EP1418906A1 - Aminoalkyl-substituted aromatic bicyclic compounds, method for the production thereof and their use as medicaments - Google Patents
Aminoalkyl-substituted aromatic bicyclic compounds, method for the production thereof and their use as medicamentsInfo
- Publication number
- EP1418906A1 EP1418906A1 EP02774498A EP02774498A EP1418906A1 EP 1418906 A1 EP1418906 A1 EP 1418906A1 EP 02774498 A EP02774498 A EP 02774498A EP 02774498 A EP02774498 A EP 02774498A EP 1418906 A1 EP1418906 A1 EP 1418906A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- independently
- aryl
- another
- phenyl
- 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- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 37
- -1 (CC 6 ) -alkyl Chemical group 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 10
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000002830 appetite depressant Substances 0.000 claims description 7
- 238000011321 prophylaxis Methods 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 229940125709 anorectic agent Drugs 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 125000006553 (C3-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000001539 anorectic effect Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 206010061428 decreased appetite Diseases 0.000 abstract 1
- 239000000047 product Substances 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
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- 239000012043 crude product Substances 0.000 description 17
- 239000000556 agonist Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- PORAAMUTFXEXNJ-UHFFFAOYSA-N 1-[2-(hydroxymethyl)-1-methylindol-5-yl]-3-(4-phenoxyphenyl)urea Chemical compound C=1C=C2N(C)C(CO)=CC2=CC=1NC(=O)NC(C=C1)=CC=C1OC1=CC=CC=C1 PORAAMUTFXEXNJ-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- OKWSKBYSBXLJSK-UHFFFAOYSA-N 1-(4-fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)urea Chemical compound C1=C(F)C([N+](=O)[O-])=CC(NC(=O)NC=2C=CC(OC=3C=CC=CC=3)=CC=2)=C1 OKWSKBYSBXLJSK-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- JTUBVESXLMDIDZ-UHFFFAOYSA-N 1-[4-[2-(dimethylamino)ethylamino]-3-nitrophenyl]-3-(4-phenoxyphenyl)urea Chemical compound C1=C([N+]([O-])=O)C(NCCN(C)C)=CC=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=CC=C1 JTUBVESXLMDIDZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 5
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000003524 antilipemic agent Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 5
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- Aminoalkyl substituted aromatic bicycles process for their preparation and their use as medicaments
- the invention relates to aminoalkyl-substituted aromatic bicycles and their physiologically acceptable salts and physiologically functional derivatives.
- the invention therefore relates to compounds of the formula
- 3-12 membered mono- or bicyclic ring which may contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 ) -alkyl, aryl, CON (R 37) (R 38), N (R 39) (R 40), OH, O- (C 1 -C 6 ) -alkyl, S- (CC 6 ) -alkyl, or NHCO (CC 6 ) alkyl;
- X is a bond, C (R8) (R9), C (OR10) (R11), O, N (R12), S, SO, S0 2 , COT-
- R8, R9, R10, R11, R12 independently of one another are H, (CC 6 ) -alkyl;
- R1, R2, R3, R41, R42, R43, R44 independently
- R 13, R 14 independently of one another are H, (CC 6 ) -alkyl,
- R 13 and R 14 together with the nitrogen atom to which they are attached form a 5-6 membered ring, in the case of the 6-membered ring a CH 2 group being replaced by O or S;
- R15, R16 independently of one another are H, (CC 6 ) -alkyl, or R15 and R16 form together with the nitrogen atom to which they are bonded a 5-6 membered ring, where in the case of the 6-ring, a CH 2 - group may be replaced by O or S;
- R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl
- R 18, R 20, R 21 independently of one another (C 1 -C 6 ) -alkyl, aryl;
- R24 is H, (C r C 6 ) alkyl
- R5 H (CC 6) alkyl
- R 26 is H, (C 1 -C 6 ) -alkyl, aryl, (C 0 -C 8 ) -alkylene-aryl, a bond to Y;
- R 27, R 30, R 31 independently of one another are H, (C 1 -C 6 ) -alkyl, a bond to Y;
- N (OR35), or N (R36) may be replaced SO, SO 2, C (R32) (R33), CO, C (R34);
- R32, R33, R34, R35, R36 independently of one another are H, (CC 6 ) -alkyl, aryl; R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
- Carbon atoms can be replaced by O, N or S and the 3-8 membered ring further substituents such as (Ci-C ⁇ J-alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH, O- ( CC 6 ) -alkyl or NHCO (C 1 -C 6 ) -alkyl can carry;
- R37, R38, R39, R40 independently of one another are H, (C 1 -C 6 ) -alkyl
- Heteroatoms from the group N, O and S may contain and the 4-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3) (-CC 6 ) - alkyl, aryl, CON (R37) (R38 ), N (R39) (R40), may carry O- (CC 6) alkyl, or NHCO (CC 6) alkyl;
- X is a bond, C (R 8) (R 9), O, N (R 12), S, SO 2 ;
- R8, R9, R12 independently of one another H, (Ci-CeJ-alkyl
- Nitrogen atom is 0, 1 or 2;
- R1, R2, R3, R41, R42, R43, R44 independently
- R 13, R 14 independently of one another are H, (C 1 -C 6 -alkyl,
- R 13 and R 14 together with the nitrogen atom to which they are attached, form a 5-6 membered ring, with a CH 2 - in the case of the 6-membered ring
- Group can be replaced by O or S;
- R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, or R 15 and R 16 together with the nitrogen atom to which they are attached form a 5-6 membered ring, with a CH 2 - in the case of the 6-membered ring Group can be replaced by O or S;
- R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl
- R18, R20, R21 are independently (CC 6 ) -alkyl, aryl;
- R 25 is H, (C 1 -C 6) -alkyl, aryl;
- R26 H (CC 6) alkyl, aryl, a bond to Y;
- R27, R31 independently of one another are H, (-CC) -alkyl, a bond to Y;
- R32, R33, R36 independently of one another are H, (CC 6 ) -alkyl, aryl;
- R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
- R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 4-7 membered ring in which one or more carbon atoms may be replaced by O, N or S and the 4-7 membered ring further substituents such as (C 1 -C 6 ) alkyl, aryl, CON (R 37) (R 38), N (R 39) (R 40), OH or NHCO (CC 6 ) alkyl;
- R37, R38, R39, R40 independently of one another are H, (CC 6 ) -alkyl
- 5-10 membered mono- or bicyclic ring which may contain 0, 1 or 2 heteroatoms from the group N, O and S and the 5-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , ( CrC 6) - can carry 6) alkyl or NHCO (CC 6) alkyl, alkyl, aryl, O- (C ⁇ -C;
- X is a bond, C (R8) (R9), O, N (R12);
- R8, R9, R12 independently of one another are H, (CC 6 ) -alkyl
- Nitrogen gas atom is 0 or 1;
- R1, R2, R3, R41, R42, R43, R44 independently
- R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl,
- R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
- R 18, R 20, R 21 independently of one another (C 1 -C 6 ) -alkyl, aryl;
- R24 H (CC 6) alkyl
- R5 H (CC 6) alkyl
- R 25 is H, (C 1 -C 6 ) -alkyl
- R 26 is H, (C 1 -C 6 ) -alkyl, a bond to Y;
- R 27 is H, (C 1 -C 6 ) -alkyl, a bond to Y;
- Y (CrC 3 ) alkylene wherein a carbon atom may be replaced by SO 2 , C (R 32) (R 33) or CO;
- R32, R33 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl;
