EP1534689A1 - Neue carbons ureamid-verbindungen mit mch-antagonistischer w irkung, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung - Google Patents

Neue carbons ureamid-verbindungen mit mch-antagonistischer w irkung, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung

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Publication number
EP1534689A1
EP1534689A1 EP03794886A EP03794886A EP1534689A1 EP 1534689 A1 EP1534689 A1 EP 1534689A1 EP 03794886 A EP03794886 A EP 03794886A EP 03794886 A EP03794886 A EP 03794886A EP 1534689 A1 EP1534689 A1 EP 1534689A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
alkyl
ethyl
carboxylic acid
ylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03794886A
Other languages
German (de)
English (en)
French (fr)
Inventor
Dirk Stenkamp
Martin Lenter
Heike-Andrea Wieland
Klaus Rudolf
Stephan Georg MÜLLER
Ralf R. H. Lotz
Kirsten Arndt
Philipp Lustenberger
Thorsten Lehmann-Lintz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1534689A1 publication Critical patent/EP1534689A1/de
Withdrawn legal-status Critical Current

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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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Definitions

  • New carboxylic acid amide compounds having MCH antagonist activity medicaments containing these compounds and methods of theirs
  • the present invention relates to novel carboxylic acid amide compounds, processes for their preparation and their physiologically acceptable salts and their use as MCH antagonists and their use for the production of a medicament which is used for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or MCH in another causal relationship is appropriate.
  • Another object of this invention relates to the use of a compound according to the invention for influencing the eating behavior as well as for reducing the body weight and / or for preventing an increase in the body weight of a mammal.
  • compositions and pharmaceutical compositions, each containing a compound of the invention, and a process for their preparation, the subject of this invention are examples of these compounds, and a process for their preparation, the subject of this invention.
  • obesity is basically considered to be any increased level of obesity leading to a health risk.
  • a distinction between normal and obesity-related individuals is ultimately not exactly possible, but the health risk associated with obesity probably increases continuously with increasing adiposity.
  • the individuals having a body mass index (BMI) defined as the kilogram of body weight divided by height (in meters) squared are above the value of 25, especially above 30, as suffering from obesity.
  • MCH antagonists inter alia WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • MCH-1 R The anorectic effects of MCH are mediated by the G ⁇ s- coupled MCH-1 R in rodents [3-6]. In contrast to primates, ferrets and dogs, no other receptor has been detected in rodents so far. After losing the MCH-1 R, knock-out mice have less fat mass, increased energy expenditure and, on a high-fat diet, no weight increase compared to control animals. Another indication of the importance of the MCH-MCH-1 R system in energy balance regulation comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the animals treated with the antagonist lose significant weight.
  • SNAP-7941 receptor antagonist
  • the MCH-1 R antagonist SNAP-7941 provides further anxiolytic and antidepressant effects in behavioral experiments with rats [3].
  • the MCH-MCH-1 R system is involved not only in the regulation of the energy balance but also the affectivity.
  • R 1 and R 2 are independently H or a hydrocarbon group in which R 1 and R 2 together with the adjacent N atom can form an N-containing heterocyclic ring and R 2 together with the adjacent N atom and Y can form an N-containing hetero ring, as MCH antagonists for the treatment of including obesity.
  • Ar 1 , Ar 2 , Ar 3 inter alia, aryl or heteroaryl, XO, S or N-CN, Y is a single bond or C ⁇ - alkylene and R 1 and R 2 have the meanings indicated.
  • Carboxylic acid amides as antagonists of the human 11CBy receptor are proposed in WO 02/10146 (Smithkline Beecham).
  • the compounds are representatives of the general structural formula
  • R 3 is H, methyl or ethyl
  • R 4 is an optionally substituted aromatic carbocyclic or heterocyclic ring
  • Z is O, S, NH, CH 2 or a Single bond
  • R 5 is an optionally substituted aromatic, saturated or unsaturated carbocyclic or heterocyclic ring
  • Q is the group -XY-NR 1 (R 2 ), wherein according to different cases XO, S or N, Y is an alkylene or a cycloalkylene group which may also be substituted, and R 1 and R 2 may be alkyl or phenyl-alkyl, wherein R 1 and R 2 , R 1 and Y or R 1 and X may also be linked together to form a ring system as indicated ,
  • WO 01/72712 (Cor Therapeutics Inc.) describes isoquinoline compounds of the following formula
  • A is an optionally substituted amino or amidino group
  • Z is a bond or an alkyl, cycloalkyl, alkenyl, alkynyl or aryl spacer group, m and n is 0 to 3
  • D is a bond or a given bridge
  • X is NR 12 or CHR 12 , p 0 to 3
  • E in addition to specified ether, amine, amide and carboxyl groups and a bond
  • J is a bond, a cycloalkylene, phenylene, naphthylene or heteroaryl group
  • G is a specified amide, Imino or amidino groups and the remaining radicals have the meanings indicated.
  • metabolic disorders such as obesity and / or diabetes
  • a first subject of the present invention are carboxylic acid amide compounds of general formula I.
