormal glucose tolerance; cerebral hemorrhage; insufficient heart function; cardiovascular disease, especially arteriosclerosis and hypertension; arthritis and knee arthritis. Use of at least one bupropion compound as claimed in one or more of claims 1 to 16 and / or a salt as claimed in claim 17 for the preparation of 99336.doc • 18 · 200540142 and / or treatment Hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, mood disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual dysfunction, Medical composition of memory disorders, epilepsy, various forms of dementia and hormonal disorders. 27. The use of at least one p-ketamine compound as claimed in one or more of claims 1 to 16 and / or a salt as claimed in claim 17 for the preparation of a substance suitable for the prevention and / or treatment of incontinence such as urinary incontinence , Frequent urination, urgency, nocturia and enuresis & urinary disorders medical composition. 28. —The use of at least one ketamine compound as claimed in one or more of claims 16 to 16 and / or the salt as claimed in claim 17 for the preparation of prophylaxis and / or treatment dependence and / Or a pharmaceutical composition of withdrawal symptoms. 29 · —A method for preparing a composition or a pharmaceutical composition according to one or more of claims 18 to 28, characterized in that at least one β-one such as one or more of claims 1 to 16 is non-chemically processed The amidamine compound and / or the salt as claimed in claim 17 is incorporated in one or more inert carriers and / or diluents. Chun 30 · —a pharmaceutical composition containing a first active substance, which is selected from the group consisting of one or more of the ketoxamine compounds and / or the salt of claim 17, and a second activity Substances, which are selected from the group consisting of active substances for treating diabetes, active substances for treating diabetic dysfunction, active substances for treating obesity which are preferably different from MCH antagonists, active substances for treating hypertension, Treatment includes arteriosclerotic dyslipidemia or hyperlipidemia active substance, active substance for arthritis treatment, 99336.doc -19-200540142 active substance for depression and active substance for depression, mixed with one or more inert substances as appropriate Carrier and / or diluent. 3 1 · A method for preparing a ketamine compound of formula I R3 R5a R5b wherein A, B, b, X, Y, Z, R1, R2, R3, R5a, and R5b are as defined in claim 1, wherein they are in a solvent or solvent mixture in the presence of at least one base of the formula A1 amine compound R \ r2 / NXY—z A1 in which X, Y, Z, R1, R2 and r3 are as defined above, and a carboxylic acid compound or carboxylic acid derivative of formula A2 Wherein A, B, b, 115 & and R5b are as defined above, and the group M represents OH, CM, Cw alkoxy, Cw alkylthio or Cw alkyl-COO-, and reacts. 32. A method for preparing a β__amidine compound of formula I, 99336.doc -20- 200540142 R1 \ 1? Y-Z1A ^ 屮 L. R3 is defined as, 'wherein it is in a solvent or a solvent mixture and Condition in activated nucleophiles In the following, the propynyl ammonium compound of formula B 1 is hydrolyzed by adding an acid or a base, B1 Among them: 8, 13, 13, Y, 2, 111, 1 ^ 2, and 1 ^ 3 are as defined above 99336.doc -21-200540142 7. Designated representative map: (1) The designated representative map in this case is : (None) (b) Brief description of the component symbols in this representative drawing: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Ο 0 R1 \ Ν-χ-Υ— Z \ r2 / N I R A-l · 6] 99336.doc