- R6, R7 independently of one another are H, (CC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, or R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 5 or 6 membered ring in which one or more carbon atoms may be replaced by O or N and the 5 or 6 membered ring may contain further substituents such as -C-C 6 ) alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH or NHCO (CC 6 ) alkyl can carry;
- R37, R38, R39, R40 independently of one another are H, (C 1 -C 6 ) -alkyl
- the invention relates to compounds of the formula I, in the form of their racemates, enantiomerically enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
- alkyl, alkylene, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R 19, R 20, R 21, R 22, R 25, R 26, R 27, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R 40, R 41, R 42, R 43 and R 44 can be straight-chain, branched or optional be halogenated.
- aryl is meant a phenyl or naphthyl group.
- ring is meant a cyclic structure which may be either aromatic, partially saturated or fully saturated. To illustrate the optional ring formation of R6, Y and the nitrogen atom to which they are attached, Examples 6 and 16 can be used without limiting the general description given above.
- Suitable pharmaceutically acceptable Salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
- Suitable pharmaceutically acceptable Acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids.
- the chloro salt is used in a particularly preferred manner.
- Suitable pharmaceutically acceptable basic salts are ammonium salts
- Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in nontherapeutic, for example, in vitro applications.
- physiologically functional derivative refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
- the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
- prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
- the compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
- references to "compound (s) according to formula (I)” refer to compound (s) of formula (I) as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.
- the amount of a compound of formula (I) required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient .
- the daily dose ranges from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, eg, 3-10 mg / kg / day.
- an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
- Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
- Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
- vials for injections, and orally administrable unit dose formulations, such as tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
- the abovementioned weights are based on the weight of the free compound on which the salt is based.
- the compounds according to formula (I) may themselves be used as a compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition.
- the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
- Other pharmaceutically active substances may also be present, including further compounds according to formula (I).
- the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods described in the essential in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
- compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is the nature and severity of the treatment State and on the nature of the particular compound used according to formula (I) is dependent.
- coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
- Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
- the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary.
- a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
- Pressed tablets may be prepared by tabletting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (multiple) surfactant / dispersing agent in a suitable machine.
- Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
- compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula (I) having a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
- Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
- Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
- Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
- Combinations of two or more of these substances are used.
- Active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
- Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
- a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
- the active ingredient may be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
- the compounds of the formula I are distinguished by favorable effects on lipid metabolism, in particular they are suitable for weight loss and after weight reduction for obtaining a reduced weight in mammals and as anorectic agents.
- the compounds are characterized by their low toxicity and their low side effects.
- the compounds can be used alone or in combination with other weight-reducing or anorectic agents.
- Such other anorectic agents are mentioned, for example in the Red List, Chapter 01 under weight loss / appetite suppressants and may also contain such agents that increase the energy expenditure of the organism and thus lead to a weight loss or even those that affect the overall metabolism of the organism, That an increased calorie intake does not lead to an increase in fat deposits and a normal calorie intake to a reduction in fat deposits of the organism.
- the compounds are suitable for the prophylaxis and in particular for the treatment of overweight or obesity.
- the compounds are furthermore suitable for the prophylaxis and in particular for the treatment of type II diabetes, atherosclerosis and for the normalization of lipid metabolism and for the treatment of hypertension.
- the compounds act as MCH antagonists and are also useful in the treatment of disorders of the Sensory and other psychiatric indications, such as depression, anxiety, anxiety disorders, schizophrenia, as well as for the management of disorders associated with the circadian rhythm and for the treatment of substance abuse.
- the compounds of the formula I can be administered in combination with one or more further pharmacologically active substances, for example selected from antidiabetics, antiadipositas, antihypertensive agents, lipid lowering agents and agents for the treatment and / or prevention of complications caused by diabetes or associated with diabetes.
- antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as e.g. those disclosed in WO 98/08871 by Novo Nordisk A / S and orally active hypoglycemic agents.
- the orally active hypoglycemic agents preferably comprise
- Sulphonylureas biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers, e.g. those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, insulin receptor kinase activators, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, e.g.
- the present compounds are administered in combination with insulin.
- the present compounds are administered in combination with a sulphonylurea such as tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepid, glibomuride or gliclazide.
- the present compounds are administered in combination with a biguanide such as metformin.
- the present compounds are used in combination with a meglitinide, such as e.g. Repaglinide administered.