  • R 1, R 2 are independently H, an optionally substituted C ⁇ 11 -8 alkyl or C 3 -7-cycloalkyl group or an optionally monosubstituted with the group R by the group R 12 or singly, multiply, and / or nitro substituted phenyl radical, or
  • R 1 and R 2 form a C 2 - 8 alkylene bridge in which
  • one or two -CH 2 groups can be replaced independently of one another by -O-, -S-, -CO-, -C (CHCH 2 ) - or -NR 13 - such that heteroatoms are not directly linked to one another,
  • alkylene bridge may be substituted with one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy
  • R 3 H de-alkyl, C 3-7 cycloalkyl, C 3 -7-cycloalkyl-C 1-4 alkyl-, C3-7-
  • Cycloalkenyl C 3 -7-Cycloalkenyl-C ⁇ . alkyl, phenyl, phenyl-d- 4- alkyl, C ⁇ - 3 -alkoxy-C2- 6 -alkyl, amino-C 2 - 6 alkyl, C 3 -alkyl-amino-C 2 - 6 -alkyI or di (C 1-3 alkyl) amino C 2-6 alkyl,
  • X is a single bond or a d- ⁇ -alkylene bridge in which
  • One or two -CH 2 groups independently of one another by -O-, -S-, - (SO) -, - (S0 2 ) -, -CO- or -NR 4 - may be replaced such that in each case two O -, S or N atoms or an O- are not directly connected to an S atom,
  • alkylene bridge may be linked to R 1 including the N atom joined to R 1 and X to form a heterocyclic group
  • Z is a C ⁇ -4 -alkylene bridge, wherein two adjacent carbon atoms can be connected to each other with an additional C ⁇ -4- alkylene bridge, wherein in the group Z is a -CH 2 group by -O- or -NR 5 - can be replaced,
  • one or two C atoms of the alkylene bridge are independent each other with a hydroxy, ⁇ -hydroxy-C- ⁇ -3-alkyl, ⁇ - (C ⁇ _ 3 -alkoxy) -C ⁇ -3-alkyl, C ⁇ -3 alkoxy radical, amino-C 1-3 alkyl, C ⁇ -3 alkyl-amino-C ⁇ -3 - alkyl or di- (. C ⁇ -C3 alkyl) amino-C ⁇ -3 alkyl and / or with same or different one or two C ⁇ -6 alkyl residues may be substituted, and / or
  • R 3 may be joined to Z including the N atom joined to R 3 to form a heterocyclic group
  • R 1 may be joined to Y including the group X and the N atom joined to R 1 and X to form a heterocyclic group fused to Y, and / or
  • R 3 may be joined to Y including the group Z and the N atom connected to R 3 and Z to form an anlY condensed, saturated or partially unsaturated heterocyclic group, or
  • a and R 3 can be connected to each other in such a way that
  • Q is a group selected from the partial formulas IIIa to IIIg
  • L 1 , L 2 , L 3 independently of one another, have the meanings given for R 20 ,
  • Group W or, if appropriate, directly to the group A via a C atom of the carbocyclic part or of the optionally fused phenyl or pyridine ring or via an N or C atom of the heterocyclic part,
  • Ring system or can be connected to each other via two common, adjacent atoms to form a fused, bicyclic ring system,
  • W is a single bond, -O-, a C ⁇ -4 alkylene, C 2-4 alkenylene, C 2-4
  • W in the meanings alkylene, oxyalkylene and alkyleneoxyalkylene can also be linked to B via a double bond
  • Cy is a carbo or heterocyclic group selected from one of the following meanings
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , and in the case of a phenyl group may also be additionally substituted simply by nitro, and / or by one or more N atoms with R 21 ,
  • R 4 , R 5 independently of one another, have the meanings given for R 16 ,
  • R 8 , R 9 are each independently H, a C ⁇ - 6 alkyl, ⁇ -C ⁇ -3 alkoxy-C ⁇ - 3 -alkyl or ⁇ hydroxy-C 3 -3 alkyl group and R 6 , R 7 , R 8, independently of one another, also halogen,
  • R 12 is one of the meanings given for R 20 .
  • R 13 is one of the meanings given for R 17 , R 14 is halogen, Ci.E alkyl, R 15 -0-, R 15 -0-CO-, R 16 R 17 N-, R 18 R 19 N-CO-, R 15 -0-
  • R 5 H C ⁇ . 4- alkyl, Cs-7-cycloalkyl, C 3 -7-cycloalkyl-C ⁇ . 3 -alkyl, phenyl, phenyl
  • R 16 is H, C ⁇ - 6 alkyl, C 3 -7-cycloalkyl, C 3 -7-cycloalkyl-C ⁇ . 3 alkyl, C 4 - 7 - cycloalkenyl, C4 -7 cycloalkenyl-C 1-3 alkyl, (D-hydroxy-C - 3 alkyl,
  • R 17 is one of the meanings given for R 16 or phenyl, phenyl-C. 3- alkyl, pyridinyl, dioxolan-2-yl, C 3 -alkylcarbonyl,
  • R 18 , R 19 independently of one another are H or C- ⁇ -alkyl
  • R 20 is halogen, hydroxy, cyano, C 1 -alkyl, C 3 . 7 cycloalkyl, hydroxy-C ⁇ - 3 - alkyl, or one of the meanings given for R 22 ,
  • R 21 C ⁇ - 3 alkyl, co-hydroxy-C 2 - 3 alkyl, phenyl, phenyl-3 C ⁇ - alkyl, C 1-3 alkyl carbonyl, carboxy, C ⁇ - 4 -alkoxy-carbonyl, C ⁇ - 3- alkylsulfonyl, phenylcarbonyl or phenyl-C 3 -alkyl-carbonyl,
  • R 22 is pyridinyl, phenyl, phenyl-C ⁇ -3 alkoxy, C ⁇ -3 alkoxy, C ⁇ -3 alkylthio, carb oxy, H-CO-, C ⁇ - 3 alkylcarbonyl, C ⁇ -4 alkoxycarbonyl, aminocarbonyl,
  • each one or more carbon atoms one or more times with F and / or in each case one or two C Atoms independently of one another can be substituted simply with Cl or Br, and / or in each case one or more phenyl rings independently of one another additionally one, two or three substituents selected from the group F, Cl, Br, I, C ⁇ .
  • the H atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by an in-vivo leaving group
  • the invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium. Another object of the present invention is a process for the preparation of carboxylic acid amide compounds of the formula I.
  • A in the case that A is a connected via a nitrogen atom with the carboxylic acid amide nitrogen-heterocyclic group, which may have one or more heteroatoms selected from N, O and S in addition to the nitrogen atom, means at least one amine compound of Formula 1-1
  • Y and Z have the meanings indicated and OMs is a leaving group, preferably mesylate, to give a phthalazinone derivative of the formula Ic.6
  • physiologically acceptable salts of the carboxylic acid amide compounds according to the invention described above and below are also an object of this invention.
  • compositions comprising at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • medicaments comprising at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more inert carriers and / or diluents are the subject of the present invention.
  • an object of this invention is the use of at least one carboxylic acid amide compound of the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • an object of the present invention is the use of at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention for the production of a medicament with MCH receptor antagonistic activity.
  • an object of this invention is the use of at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention for the preparation of a medicament, which for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH in one other causal relationship is appropriate.
  • Another object of this invention is the use of at least one carboxylic acid amide compound of the invention and / or a salt according to the invention for the manufacture of a medicament, soft for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, in particular of obesity, bulimia, bulimia nervosa, cachexia , Anorexia, anorexia nervosa and hyperphagia, is suitable.
  • an object of this invention is the use of at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention for the preparation of a medicament which is used for the prophylaxis and / or treatment of obesity-associated diseases and / or disorders, in particular diabetes, especially type II Diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • diabetes especially type II Diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • the present invention has the use of at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention for the manufacture of a medicament which is used for the prophylaxis and / or treatment of hyperiipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, Depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
  • Another object of this invention is the use of at least one carboxylic acid amide compound of the invention and / or a salt of the invention for the manufacture of a medicament useful in the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis.
  • an object of this invention relates to processes for the preparation of a medicament according to the invention, characterized in that at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents by non-chemical means.
  • a further subject of this invention is a medicament containing a first active substance which is selected from the carboxylic acid amide And a second active ingredient selected from the group consisting of active ingredients for the treatment of diabetes, agents for the treatment of diabetic complications, agents for the treatment of obesity, preferably other than MCH antagonists, active ingredients Treatment of hypertension,
  • Active ingredients for the treatment of hyperlipidemia including arteriosclerosis, agents for the treatment of arthritis, drugs for the treatment of anxiety and drugs for the treatment of depression, optionally with one or more inert carriers and / or diluents.
  • the groups, radicals, substituents and indices have, in particular A, B, W, X, Y, Z, R 1 to R 9 , R 11 to R 22 , L 1 , L 2 , L 3 and k, one of the meanings given above and / or below.
  • R 3 is H, C 1-e-alkyl, C 3-7 -cycloalkyl, C 3 . 7 -cycloalkyl-C ⁇ . 4- alkyl-, C 1-3 -alkoxy-
  • Group W or, if appropriate, directly to the group A via a C atom of the carbocyclic part or of the optionally fused phenyl or pyridine ring or via an N or C atom of the heterocyclic part,
  • a phenyl group a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having an N, O or S atom as heteroatom,
  • R 15 is H, d-4 alkyl, C 3rd 7 -cycloalkyl, C 3-7 -cycloalkyl-C. 3- alkyl, phenyl or phenyl-C 3-alkyl,
  • R 17 is one of the meanings given for R 16 or
  • R 22 is phenyl, phenyl-C ⁇ . 3 alkoxy, C ⁇ -3 alkoxy, C ⁇ . 3- alkylthio, carboxy,
  • the H atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by an in-vivo leaving group
  • the group A and the radical R 3 are not directly connected to each other. Therefore, the group A has one of the meanings given for Cy.
  • the group A and the radical R 3 are connected to each other such that
  • Q is a group selected from the subformulae purple to IIIg
  • preferred meanings of the group Q are selected from the subformulae IIIb, IIId, IIIe, IIIf and IIIg, in particular IIId, IIIe, IIIf and IIIg.
  • R 6, R 7, R 8 and R 9 are independently H and C ⁇ -4 alkyl, in particular H, methyl or ethyl.
  • the substituents L 1 , L 2 , L 3 independently of one another preferably have one of the following meanings H, F, Cl, Br, CH 3 , CHF 2 , CF 3 , C 2 H 5 , C 3 H 7 , CH (CH 3 ) 2 , OCH 3 , OCHF 2 , OCFs, OC 2 H 5, OC 3 H 7 and OCH (CH 3 ) 2 .
  • substituents L 1 , L 2 , L 3 has a meaning other than H, in particular one of the meanings given above as preferred. Particularly preferably, all three substituents L 1 , L 2 , L 3 H.
  • the radicals R 1, R 2 are independently H, C ⁇ -6 alkyl, C3-7 mean - cycloalkyl, C 3 - 7 cycloalkyl-C ⁇ alkyl-3, co-hydroxy-C 2 -s-alkyl -, (3 C ⁇ - alkoxy) ⁇ - - C 2-3 alkyl, C ⁇ -4 -alkoxy-carbonyl-3 C ⁇ - alkyl, alkyl amino-C 2-4 alkyl -3 C ⁇ amino-2- C 4-alkyl or di- (C ⁇ -3 alkyl) amino-C 2 - 4 alkyl, phenyl or phenyl-3 C ⁇ - alkyl, wherein, in the above-mentioned groups and radicals or more C atoms can be mono- or polysubstituted with F and / or one or two C atoms independently of one another with Cl or Br, and where the phenyl radical is mono- or polysubstituted by the previously defined R 12 radical and
  • the radicals R 1 , R 2 are independently C 1 -C 4 -alkyl, C 3 . 7 -cycloalkyl, C 3-7 -cycloalkyl-C 3 -alkyl-, ⁇ -hydroxy-C 2 - 3 -alkyl-, ⁇ - (C 1-3 -alkoxy) -C 2 . 3 -alkyl, C ⁇ . 4- alkoxy-carbonyl -C. 3 -alkyl-, where one of the radicals R 1 , R 2 can also be H.
  • R 1 and R 2 form an alkylene bridge such that R 1 R 2 N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1 H-pyrrole, 1, 2,3, 6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, wherein the free imine function may be substituted with R 13 , Morpholine and thiomorpholine, according to the general definition of R 1 and R 2, one or more H atoms may be replaced by R 14 , and / or the aforementioned groups in one according to the general definition of R 1 and R 2 in the manner indicated with one or two identical or different carbo- or heterocyclic Cy groups can be substituted.
  • R 1 R 2 N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-di
  • the group has a meaning according to one of the following sub-formulas
  • one or more H atoms of the heterocycle formed by the group R 1 R 2 N- may be replaced by R 14 and the ring connected to the heterocycle formed by the group R 1 R 2 N- one or more times on one or more several C atoms with R 20 , in the case of a phenyl ring also in addition may be substituted with nitro.
  • R 1 and R 2 with the N atom of the group R 1 R 2 N- are a pyrrolidine, piperidine or 2,5-dihydro-1H-pyrrole Ring, which may be substituted as indicated.
  • Preferred meanings of the group R 14 are C ⁇ - alkyl, C ⁇ _ 4 -cycloalkyl, hydroxy, -C. 4 -alkoxy, C ⁇ - 4- alkoxy-C- ⁇ - 3 -alkyl-, hydroxy-C ⁇ . 3 -alkyl-, C ⁇ - 4 -alkyl- carbonyl, -C.
  • a preferred, substituted with the group Cy piperidine group has the following
  • the alkylene bridge X has no or at most a -NR 4 - group.
  • the position of the NR 4 group within the alkylene bridge X is preferably selected such that together with the amino group NR 1 R 2 or another adjacent amino group no aminal function is formed or two N atoms are adjacent to one another. Therefore, in the case where a -CH 2 group is replaced by -NR 4 -, the alkylene bridge preferably has the meaning C 2 . 7 - alkylene-NR 4 -C 0 -5-alkylene, wherein the bridge X in addition to the N-atom has a maximum of 7 bridging carbon atoms and wherein the carbon atoms may be substituted in the manner indicated.
  • X is preferably a single bond or an unbranched bridge selected from C 1 -C 6 -alkylene, C 2 . 6- alkenylene, C 2 -6-alkynylene, d- ⁇ -alkyleneoxy, carbonyl, carbonyl-C ⁇ - 6 -alkylene or C ⁇ - 6 -alkylene-amino, wherein the amino group may be substituted with R 4 , wherein one or two C atoms may be substituted according to the manner given in the general definition of X. and / or the alkylene bridge may be joined to R in the manner indicated.
  • X is a single bond, carbonyl or an alkylene bridge selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, wherein one or two C atoms independently of one another with a hydroxy, ⁇ -Hydroxy-C 1-3 -alkyl-, ⁇ - (C 1-3 -alkoxy) -C 1-3 -alkyl and / or C 1-3 -alkoxy radical and / or in each case with one or two identical or different C 1 - Alkyl radicals may be substituted, and wherein in each case one or more C atoms mono- or polysubstituted with F and / or in each case one or two C atoms may be independently substituted with Cl or Br independently.
  • the substituted C atom is preferably not directly linked to an amino group, in particular -NR 1 R 2 or -NR 4 -, adjacent.
  • a very particularly preferred meaning of the bridge X is a single bond, -CH 2 - or -CH (CH 3 ) -.