- a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med.
- the present compounds are administered in combination with a ⁇ -glucosidase inhibitor such as miglitol or acarbose.
- the present compounds are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.
- the present compounds are administered in combination with an antihyperlipidemic agent or an antilipidemic agent, such as cholestyramine, colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.
- the present compounds are used in combination with more than one of the aforementioned compounds, eg in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, Insulin and lovastatin, etc. administered.
- the compounds according to the invention can be administered in combination with one or more antiadipositas or appetite regulating active ingredients.
- Such agents may be selected from the group consisting of CART
- Agonists NPY antagonists, MC4 agonists, orexin antagonists, H3 agonists,
- TNF agonists TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, ⁇ 3-
- MSH melanocyte stimulating hormone
- CCK serotonin reuptake inhibitors
- Reuptake inhibitors 5HT modulators, MAO inhibitors, bombesin agonists,
- Leptin agonists dopamine agonists (bromocriptine, doprexin), lipase / amylase inhibitors, antagonists of the cannabinoid receptor 1, modulators of the
- ASP Acylation stimulating protein
- PPAR modulators PPAR modulators
- RXR modulators PPAR modulators
- hCNTF mimetics TR-? Agonists.
- the anti-adiposity is leptin or modified leptin. In another embodiment, the anti-adiposity is dexamphetamine or
- the anti-adiposity is fenfluramine or
- the anti-adiposity is sibutramine or the mono- and bis-demethylated active metabolites of sibutramine.
- the anti-obesity agent is orlistat.
- the anti-obesity agent is mazindol, diethylpropion or phentermine.
- present compounds may be administered in combination with one or more antihypertensive agents.
- antihypertensive agents are beta blockers such as alprenolol, atenol, timolol, pindolol,
- ACE Angiotensin Converting Enzyme
- Calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, as well as alpha-blockers such as doxazosin, urapidil, prazosin and
- the anorectic effect was tested on female NMRI mice. After ten 17-hour feed withdrawal, the test preparation was administered via a gavage. In individual housing and with free access to drinking water was the animals
- Table 1 Anorectic effect, measured as a reduction of cumulated milk consumption treated compared to control animals.
- the host used for the transfection was a transformed HEK cell line named "PEAK Stable Cells" (likewise from EDGE Biosystems)
- the functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligands according to the invention were carried out with the aid of the FLIPR apparatus of the company. Molecular Devices (USA), using equipment manufacturer's instructions The results from the cellular assay are reported in Table 2.
- Example 1 1 - [1- (2-Dimethylamino-ethyl) -1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
- Reaction product was dissolved in methanol and triethyl orthoacetate (0.5 mL) and
- Glacial acetic acid (0.2 mL) is added. The mixture was heated to reflux for 5 minutes. Volatile shares were removed. The residue was partitioned between dichloromethane and
- the compound was prepared as described in Example 4 from 1- (4-fluoro-3-nitro-phenyl) -3- (4-isopropoxy-phenyl) -urea and 1-ethyl-pyrrolidin-2-yl-methylamine and without further Cleaning further implemented.
- Example 13 1 - [1- (2-Dimethylamino-ethyl) -2-phenyl-1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
- Example 15 1- [4- (2-Pyrrolidino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea was reduced as described in Example 4.
- the crude product was reacted analogously to Example 5 with triethyl orthopropionate.
- the crude product was purified by preparative HPLC. This gave the product with the molecular weight 469.59 (C 28 H 3 ⁇ N 5 ⁇ 2); MS (ESI): 470 (M + H + ).
- Example 15
- the compound was prepared as described in Example 4 from 1- (4-fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea and 1- (2-aminoethyl) piperidine (60 ° C, 4 H). Melting point (ethyl acetate / hexane): 163-165 ° C.
- Example 4 1- ⁇ 4 - [(1-Ethylpyrrolidin-2-ylmethyl) amino] -3-nitro-phenyl ⁇ -3- (4-phenoxy-phenyl) -urea was reduced as described in Example 4.
- the crude product was reacted as described in Example 5 with triethyl orthoacetate.
- the crude product was purified by preparative HPLC. This gave the product with the molecular weight 469.59 (C 28 H 3 iN 5 ⁇ 2 ); MS (ESI): 470 (M + H + ).
- the compound was prepared as described in Example 1 from 1- (2-dimethylamino-ethyl) -2,3-dimethyl-1H-indol-5-ylamine and 4-phenoxyaniline.
- the crude product was purified by preparative HPLC. This gave the product with the molecular weight 442.57 (C 27 H 3 oN 4 O 3 ); MS (ESI): 443 (M + H + ).
- the compound was prepared as described in Example 1 from 1- (2-dimethylamino-ethyl) -2-methyl-1H-indol-5-ylamine and 4-phenoxyaniline.
- the crude product was purified by preparative HPLC. This gave the product with the molecular weight 428.54 (C 26 H 28 N 4 O 3 ); MS (ESI): 428 (M + H + ).
- the molecular ion peak ([M + H] + ) was taken from ESI mass spectra.
- Examples 20-51 and 71-109 were prepared analogously to Example 1.
- Example 110 [1- (2-Dimethylamino-ethyl) -1H-indol-5-yl] -carbamic acid 4-phenoxy-phenyl ester
Abstract
The invention relates to aminoalkyl-substituted aromatic bicyclic compounds and to their physiologically acceptable salts and physiologically functional derivatives. Disclosed are compounds of formula (I), wherein the radicals have the meaning cited in the description. Further disclosed are the physiologically acceptable salts of said compounds and to a method for the production thereof. Said compounds can be suitably used as anorectic drugs.
Description
Beschreibungdescription
Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als ArzneimittelAminoalkyl substituted aromatic bicycles, process for their preparation and their use as medicaments
Die Erfindung betrifft Aminoalkyl substituierte aromatische Bicyclen sowie deren physiologisch verträgliche Salze und physiologisch funktioneile Derivate.The invention relates to aminoalkyl-substituted aromatic bicycles and their physiologically acceptable salts and physiologically functional derivatives.
Es sind bereits strukturähnliche nichtaromatische Bicyclen mit pharmakologischer Wirkung im Stand der Technik beschrieben (wie zum Beispiel in WO 01/21577).Structure-like non-aromatic bicyclics with pharmacological activity are already described in the prior art (as for example in WO 01/21577).
Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Verfügung zu stellen, die eine Gewichtsreduktion bei Säugetieren bewirken und die zur Prävention und Behandlung von Obesitas geeignet sind.It is an object of the invention to provide compounds which bring about weight reduction in mammals and which are suitable for the prevention and treatment of obesity.
Die Erfindung betrifft daher Verbindungen der FormelThe invention therefore relates to compounds of the formula
worin bedeutenin which mean
A (CrC8)-Alkyl, (Co-C8)-Alkylen-Aryl;A (C 1 -C 8 ) -alkyl, (C 0 -C 8 ) -alkylene-aryl;
3-12 gliedriger mono- oder bicyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO2, CF3, OCF3, CN,
(Cι-C6)-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH, O-(C1-C6)-Alkyl, S-(C C6)-Alkyl, oder NHCO(C C6)-Alkyl tragen kann;3-12 membered mono- or bicyclic ring, which may contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 ) -alkyl, aryl, CON (R 37) (R 38), N (R 39) (R 40), OH, O- (C 1 -C 6 ) -alkyl, S- (CC 6 ) -alkyl, or NHCO (CC 6 ) alkyl;
X eine Bindung, C(R8)(R9), C(OR10)(R11 ), O, N(R12), S, SO, S02, COT-X is a bond, C (R8) (R9), C (OR10) (R11), O, N (R12), S, SO, S0 2 , COT-
R8, R9, R10, R11 , R12 unabhängig voneinander H, (C C6)-Alkyl;R8, R9, R10, R11, R12 independently of one another are H, (CC 6 ) -alkyl;
D N, C(R41 );D N, C (R41);
E N, C(R42);E N, C (R42);
G N, C(R43);G N, C (R43);
L N, C(R44);L N, C (R44);
R1 , R2, R3, R41 , R42, R43, R44 unabhängig voneinanderR1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C C6)-Alkyl, (C C )- Alkoxyalkyl, S-(C C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)- Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)- Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, -O-(C0-C8)-Alkylen-H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (CC 6) alkyl, (CC) - alkoxyalkyl, S- (CC 6) alkyl, (CC 6 ) -Alkyl, (C 2 -C 6 ) -alkenyl, (C 3 -C 8 ) -cycloalkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, O- (C 3 -C 8 ) - cycloalkenyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, -O- (C 0 -C 8 ) -alkylene
Aryl, S-Aryl, N(R13)(R14), SO2-CH3, COOH, COO-(Cι-C6)-Alkyl, CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21), ein 5-7 gliedriger Heterocyclus mit 1-4 Heteroatomen;Aryl, S-aryl, N (R 13) (R 14), SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CON (R 15) (R 16), N (R 17) CO (R 18), N (R19) SO 2 (R20), CO (R21), a 5-7 membered heterocycle having 1-4 heteroatoms;
R13, R14 unabhängig voneinander H, (C C6)-Alkyl,R 13, R 14 independently of one another are H, (CC 6 ) -alkyl,
oder R13 und R14 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;or R 13 and R 14 together with the nitrogen atom to which they are attached form a 5-6 membered ring, in the case of the 6-membered ring a CH 2 group being replaced by O or S;
R15, R16 unabhängig voneinander H, (C C6)-Alkyl,
oder R15 und R16 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;R15, R16 independently of one another are H, (CC 6 ) -alkyl, or R15 and R16 form together with the nitrogen atom to which they are bonded a 5-6 membered ring, where in the case of the 6-ring, a CH 2 - group may be replaced by O or S;
R17, R19 unabhängig voneinander H, (CrC6)-Alkyl;R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (Cι-C6)-Alkyl, Aryl;R 18, R 20, R 21 independently of one another (C 1 -C 6 ) -alkyl, aryl;
B N(R24), 0;B N (R24), 0;
R24 H, (CrC6)-Alkyl;R24 is H, (C r C 6 ) alkyl;
R5 H, (C C6)-Alkyl;R5 H, (CC 6) alkyl;
W N, C(R25);W N, C (R25);
R25 H, (CrCβ)-AlkyΙ, Aryl, eine Bindung zu Y;R25 H, (CrCβ) -AlkyΙ, aryl, a bond to Y;
T N, C(R26);T N, C (R26);
R26 H, (C-ι-C6)-Alkyl, Aryl, (C0-C8)-Alkylen-Aryl, eine Bindung zu Y;R 26 is H, (C 1 -C 6 ) -alkyl, aryl, (C 0 -C 8 ) -alkylene-aryl, a bond to Y;
U O, S, N(R27), -C(R30)=N-, -N=C(R31 )-;U O, S, N (R27), -C (R30) = N-, -N = C (R31) -;
R27, R30, R31 unabhängig voneinander H, (CrC6)-Alkyl, eine Bindung zu Y;R 27, R 30, R 31 independently of one another are H, (C 1 -C 6 ) -alkyl, a bond to Y;
Y (C-ι-C8)-Alkylen, worin ein oder mehrere Kohlenstoffatome durch O, S,Y (C 1 -C 8 ) -alkylene, in which one or more carbon atoms are substituted by O, S,
SO, SO2, C(R32)(R33), CO, C(R34)(OR35) oder N(R36) ersetzt sein können;(OR35), or N (R36) may be replaced SO, SO 2, C (R32) (R33), CO, C (R34);
R32, R33, R34, R35, R36 unabhängig voneinander H, (C C6)-Alkyl, Aryl;
R6, R7 unabhängig voneinander H, (CrC6)-Alkyl, (C3-C7)-Cycloalkyl,R32, R33, R34, R35, R36 independently of one another are H, (CC 6 ) -alkyl, aryl; R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 3-8 gliedrigen Ring, worin ein oder mehrereor R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 3-8 membered ring wherein one or more