  • the position of the NR 5 group within the group Z is preferably selected such that together with the amino group -NR 3 - or one other adjacent amino group no aminal function is formed or two N atoms are adjacent to each other.
  • Preferred meanings of the bridge Z are methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy and 1,4-butyleneoxy, wherein one or two C atoms independently of one another with a hydroxy, ⁇ -hydroxy-C ⁇ .
  • the substituted C atom is preferably not directly linked to an amino group, in particular -NR 3 - or -NR 5 -, adjacent.
  • Z is particularly preferably selected from the group -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH (CH 3 ) -, -CH 2 -C (CH 3 ) 2 -, -CH (CH 3 ) -CH 2 -, -C (CH 3 ) 2 -CH 2 - and -CH 2 -O-, in particular -CH 2 -CH 2 - or -CH (CH 3 ) -CH 2 -.
  • Z is connected to R 3 in this way
  • the radical R 3 is selected from the group methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or 2-hydroxy-1-methyl-ethyl, wherein in said groups , two or three H atoms may be replaced by F, or R 3 is selected from the group H, amino-C - 3 -alkyl, C 3 -alkyl-amino-C 2 -3-alkyl or di- (C ⁇ - 3- alkyl) -amino-C 2 - 3 -alkyl.
  • radical R 3 are H, methyl or ethyl, in particular H or methyl.
  • Preferred meanings of the radicals R 4 and / or R 5 are H, 4 C ⁇ - -alkyl, C 3-6 - cycloalkyl and C3-6-cycloalkyl-C ⁇ -3 alkyl, in particular H and C ⁇ -4-alkyl.
  • Preferred meanings of the group R 1 are C 6 -cycloalkyl, hydroxy, C 1 . 4 - alkoxy, amino, -C -4 -alkyl-amino- and di- (-C ⁇ - 4- alkyl) -amino-.
  • R 20 are halogen, hydroxy, cyano, C 1 -4-alkyl, C 3 . 7 -cycloalkyl and hydroxy-C ⁇ - 3 -alkyl. More preferably R 20 is F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.
  • the group Y is preferably selected from the quantity of the bivalent cyclic groups 1, 2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1, 3-phenylene, 1, 4-phenylene, 1,3- and 1, 4-cyclohexenylene, 1, 4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1, 3-pyrrolinylene, 1, 3-pyrrolylene , 1, 4-piperidinylene, 1, 4-tetrahydropyridinylene, 1, 4-dihydropyridinylene, 2,4- and 2,5-pyridinylene or 1, 4-piperazinylene, wherein the above-mentioned 5-, 6- or 7-membered groups may be connected in a condensed form via a pair of adjacent, adjacent carbon atoms with a phenyl or pyridine ring, the abovementione
  • Very particularly preferred meanings of the group Y are selected from the group of cyclic structures consisting of:
  • cyclic groups one or two times, preferably simply, with R 20 , preferably with halogen, CF 3 , -C. 4- alkyl and / or C ⁇ - 4- alkoxy, may be substituted.
  • group Y may also be connected to the radical R 1 in such a way that
  • Preferred meanings of group A are selected from the group of bivalent cyclic groups 1,2-cyclopropyls, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1 , 3- and 1, 4-phenylene, 1, 3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene , 1, 4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene, 7-azabicyclo [2.2.1] heptan-2, 7-diyl and 8-azabicyclo [3.2.1] octane-3,8-diyl, wherein the above-ment
  • group A is selected from the group of cyclic structures consisting of:
  • the cyclic groups being mono- or disubstituted, preferably monosubstituted, with R 20, preferably with halogen, CF 3, C ⁇ - 4 alkyl and / or C ⁇ -4 alkoxy, may be substituted.
  • the mirror-image forms i. E. the forms in which the linkage with the adjacent groups, in the case of Y with X and Z and in the case of A with CO and W, reversed, comprises.
  • 1,4-cyclohexenylene means both
  • the meaning tetrahydropyridinylene includes the meanings 1, 2,3,4-tetrahydropyridine-1, 4 and -3,6-ylene, 1, 2,3,6-tetrahydropyridine-1, 4, 2, 5 and 3,6-ylene, 2,3,4,5-tetrahydropyridine-2,5- and -3,6-ylene.
  • the preferred meaning here is 1, 2,3,6-tetrahydropyridin-1, 4-ylene.
  • Dihydropyridinylen includes the meanings 1,4- and 1, 2-dihydro-pyridin-1, 4-ylen and 1, 2-, 1, 4-, 1,6-, 2,3-, 2,5-, 3,4-, 4,5- and 5,6-dihydropyridine-2,5-ylene.
  • the preferred meaning here is 1, 2-dihydropyridin-1, 4-ylene.
  • the groups A and / or B are preferably unsubstituted or monosubstituted or disubstituted by R 20 , particularly preferably unsubstituted or simply substituted by R 20 .
  • Preferred meanings of the group B are selected according to a first embodiment from the group C ⁇ - 6 alkyl, C ⁇ - 6 alkenyl, C ⁇ . 6 alkynyl, C 3 . 7 -
  • W is a single bond, -O-, a C 1 .
  • k is 0 or 1, in particular 1 and
  • R 20 has one of the meanings indicated.
  • k preferably has the value 1 and W preferably has the meaning single bond, imino or N- (C 1-3 -alkyl) -imino-, in particular single bond.
  • Preferred meanings of group B according to a second embodiment are selected from the amount of the cyclic groups cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl , Dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl,
  • Cyclohexyliden-methyl and cyclohexanone-4-ylidene-methyl and wherein the aforementioned cyclic groups one or more times to one or more carbon atoms with R 20 , in the case of a phenyl group also additionally simply with nitro, and / or to an or may be substituted by several N atoms with R 21 .
  • the group B is phenyl which is monosubstituted, disubstituted or trisubstituted, preferably monosubstituted or disubstituted by R 20 .
  • pyrazole includes the isomers 1 H, 3H and 4H-pyrazole.
  • Pyrazolyl is preferably 1H-pyrazol-1-yl.
  • imidazole includes the isomers 1 H, 2H and 4H imidazole.
  • a preferred meaning of imidazolyl is 1H-imidazol-1-yl.
  • tetrahydropyridine includes the isomers 1, 2,3,4-, 1, 2,3,6- and 2,3,4,5-tetrahydropyridine.
  • tetrahydropyridinyl 1, 2,3,4- and 1,2,3,6-tetrahydropyridin-1-yl.
  • dihydropyridine includes the isomers 1, 2, 1, 4, 2,3, 2,5 and 4,5 dihydropyridine.
  • dihydropyridinyl means 1, 2 and 1,4-dihydropyridine-1-yl.
  • the meaning triazole includes the isomers 1H-, 3H- and 4H- [1, 2,4] -triazole and 1 H, 2H and 4H [1,2,3] triazole.
  • the meaning triazolyl therefore includes 1 H- [1,2,4] -triazole-1, 3- and 5-yl, 3H- [1, 2,4] -triazol-3-and 5-yl, 4H- [ 1,2,4] triazole-3, 4 and 5-yl, 1 H- [1,2,3] triazole-1, 4 and 5-yl, 2H- [1, 2,3 ] Triazole-2-, 4- and 5-yl and 4H- [1,2,3] triazole-4 and 5-yl.
  • tetrazole includes the isomers 1H, 2H and 5H-tetrazole.
  • the meaning tetrazolyl therefore includes 1 H-tetrazol-1 - and 5-yl, 2H-tetrazol-2 and 5-yl and 5H-tetrazol-5-yl.
  • indole includes the isomers 1 H and 3H indole.
  • indolyl is preferably 1H-indol-1-yl.
  • isoindole includes the isomers 1 H and 2H isoindole.
  • isoindolyl is preferably 2H-isoindol-2-yl.
  • the bond to one of the abovementioned heterocyclic groups in particular to a pyrazolyl, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl group, via a C atom or, if appropriate, an N- Atom of an imine function.
  • the group B is preferably unsubstituted, monosubstituted, disubstituted or trisubstituted by R 20 .
  • B is particularly preferably monosubstituted or disubstituted by R 20 .
  • B is a substituted six-membered ring, it is preferably one
  • the index k can take the values 0 or 1.
  • Preferred meanings of the sub-formula -AW-B are selected from the structures listed in the list below, wherein V is a C or N atom, preferably a C atom, and the cyclic groups listed one or more times to one or more C- Atoms with R 20 and in the case of phenyl or phenylene groups may also additionally be substituted by nitro:
  • the index k can also assume the value 0.
  • the group A is connected to the group B via a common carbon atom to form a spirocyclic ring system, wherein the group A is a saturated 5- to 7-membered and the group B is a saturated 4- to 7-membered carbo- or heterocyclic group, and wherein the heterocyclic groups each have an N, O or S atom, and wherein a 5- to 7-membered group B via two adjacent carbon atoms, a phenyl or pyridine ring may be fused, and wherein the aforementioned cyclic groups one or more times to one or more C atoms with R 20 , in the case of a fused phenyl ring also additionally simply with nitro, and / or to one or more N atoms with R 21 may be substituted.
  • Preferred meanings of the sub-formula -AWB according to these second sub-variants are selected from the structures listed in the table below, wherein the cyclic groups listed one or more times to one or more C atoms with R 20 and in the case of the phenyl ring also additionally with nitro may be substituted:
  • the group B is connected to the group A via two common adjacent atoms to form a fused, bicyclic saturated, unsaturated or aromatic, 8 to 12 membered ring system having one or more same or may have different heteroatoms selected from N, O and / or S, and wherein the bicyclic ring system one or more times to one or more C atoms with R 20 , in the case of a fused phenyl ring also additionally simply with nitro, and / or at one or more N atoms may be substituted with R 21 .
  • Preferred meanings of the sub-formula -AWB according to these first sub-variants are selected from the structures listed in the table below, wherein the cyclic groups listed one or more times to one or more C atoms with R 20 and in the case of the phenyl ring also additionally simply with nitro may be substituted.
  • substituent R 20 are selected from the group consisting of fluorine, chlorine, bromine, CF 3 , C ⁇ - alkyl, C ⁇ - alkoxy
  • Y, A are independently selected from the group of bivalent cyclic groups 1, 4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6-tetrahydropyridine 1,4-ylene,
  • Z is -CH 2 -CH 2 -, -CH 2 -CH (CH 3 ) -, -CH 2 -C (CH 3 ) 2 -, -CH (CH 3 ) -CH 2 -,
  • R 5 23, D R24 independently of one another are H, F, methyl, trifluoromethyl, ethyl, isopropyl or n-propyl,
  • n independently of one another denote 0, 1 or 2.
  • B is selected from the group Ci-e-alkyl, -6- alkenyl, -6- alkynyl, C 3-7 - cycloalkyl-C 3 -3 alkyl, C 3 -7-cycloalkenyl-C. 3 -alkyl-, C 3-7 -cycloalkyl-C ⁇ -3 - alkenyl or C 3 - 7 -cycloalkyl-C ⁇ -3 -alkynyl-, wherein one or more carbon atoms one or more times with halogen and / or simple with hydroxy or cyano and / or cyclic groups may be monosubstituted or polysubstituted by R 20 , and
  • W is a single bond, -O-, a d- 4- alkylene, C 2- alkenylene, C 2 - 4 -
  • k 0 or 1.
  • those compounds according to the invention are particularly preferred in which X is selected from -CH 2 -, -CH (CH 3 ) - or -C (CH 3 ) 2 -.
  • those of the compounds of sub-formulas 1.1 to 1.15 are particularly preferred in which a) the group U is an N atom and the group V is a C atom, or b) the group U is a C atom and the group V is an N atom Atom, or c) both groups U and V each represent a C atom.
  • the substituents R 25 , R 26 , R 27 independently of one another have a meaning selected from F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, Methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy, in the case of the substitution of a phenyl group also simply nitro, where multiple occurring radicals R 25 , R 26 , R 27 may have the same or different meanings, and j 0, 1 or 2, and m, n are independently 0 or 1.
  • R 6 , R 7 , R 8 and / or R 9 in the compounds according to the invention described as being preferred are independently H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, in the case of R 6 , R 7 also F.
  • Particularly preferred single compounds are selected from the group consisting of:
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I.
  • C n- alkyl wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • C ⁇ - may have n -alkylene, where n is from 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms.
  • groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-ethylene (-CH (CH 3 ) -CH 2 -), 1, 1-dimethyl-ethylene (- C (CH 3 ) 2 -CH 2 -), n -prop-1,3-ylene (-CH 2 -CH 2 -CH 2 -), 1-methylprop-1, 3-ylene (--CH (CH 3 ) -CH 2 -CH 2 -), 2-methylprop-1, 3-ylene (-CH 2 -CH (CH 3 ) -CH 2 -), etc., as well as the corresponding mirror-image forms.
  • groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2- Pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, etc.
  • C 1- n -alkoxy denotes a -O-C 1 -n- alkyl group in which C 1- n -alkyl is as defined above.
  • groups include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • C 1 -n- alkylthio denotes an -S-C 1 -n -alkyl group, in which C 1- n -alkyl is as defined above.
  • groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.
  • Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-butyl Hexylcarbonyl, isohexylcarbonyl, etc.
  • C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group having 3 to n C atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.
  • aryl refers to a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.
  • heteroaryl used in this application denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S.
  • heteroaryl denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S.
  • groups are furanyl, thiophenyl (thienyl), pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl,
  • heteroaryl also includes the partially hydrogenated heterocyclic aromatic ring systems, in particular the listed above.
  • Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
  • Ci- n -alkyl which is substituted with an aryl or heteroaryl group as defined above.