Kohlenstoffatome durch O, N oder S ersetzt sein können und der 3-8 gliedrige Ring weitere Substituenten wie (Ci-CβJ-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH, O-(C C6)-Alkyl oder NHCO(C1-C6)- Alkyl tragen kann;Carbon atoms can be replaced by O, N or S and the 3-8 membered ring further substituents such as (Ci-CβJ-alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH, O- ( CC 6 ) -alkyl or NHCO (C 1 -C 6 ) -alkyl can carry;
R37, R38, R39, R40 unabhängig voneinander H, (Cι-C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (C 1 -C 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
Bevorzugt sind Verbindungen der Formel I worin ein oder mehrere Reste folgende Bedeutung haben:Preference is given to compounds of the formula I in which one or more radicals have the following meanings:
A (C2-C7)-Alkyl, (C0-C3)-Alkylen-Aryl; 4-10 gliedriger mono- oder bicyclischer Ring, der ein oder mehrereA (C 2 -C 7 ) -alkyl, (C 0 -C 3 ) -alkylene-aryl; 4-10 membered mono- or bicyclic ring containing one or more
Heteroatome aus der Gruppe N, O und S enthalten kann und der 4-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO2, CF3)(Cι-C6)- Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), O-(C C6)-Alkyl, oder NHCO(C C6)-Alkyl tragen kann;Heteroatoms from the group N, O and S may contain and the 4-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3) (-CC 6 ) - alkyl, aryl, CON (R37) (R38 ), N (R39) (R40), may carry O- (CC 6) alkyl, or NHCO (CC 6) alkyl;
X eine Bindung, C(R8)(R9), O, N(R12), S, SO2;X is a bond, C (R 8) (R 9), O, N (R 12), S, SO 2 ;
R8, R9, R12 unabhängig voneinander H, (Ci-CeJ-Alkyl;R8, R9, R12 independently of one another H, (Ci-CeJ-alkyl;
D N, C(R41);D N, C (R41);
E N, C(R42);
G N, C(R43);EN, C (R42); GN, C (R43);
L N, C(R44); wobei die Gesamtzahl der durch D, E, G und L definiertenL N, C (R44); where the total number of defined by D, E, G and L.
Stickstoffatome 0, 1 oder 2 beträgt;Nitrogen atom is 0, 1 or 2;
R1 , R2, R3, R41 , R42, R43, R44 unabhängig voneinanderR1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, Br, CF3, NO2, O-(Cι-C6)-Alkyl, (C Cβ)-Alkyl, (C3-C8)-Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, -O-(C0-C3)-H, F, Cl, Br, CF 3 , NO 2 , O- (-CC 6 ) -alkyl, (CC β ) -alkyl, (C 3 -C 8 ) -cycloalkyl, O- (C 3 -C 8 ) -Cycloalkyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, -O- (C 0 -C 3 ) -
Alkylen-Aryl, S-Aryl, N(R13)(R14), S02-CH3,
CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21);Alkylene-aryl, S-aryl, N (R13) (R14) S0 2 CH 3, CON (R15) (R16), N (R17) CO (R18), N (R19) SO 2 (R20), CO (R21);
R13, R14 unabhängig voneinander H, (CrCβVAlkyl,R 13, R 14 independently of one another are H, (C 1 -C 6 -alkyl,
oder R13 und R14 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2-or R 13 and R 14, together with the nitrogen atom to which they are attached, form a 5-6 membered ring, with a CH 2 - in the case of the 6-membered ring
Gruppe durch O oder S ersetzt sein kann;Group can be replaced by O or S;
R15, R16 unabhängig voneinander H, (Cι-C6)-Alkyl, oder R15 und R16 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, or R 15 and R 16 together with the nitrogen atom to which they are attached form a 5-6 membered ring, with a CH 2 - in the case of the 6-membered ring Group can be replaced by O or S;
R17, R19 unabhängig voneinander H, (CrC6)-Alkyl;R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (C C6)-Alkyl, Aryl;R18, R20, R21 are independently (CC 6 ) -alkyl, aryl;
B N(R24), O;B N (R24), O;
R24 H, (C C6)-Alkyl;
R5 H, (C C6)-Alkyl;R24 H, (CC 6) alkyl; R5 H, (CC 6) alkyl;
W N, C(R25);W N, C (R25);
R25 H, (CrCβ)-Alkyl, Aryl;R 25 is H, (C 1 -C 6) -alkyl, aryl;
T C(R26);T C (R26);
R26 H, (C C6)-Alkyl, Aryl, eine Bindung zu Y;R26 H, (CC 6) alkyl, aryl, a bond to Y;
U O, S, N(R27), -N=C(R31)-;U O, S, N (R 27), -N = C (R 31) -;
R27, R31 unabhängig voneinander H, (Cι-Ce)-Alkyl, eine Bindung zu Y;R27, R31 independently of one another are H, (-CC) -alkyl, a bond to Y;
Y (C O -Alkylen, worin ein Kohlenstoffatom durch SO2, C(R32)(R33), CO oder N(R36) ersetzt sein kann;Y (CO alkylene in which a carbon atom may be replaced by SO 2 , C (R 32) (R 33), CO or N (R 36);
R32, R33, R36 unabhängig voneinander H, (C C6)-Alkyl, Aryl;R32, R33, R36 independently of one another are H, (CC 6 ) -alkyl, aryl;
R6, R7 unabhängig voneinander H, (Cι-C6)-Alkyl, (C3-C7)-Cycloalkyl,R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7 gliedrigen Ring, worin ein oder mehrere Kohlenstoffatome durch O, N oder S ersetzt sein können und der 4-7 gliedrige Ring weitere Substituenten wie (CrC6)-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH oder NHCO(C C6)-Alkyl tragen kann;or R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 4-7 membered ring in which one or more carbon atoms may be replaced by O, N or S and the 4-7 membered ring further substituents such as (C 1 -C 6 ) alkyl, aryl, CON (R 37) (R 38), N (R 39) (R 40), OH or NHCO (CC 6 ) alkyl;
R37, R38, R39, R40 unabhängig voneinander H, (C C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (CC 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze.