  • unsaturated carbocyclic group or "unsaturated heterocyclic group”, as used in particular in the definition of the group Cy, in addition to the fully unsaturated groups, also includes the corresponding, only partially unsaturated groups, especially mono- and diunsaturated groups.
  • radicals and substituents described above may be mono- or polysubstituted by fluorine in the manner described.
  • Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethyl isulfonyl.
  • the compounds of general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups such as amino functions.
  • Compounds of the general formula I can therefore be used as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, Sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as diethylamine, triethylamine, triethanolamine, inter alia.
  • pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, Sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid)
  • pharmaceutically usable bases such as alkali or al
  • the compounds according to the invention can be obtained using synthesis methods known in principle.
  • the compounds are preferably obtained by the preparation process described above and explained in more detail below.
  • the erfindunsgshunte manufacturing method for the first group of preferred embodiments ie those compounds in which the group A and the radical R 3 is not directly connected to each other, basically distinguishes two applications.
  • the first case covers those compounds of the formula I in which the group A represents a nitrogen-heterocyclic group which is bonded via a nitrogen atom to the carboxylic acid amide group and may also have one or more heteroatoms selected from N, O and S in addition to the nitrogen atom ,
  • the reaction of the amine of formula 1-1 with the secondary amine of formula I-2 is illustrated in the following general reaction scheme:
  • the amine compound of the formula 1-1 is first reacted with CDT (1,1'-carbonyldi (1, 2,4-triazole)) in a solvent or solvent mixture and then the reaction mixture with the amine compound of the formula I. -2, wherein the at least one base is added to the reaction mixture before and / or after the reaction of the amine compound with CDT.
  • CDT 1,1'-carbonyldi (1, 2,4-triazole
  • the amine compound of formula 1-1 with CDT in a temperature range from -20 ° C to 20 ° C and then this reaction mixture with the amine compound of formula I-2 in a temperature range of 40 ° C to 100 ° C in a molar ratio of the amine compound of formula 1-1: amine compound of formula I-2: CDT: base of 1 + 0.25: 1 ⁇ 0.25: 1 ⁇ 0.25: 3 ⁇ 1, 5 implemented.
  • Preferred bases are nitrogen bases, in particular tert.
  • the amine compound of the formula I-2 may be a saturated N-heterocyclic compound, such as, for example, a piperazine derivative according to the following Reaction Scheme 2.
  • Reaction Scheme 2 Reaction scheme 2
  • the second case of the production process comprises the other compounds of formula I not covered by case 1, in which group A is not directly linked to R 3 .
  • the reaction of the carboxylic acid compound of formula I-3 with TBTU (2- (1H-benzotriazol-1-yl) -1,3,3,3-tetramethyluronium tetrafluoroborate) and the amine compound of formula 1-1 in one Solvent or solvent mixture in the presence of at least one base is shown in Reaction Scheme 3.
  • the carboxylic acid compound of formula 1-3 is reacted with TBTU in a solvent or solvent mixture and then the reaction mixture further reacted with the amine compound of formula 1-1, wherein the at least one base before and / or after the reaction of Carboxylic acid compound with TBTU is added to the reaction mixture.
  • a carboxylic acid and the corresponding activated carboxylic acid derivatives such as esters, ortho-esters, carboxylic acid chlorides or anhydrides, are used.
  • the base used is preferably a nitrogen base, in particular a tertiary amine, for example triethylamine.
  • biaryl compounds can be obtained by Suzuki coupling, for example starting from p-bromoarylcarboxylic acid derivatives and aryl boronic acid derivatives in the presence of Pd [0] catalysts.
  • the o-bromomethyl-benzoic acid derivative of the formula Ia.2 is reacted with the amine compound of the formula Ia in a solvent or solvent mixture, at least one base being added.
  • a solvent or solvent mixture instead of an o-bromomethylbenzoic acid ester derivative of the formula Ia.2, other corresponding o-benzylbenzoic acid ester derivatives (iodine or mesylate instead of bromine) can also be used.
  • potassium carbonate or cesium carbonate is used as the base, and tert.
  • Amine bases such as triethylamine.
  • an isoquinolinone derivative of the formula Ib.3 is reacted with an electrophilic compound of the formula Formula lb.4 converted to an isoquinoline derivative of formula Ib.5, which is further derivatized by known methods to the compound of formula I.
  • the isoquinolinone derivative of formula lb.3 is obtainable from cinnamic acid derivatives of the formula lb.1 by reaction with (EtO) 2 P (0) N. 3
  • the synthesis of the basic body was described by M. Becker et al. in Bioorganic & Medicinal Chemistry Letters 9 (1999), 2753-2758. The reaction is illustrated in the following Reaction Scheme 5, in which, for reasons of clarity, the substituents L 1 , L 2 , L 3 on the phenyl ring have been omitted.
  • a compound of the formula Ib 2 is advantageously obtained by the reaction sequence described below.
  • the acrylic acid derivative Ib.1 is first reacted by the action of chlorinating agents such as thionyl chloride, phosphorus pentachloride or oxalyl chloride without or optionally in an inert solvent such as dichloromethane to the acid chloride at temperatures between 0 ° C and 80 ° C.
  • chlorinating agents such as thionyl chloride, phosphorus pentachloride or oxalyl chloride without or optionally in an inert solvent such as dichloromethane
  • This is converted to the acrylic acid azide derivative by the action of sodium azide in a solvent or solvent mixture.
  • a solvent for example, dioxane, tetrahydrofuran or water can serve.
  • the synthesis of the isocyanate derivative lb.2 is carried out directly by the action of
  • Suitable solvents are, for example, toluene or dioxane.
  • Tertiary amines such as triethylamine can be used as bases.
  • the above reactions have reaction times between one and twelve hours.
  • Phosphoric acid diphenyl ester azide and triethylamine in a molar ratio of 1 + 0.25: 1 + 0.25: 1 + 0.25 in toluene as solvent.
  • the isocyanate derivative Ib.2 is heated in a solvent, optionally in the presence of a base such as tributylamine, to form the isoquinolone derivative of the formula Ib.3.
  • the reaction preferably proceeds in diphenyl ether in the region of the boiling point. Heating sources are oil, metal or microwave.
  • the reaction of the isoquinolone derivative of the formula Ib 3 with the mesylate derivative of the formula Ib 4 to the isoquinolone derivative of the formula Ib 5 is carried out in a solvent in the presence of a base at temperatures between 0 ° C. and 150 ° C.
  • the reaction of the isoquinolone derivative Ib.3 with the mesylate derivative of the formula Ib.4 and sodium hydride proceeds in a molar ratio of 1 + 0.25: 1 + 0.25: 1 + 0.25 in DMF as solvent.
  • the isoquinolone derivative of formula Ib.5 is first reacted in a solvent in the presence of an acid to convert the acetal to the corresponding aldehyde. This is in the presence of a hydride, an amine and an acid in a solvent in one Compound of formula Ib transferred.
  • suitable hydride carriers are sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride.
  • a phthalazinone derivative of the formula Ic.4 is reacted with an electrophilic compound of the formula Ic.5 to give a phthalazinone derivative of the formula Ic.6, which is further derivatized by known methods to the compound of formula Ic.
  • the above reaction sequence is described in more detail below:
  • the oxazoline derivative lc.1 is metallated by a suitable organometallic reagent and then with a formaldehyde equivalent such as dimethylformamide or a formic acid orthoester at temperatures between -70 ° C and 20 ° C, preferably at temperatures between -20 ° C and 0 ° C to give a compound of formula lc.2 implemented.
  • a solvent for example, dioxane, tetrahydrofuran or diethyl ether can serve.
  • a compound of the general formula Ic.3 is available.
  • the phthalazinone derivative of formula Ic.4 can be obtained by reacting a compound of formula Ic.3 with hydrazine in acetic acid and optionally in a solvent at temperatures between 20 and 120 degrees Celsius.
  • the synthesis route to the phthalazinone derivative of the formula Ic is carried out analogously to the reactions as described for the synthesis of a compound of the general formula Ib.
  • synthesis of phthalazinone derivatives of the formula Ic is illustrated by a synthesis scheme 8 of a specific compound in which the abbreviations LAH lithium aluminum hydride, BuLi n-butyllithium, DMF dimethylformamide, MeOH methanol and Ms-Cl methanesulfonyl chloride mean.
  • a compound of general formula Id.1 is reacted in a solvent such as methanol in the presence of a mineral acid, for example hydrochloric acid, and a salt containing the nitrite ion at a temperature between -10 ° C and 30 ° C.
  • a mineral acid for example hydrochloric acid
  • a salt containing the nitrite ion at a temperature between -10 ° C and 30 ° C.
  • the reaction of the amino compound ld.1 proceeds with sodium nitrite in a molar ratio of 1 + 0.25: 1.5 + 0.25 in methanol as a solvent and in the presence of hydrochloric acid.
  • an o-aminobenzamide derivative of the formula le.1 is converted in the presence of CDI to a quinazolinedione derivative of the formula Ie.
  • CDI is used for the benzamide derivative of the formula le.1 in a molar ratio of greater than or equal to 1 and the reaction is carried out at least partially in a temperature range from 35 ° C to 100 ° C, preferably in the range of the boiling temperature of the reaction mixture.
  • the reaction is illustrated in the following Reaction Scheme 10, in which, for reasons of clarity, the substituents L 1 , L 2 , L 3 on the phenyl ring have been omitted.
  • an o-aminobenzamide derivative of the formula If 1 with a carboxylic acid R 8 COOH and / or a corresponding activated carboxylic acid derivative is added to the quinazolinone derivative.
  • Suitable activated carboxylic acid derivatives are, for example, esters, ortho-esters, carboxylic acid chlorides and anhydrides.
  • the optionally activated carboxylic acid becomes the carboxylic acid amide compound of Formula lf.1 used in a molar ratio greater than or equal to 1 and the reaction is carried out at least partially in a temperature range of 35 ° C to 100 ° C, preferably in the range of the boiling temperature of the reaction mixture.
  • the reaction is illustrated in the following Reaction Scheme 11, in which, for reasons of clarity, the substituents L 1 , L 2 , L 3 on the phenyl ring have been omitted.
  • the starting compounds 1_ and 2 are linked via an amide linkage using TBTU.
  • the nitro group ortho to the amide bond obtained is reduced to the amine in the presence of PtO 2 .
  • the ring closure to quinazolinone is carried out using a carboxylic acid, here formic acid.
  • the isobenzofurandione derivative lg.2 is reacted in a solvent such as acetic acid with an amine of the general formula Ig.1 in a molar ratio of 1 + 0.25: 1, 5 + 0.25.
  • the temperature in the reaction is preferably at the boiling point of the solvent.
  • the isoindoldione derivative of the formula Ig can also be obtained according to the following Synthetic Scheme 14.
  • the illustrated synthesis of a single compound can be readily modified by the skilled person to other compounds of formula Ig optionally modified.
  • the isoindoldione function is obtained from an isobenzofurandione derivative with attachment of an amine, and then a further aryl group is added by means of Suzuki coupling in the presence of Pd [0].
  • optionally present reactive groups such as hydroxyl, carboxy, amino or imino groups can be protected by literature methods during the reaction by conventional protecting groups which are cleaved again after the reaction, in particular the usual protective groups in peptide chemistry can be used become. Information on this can be found, for example, in WO 98/11128.
  • stereoisomeric compounds of the formula (I) can be separated by customary methods.
  • the separation of the respective diastereomers succeeds due to their different physicochemical properties, eg by fractionated Crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen by reaction with inorganic bases, the compound of formula (I) can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid are suitable for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used.
  • the alkali metal and alkaline earth metal salts of the compound of formula (I) with acidic hydrogen are preferably the alkali and alkaline earth metal hydroxides and hydrides into consideration, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium preferably, sodium and potassium hydroxide are particularly preferred.
  • the compounds of the present invention have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies.
  • Pharmacological test systems for MCH antagonistic properties are described in the following experimental section.
  • the compounds of the invention are advantageously useful as pharmaceutical agents for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.
  • MCH antagonists which have at least one compound of the invention, especially in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and / or prophylaxis of Phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • Diseases caused by MCH or otherwise causally related to MCH include, in particular, metabolic disorders, such as obesity, and eating disorders, such as bulimia, including bulimia nervosa.
  • Obesity includes primarily obesity, hyperinsulinic obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity.
  • cachexia, anorexia and hyperphagia are to be mentioned in this indication environment.
  • compounds of the present invention may be useful in reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety,
  • diseases caused by MCH or otherwise causally related to MCH may include hyperiipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, reproductive disorders, memory disorders, forms of Dementia and hormonal disorders are counted.
  • Compounds of the invention are also useful as agents for the prophylaxis and / or treatment of other diseases and / or disorders, in particular those associated with obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, cardiovascular disease, especially arteriosclerosis and hypertension, and gonitis suitable.
  • diseases and / or disorders in particular those associated with obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, cardiovascular disease, especially arteriosclerosis and hypertension, and gonitis suitable.
  • MCH antagonists and formulations according to the invention can advantageously be used in combination with an alimentary therapy, such as, for example, an alimentary diabetes therapy, and exercise.
  • Another indication for which the compounds of the invention are advantageously useful is the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • voiding disorders such as urinary incontinence, overactive bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign prostatic hyperplasia Need to be connected.
  • the dosage required to achieve a corresponding effect is expediently from 0.001 to 30 mg / kg body weight, preferably from 0.01 to 5 mg / kg body weight, by intravenous or subcutaneous administration, and from 0.01 to 50 mg / kg by oral, nasal or inhalative administration Body weight, preferably 0.1 to 30 mg / kg body weight, in each case 1 to 3 times daily.