Besonders bevorzugt sind Verbindungen der Formel I worin ein oder mehrere Reste folgende Bedeutung haben:and their physiologically acceptable salts. Particular preference is given to compounds of the formula I in which one or more radicals have the following meanings:
A (C3-C7)-Alkyl, (C0-C2)-Alkylen-Aryl;A (C 3 -C 7 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl;
5-10 gliedriger mono- oder bicyclischer Ring, der 0, 1 oder 2 Heteroatome aus der Gruppe N, O und S enthalten kann und der 5-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO2, CF3, (CrC6)- Alkyl, Aryl, O-(Cι-C6)-Alkyl oder NHCO(C C6)-Alkyl tragen kann;5-10 membered mono- or bicyclic ring, which may contain 0, 1 or 2 heteroatoms from the group N, O and S and the 5-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , ( CrC 6) - can carry 6) alkyl or NHCO (CC 6) alkyl, alkyl, aryl, O- (Cι-C;
X eine Bindung, C(R8)(R9), O, N(R12);X is a bond, C (R8) (R9), O, N (R12);
R8, R9, R12 unabhängig voneinander H, (C C6)-Alkyl;R8, R9, R12 independently of one another are H, (CC 6 ) -alkyl;
D N, C(R41);D N, C (R41);
E N, C(R42);E N, C (R42);
G N, C(R43);G N, C (R43);
L N, C(R44); wobei die Gesamtzahl der durch D, E, G und L definiertenL N, C (R44); where the total number of defined by D, E, G and L.
Stickstöffatome 0 oder 1 beträgt;Nitrogen gas atom is 0 or 1;
R1 , R2, R3, R41 , R42, R43, R44 unabhängig voneinanderR1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, CF3, NO2, 0-(C C6)-Alkyl, (CrC6)-Alkyl, O-(C3-C8)-Cycloalkyl, (C0-C2)-Alkylen-Aryl, -O-(C0-C3)-Alkylen-Aryl, N(R13)(R14), COO~(C C6)- Alkyl, CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21);H, F, Cl, CF 3 , NO 2 , 0- (CC 6 ) -alkyl, (C 1 -C 6 ) -alkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 0 -C 2 ) -alkylene Aryl, -O- (C 0 -C 3 ) -alkylene-aryl, N (R 13) (R 14), COO ~ (CC 6 ) -alkyl, CON (R 15) (R 16), N (R 17) CO (R 18) , N (R19) SO 2 (R20), CO (R21);
R13, R14 unabhängig voneinander H, (CrC6)-Alkyl,R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl,
R15, R16 unabhängig voneinander H, (Cι-C6)-Alkyl,
R17, R19 unabhängig voneinander H, (Cι-C6)-Alkyl;R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (Cι-C6)-Alkyl, Aryl;R 18, R 20, R 21 independently of one another (C 1 -C 6 ) -alkyl, aryl;
B N(R24);B N (R24);
R24 H, (C C6)-Alkyl;R24 H, (CC 6) alkyl;
R5 H, (C C6)-Alkyl;R5 H, (CC 6) alkyl;
W N, C(R25);W N, C (R25);
R25 H, (Cι-C6)-Alkyl;R 25 is H, (C 1 -C 6 ) -alkyl;
T C(R26);T C (R26);
R26 H, (Cι-C6)-Alkyl, eine Bindung zu Y;R 26 is H, (C 1 -C 6 ) -alkyl, a bond to Y;
U O, S, N(R27);U O, S, N (R27);
R27 H, (CrC6)-Alkyl, eine Bindung zu Y;R 27 is H, (C 1 -C 6 ) -alkyl, a bond to Y;
Y (CrC3)-Alkylen, worin ein Kohlenstoffatom durch SO2, C(R32)(R33) oder CO ersetzt sein kann;Y (CrC 3 ) alkylene, wherein a carbon atom may be replaced by SO 2 , C (R 32) (R 33) or CO;
R32, R33 unabhängig voneinander H, (Cι-C6)-Alkyl, Aryl;R32, R33 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl;
R6, R7 unabhängig voneinander H, (C C6)-Alkyl, (C3-C7)-Cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5 oder 6 gliedrigen Ring, worin ein oder mehrere Kohlenstoffatome durch O oder N ersetzt sein können und der 5 oder 6 gliedrige Ring weitere Substituenten wie (Cι-C6)-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH oder NHCO(C C6)-Alkyl tragen kann;R6, R7 independently of one another are H, (CC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, or R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 5 or 6 membered ring in which one or more carbon atoms may be replaced by O or N and the 5 or 6 membered ring may contain further substituents such as -C-C 6 ) alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH or NHCO (CC 6 ) alkyl can carry;
R37, R38, R39, R40 unabhängig voneinander H, (Cι-C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (C 1 -C 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
Die Erfindung bezieht sich auf Verbindungen der Formel I, in Form ihrer Racemate, enantiomerenangereicherten Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.The invention relates to compounds of the formula I, in the form of their racemates, enantiomerically enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
Die Alkyl-, Alkylen-, Alkenyl- und Alkinylreste in den Substituenten R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 , R22, R25, R26, R27, R30, R31 , R32, R33, R34, R35, R36, R37, R38, R39, R40, R41 , R42, R43 und R44 können sowohl geradkettig, verzweigt oder optional halogeniert sein.The alkyl, alkylene, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R 19, R 20, R 21, R 22, R 25, R 26, R 27, R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R 40, R 41, R 42, R 43 and R 44 can be straight-chain, branched or optional be halogenated.