  • Active substances as described in more detail below, together with one or more physiologically acceptable adjuvants, inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine,
  • Water / sorbitol water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, Dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories.
  • compositions comprising at least one carboxylic acid amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • Such compositions may, for example, also be foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.
  • suitable further active substances are, in particular, those which, for example, enhance the therapeutic efficacy of an MCH antagonist according to the invention with regard to one of the indicated indications and / or which allow a reduction in the dosage of an MCH antagonist according to the invention.
  • one or more further active substances are selected from the group consisting of
  • agents for the treatment of diabetic complications - agents for the treatment of obesity, preferably non-MCH antagonists,
  • insulin sensitizers examples include pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably maleates), JTT-501, G 1-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.
  • Insulin secretion enhancers include sulfonylureas such as tolbutamide, chlorpropamide, trazamide, acetohexamide, glydlopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.
  • Biguanides include metformin, buformin, phenformin.
  • Insulins include insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins enzymatically synthesized from animal-derived insulin, human insulin obtained by genetic engineering, for example, from Escherichia coli or yeasts. Further, insulin is understood as meaning insulin zinc (containing 0.45 to 0.9% by weight of zinc) and protamine insulin zinc available from zinc chloride, protamine sulfate and insulin. In addition, insulin may come from
  • Insulin fragments or derivatives for example, INS-1, etc. can be obtained.
  • Insulin may also include different types, for example with regard to the time of onset and duration of action ("ultra-immediate action type",
  • immediate action type "two-phase type”, “intermediate type”, “prolonged action type”, etc.), which are selected depending on the pathological condition of the patients.
  • Glucosidase inhibitors include acarbose, voglibose, miglitol,
  • ⁇ 3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • Other than the aforementioned drugs for the treatment of diabetes include ergoset, pramlintide, leptin, BAY-27-9955 and glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipazides, glyburides.
  • Agents for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors.
  • Aldose reductase inhibitors are, for example, Tolrestat, Epalrestat, Imirestat, Zenarestat, SNK-860, Zopolrestat, ARI-50 ⁇ , AS-3201.
  • An example of a glycation inhibitor is pimagedine.
  • Protein kinase C inhibitors are, for example, NGF, LY-333531.
  • Alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-) are other than the aforementioned active ingredients for the treatment of diabetic complications.
  • Agents for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • Examples of preferred anorectic agents are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.
  • CCK-A cholecystokinin A
  • a monoamine reuptake Inhibitor such as sibutramine
  • a sympathomimetic agent such as sibutramine
  • a serotonergic agent such as dexfenfluramine or fenfluramine
  • a dopamine antagonist such as bromocriptine
  • a melanocyte-stimulating hormone receptor agonist or mimetic an analog of the melanocyte-stimulating hormone
  • a cannabinoid receptor antagonist an MCH antagonist
  • the OB protein hereinafter referred to as leptin
  • leptin analog a leptin receptor agonist
  • Agonist a galanin antagonist, an Gl lipase inhibitor or reducer (such as orlistat).
  • Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like
  • Peptide-1 receptors such as exendin and ciliary neurotrophic factors such as axokines.
  • Agents for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.
  • Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).
  • Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.
  • Potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121.
  • Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbeartan, CS-866, E4177.
  • Agents for the treatment of hyperlipidemia include arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-
  • Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.
  • Agents for the treatment of arthritis include ibuprofen.
  • Agents for the treatment of anxiety include chlordiazepoxides, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Agents for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.
  • the invention also relates to the use of at least one carboxylic acid amide 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 compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or a To cause satiety.
  • the eating behavior is favorably influenced so that the food intake is reduced. Therefore, the compounds of the invention find advantageous application for reducing body weight.
  • Another use of the invention is to prevent an increase in body weight, for example, in people previously
  • a non-therapeutic use is preferably a cosmetic application, for example, for altering the appearance or an application for improving the general condition.
  • the compounds of the invention are preferably used non-therapeutically for mammals, especially humans, who have no diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and / or no diagnosed voiding disorders, especially urinary incontinence.
  • the compounds of the invention are suitable for non-therapeutic use in humans whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, in particular below 25, lies.
  • BMI body mass index
  • Method A Water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 over 9 min
  • Method B water: acetonitrile: formic acid 9: 1: 0.01 to 1: 9: 0.01 over 4 min, then 6 min 1: 9: 0.01
  • Reaction solution for 30 min to 3 h at 60 to 80 ° C. DMF is removed in vacuo and the residue taken up with dichloromethane and 5% Na 2 CO 3 solution or with water and tert-butyl methyl ether.
  • the organic phase is extracted with water and, if appropriate after drying over magnesium sulfate, the solvent is removed on a rotary evaporator; Further purification is carried out by column chromatography or crystallization.
  • the reaction can also be carried out in the automatic synthesizer Chemspeed.
  • a solution of 500 g (2.057 mol) of ethyl 4-bromomethylbenzoate in 1000 ml of ethanol is added dropwise to a solution of 147.5 g (2.263 mol) of potassium cyanide in 250 ml of hot water.
  • the reaction mixture is heated to reflux for one hour and stirred for 12 hours at room temperature.
  • Another 73.7 g (0.5 mol) of potassium cyanide are added and heated to reflux for two hours.
  • the solid present in the reaction mixture is filtered off and the filtrate is filtered through a mixture of silica gel and activated carbon. The resulting filtrate is concentrated and the residue poured into 1000 ml of water.
  • a reaction mixture of 0.47 g (1.01 mmol) of 4'-chloro-3-nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0, 1 g Raney nickel in 50 ml methanolic ammonia solution is hydrogenated for 24 hours at 20 ° C and 3 bar of hydrogen.
  • the crude product is reacted further without purification.
  • a reaction mixture of 0.1 g (0.2 mmol) of 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0, 08 g of platinum oxide in 50 ml of ethyl acetate is hydrogenated at 20 ° C 2.5h.
  • the catalyst is filtered off.

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CA2496563A1 (en) 2004-03-25
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BR0313790A (pt) 2005-07-12
AU2003258620A1 (en) 2004-04-30
DE10238865A1 (de) 2004-03-11
ZA200500086B (en) 2006-07-26
JP2006507246A (ja) 2006-03-02
AR043046A1 (es) 2005-07-13
HRP20050179A2 (en) 2006-05-31
MXPA05002158A (es) 2005-05-23
EA200500301A1 (ru) 2006-02-24
EA012834B1 (ru) 2009-12-30
RS20050173A (en) 2007-09-21
CN1678591A (zh) 2005-10-05
UA82853C2 (en) 2008-05-26
PL375344A1 (en) 2005-11-28
NO20050068L (no) 2005-03-04
WO2004024702A1 (de) 2004-03-25
TW200413332A (en) 2004-08-01
PE20040974A1 (es) 2005-01-12

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