Unter dem Begriff "Aryl" wird eine Phenyl oder Naphthylgruppe verstanden. Unter dem Begriff "Ring" wird eine cyclische Struktur verstanden, die entweder aromatisch, teilweise gesättigt oder vollständig gesättigt sein kann. Zur Illustration der optionalen Ringbildung von R6, Y und dem Stickstoffatom, an das sie gebunden sind, können die Beispiele 6 und 16 herangezogen werden, ohne die oben gegebene allgemeine Beschreibung einzuschränken.By the term "aryl" is meant a phenyl or naphthyl group. By the term "ring" is meant a cyclic structure which may be either aromatic, partially saturated or fully saturated. To illustrate the optional ring formation of R6, Y and the nitrogen atom to which they are attached, Examples 6 and 16 can be used without limiting the general description given above.
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche
Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter-, Sulfon- und Schwefelsäure sowie organischer Säuren, wie z.B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isethion-, Milch-, Lactobion-, Malein-, Äpfel-, Methansulfon-, Bernstein-, p-Toluolsulfon-, Wein- und Trifluoressigsäure. Für medizinische Zwecke wird in besonders bevorzugter Weise das Chlorsalz verwendet. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze) und Erdalkalisalze (wie Magnesium- und Calciumsalze).Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable Acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. For medical purposes, the chloro salt is used in a particularly preferred manner. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
Salze mit einem nicht pharmazeutisch verträglichen Anion gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nichttherapeutischen, zum Beispiel in-vitro-Anwendungen.Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in nontherapeutic, for example, in vitro applications.
Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiologisch verträgliche Derivat einer erfindungsgemäßen Verbindung der Formel I, z.B. einen Ester, der bei Verabreichung an einen Säuger, wie z.B. den Menschen, in der Lage ist, (direkt oder indirekt) eine Verbindung der Formel I oder einen aktiven Metaboliten hiervon zu bilden.As used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
Zu den physiologisch funktioneilen Derivaten zählen auch Prodrugs der erfindungsgemäßen Verbindungen. Solche Prodrugs können in vivo zu einer erfindungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z.B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.
Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel (I)" auf Verbindung(en) der Formel (I) wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktioneilen Derivate wie hierin beschrieben.The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention. Hereinafter, all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.
Die Menge einer Verbindung gemäß Formel (I), die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z.B. der gewählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg bis 50 mg) pro Tag pro Kilogramm Körpergewicht, z.B. 3-10 mg/kg/Tag. Eine intravenöse Dosis kann z.B. im Bereich von 0,3 mg bis 1 ,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. Geeignete Infusionslösungen für diese Zwecke können z.B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z.B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Ampullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisformulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1 ,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Im Falle pharmazeutisch verträglicher Salze beziehen sich die vorgenannten Gewichtsangaben auf das Gewicht der dem Salz zugrunde liegenden freien Verbindung. Zur Prophylaxe oder Therapie der oben genannten Zustände können die Verbindungen gemäß Formel (l) selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muß natürlich verträglich sein, in dem Sinne, daß er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel (I). Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im
wesentlichen darin bestehen, daß die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen gemischt werden.The amount of a compound of formula (I) required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient , Generally, the daily dose ranges from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, eg, 3-10 mg / kg / day. For example, an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, for example, from 1 mg to 100 mg, vials for injections, and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the abovementioned weights are based on the weight of the free compound on which the salt is based. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) may themselves be used as a compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition. The carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may also be present, including further compounds according to formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods described in the essential in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z.B. sublinguale) und parenterale (z.B. subkutane, intramuskuläre, intradermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel (I) abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Polyvinylacetatphthalat, Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is the nature and severity of the treatment State and on the nature of the particular compound used according to formula (I) is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung gemäß Formel (I) enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wäßrigen oder nicht-wäßrigen Flüssigkeit; oder als eine Öl-in-Wasser- oder Wasser-in Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfaßt, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allge- meinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpreßt oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepreßte Tabletten können durch Tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner
und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients). In general, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary. For example, a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Pressed tablets may be prepared by tabletting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (multiple) surfactant / dispersing agent in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel (I) mit einem Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula (I) having a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wäßrige Zubereitungen einer Verbindung gemäß Formel (I), die vorzugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. Diese Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich die Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann. Diese Zubereitungen können vorzugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die erhaltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungsgemäße Zusammensetzungen enthalten im allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vorzugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel (I) mit einem oder mehreren herkömmlichen festen Trägern, beispielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt.Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglycole, Alkohole undSuitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols and
Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der
Wirkstoff ist im allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%.Combinations of two or more of these substances are used. Of the Active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammensetzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wäßrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine geeignete Wirkstoff-Konzentration beträgt ca. 1 % bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondereTransdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a special
Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder lontophorese freigesetzt werden.Alternatively, the active ingredient may be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
Die Verbindungen der Formel I zeichnen sich durch günstige Wirkungen auf den Fettstoffwechsel aus, insbesondere sind sie zur Gewichtsreduktion und nach erfolgter Gewichtsreduktion zum Erhalt eines reduzierten Gewichtes bei Säugetieren und als Anorektika geeignet. Die Verbindungen zeichnen sich sich durch ihre geringe Toxizität und ihre geringen Nebenwirkungen aus. Die Verbindungen können allein oder in Kombination mit weiteren gewichtsreduzierenden oder anorektischen Wirkstoffen eingesetzt werden. Solche weiteren anorektischen Wirkstoffe werden z.B. in der Roten Liste, Kapitel 01 unter Abmagerungsmittel/Appetitzügler genannt und können auch solche Wirkstoffe beinhalten, die den Energieumsatz des Organismus erhöhen und damit zu einer Gewichtsreduktion führen oder auch solche, welche den allgemeinen Metabolismus des Organismus so beeinflussen, dass eine erhöhte Kalorienzufuhr nicht zu einer Vergrößerung der Fettdepots und eine normale Kalorienzufuhr zu einer Verringerung der Fettdepots des Organismus führt. Die Verbindungen eignen sich zur Prophylaxe sowie insbesondere zur Behandlung von Übergewicht oder Obesitas. Die Verbindungen eignen sich weiterhin zur Prophylaxe sowie insbesondere zur Behandlung von Typ II Diabetes, der Arteriosklerose sowie zur Normalisierung des Lipidstoffwechsels und zur Behandlung des Bluthochdrucks. Die Verbindungen wirken als MCH Antagonisten und eignen sich auch zur Behandlung von Störungen des
Empfindens und anderer psychiatrischen Indikationen, wie zum Beispiel Depressionen, Angstzuständen, Angstneurosen, Schizophrenie sowie zur Behandlung von Störungen assoziiert mit dem zirkadianen Rhythmus und zur Behandlung von Drogenmissbrauch.The compounds of the formula I are distinguished by favorable effects on lipid metabolism, in particular they are suitable for weight loss and after weight reduction for obtaining a reduced weight in mammals and as anorectic agents. The compounds are characterized by their low toxicity and their low side effects. The compounds can be used alone or in combination with other weight-reducing or anorectic agents. Such other anorectic agents are mentioned, for example in the Red List, Chapter 01 under weight loss / appetite suppressants and may also contain such agents that increase the energy expenditure of the organism and thus lead to a weight loss or even those that affect the overall metabolism of the organism, That an increased calorie intake does not lead to an increase in fat deposits and a normal calorie intake to a reduction in fat deposits of the organism. The compounds are suitable for the prophylaxis and in particular for the treatment of overweight or obesity. The compounds are furthermore suitable for the prophylaxis and in particular for the treatment of type II diabetes, atherosclerosis and for the normalization of lipid metabolism and for the treatment of hypertension. The compounds act as MCH antagonists and are also useful in the treatment of disorders of the Sensory and other psychiatric indications, such as depression, anxiety, anxiety disorders, schizophrenia, as well as for the management of disorders associated with the circadian rhythm and for the treatment of substance abuse.
Bei einem weiteren Aspekt der Erfindung können die Verbindungen der Formel I in Kombination mit einer oder mehreren weiteren pharmakologisch wirksamen Substanzen verabreicht werden, die beispielsweise ausgewählt sind aus Antidiabetika, Antiadiposita, blutdrucksenkenden Wirkstoffen, Lipidsenkern und Wirkstoffen zur Behandlung und/oder Prävention von Komplikationen, die von Diabetes verursacht werden oder mit Diabetes assoziiert sind. Geeignete Antidiabetika umfassen Insuline, Amylin, GLP-1- und GLP-2-Derivate wie z.B. diejenigen die in WO 98/08871 von Novo Nordisk A/S offenbart wurden, sowie oral wirksame hypoglykämische Wirkstoffe. Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweiseIn a further aspect of the invention, the compounds of the formula I can be administered in combination with one or more further pharmacologically active substances, for example selected from antidiabetics, antiadipositas, antihypertensive agents, lipid lowering agents and agents for the treatment and / or prevention of complications caused by diabetes or associated with diabetes. Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as e.g. those disclosed in WO 98/08871 by Novo Nordisk A / S and orally active hypoglycemic agents. The orally active hypoglycemic agents preferably comprise
Sulphonylhamstoffe, Biguanidine, Meglitinide, Oxadiazolidindione, Thiazolidindione, Glukosidase-Inhibitoren, Glukagon-Rezeptor-Antagonisten, GLP-1 -Agonisten, Kaliumkanalöffner wie z.B. diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden, Insulin-Sensitizer, Aktivatoren der Insulin Rezeptor Kinase, Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind, z.B. Inhibitoren der Glycogenphosphorylase, Modulatoren der Glukoseaufnahme und Glukoseausscheidung, den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe, z.B. HMGCoA- Reduktase-Inhibitoren, Inhibitoren des Cholesteroltransports/derSulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers, e.g. those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, insulin receptor kinase activators, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, e.g. Inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, lipid metabolism altering compounds such as antihyperlipidemic agents and antilipidemic agents, e.g. HMGCoA reductase inhibitors, cholesterol transport inhibitors / inhibitors
Cholesterolaufnahme, Inhibitoren der Gallensäurerückresorption oder Inhibitoren des mikrosomalen Triglycerid-Transfer Proteins (MTP), Verbindungen, die die Nahrungsmitteleinnahme verringern, PPAR- und RXR-Agonisten und Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal der Betazellen wirken. Bei einer Ausführungsform der Erfindung werden die vorliegenden Verbindungen in Kombination mit Insulin verabreicht.
Bei einer weiteren Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem Sulphonylhamstoff wie z.B. Tolbutamid, Glibenclamid, Glimepirid, Glipizid, Gliquidon, Glisoxepid, Glibomurid oder Gliclazid verabreicht. Bei einer anderen Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem Biguanid wie z.B. Metformin verabreicht.Cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of microsomal triglyceride transfer protein (MTP), compounds that reduce food intake, PPAR and RXR agonists, and drugs that act on the ATP-dependent potassium channel of beta cells. In one embodiment of the invention, the present compounds are administered in combination with insulin. In another embodiment, the present compounds are administered in combination with a sulphonylurea such as tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepid, glibomuride or gliclazide. In another embodiment, the present compounds are administered in combination with a biguanide such as metformin.
Bei wieder einer anderen Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem Meglitinid wie z.B. Repaglinid verabreicht. Bei noch einer weiteren Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem Thiazolidindion wie z.B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[[4-[(3,4-Dihydro-3-methyl-4-oxo-2- chinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidindion, verabreicht. Bei einer weiteren Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem σ-Glukosidase-lnhibitor wie z.B. Miglitol oder Acarbose verabreicht.In yet another embodiment, the present compounds are used in combination with a meglitinide, such as e.g. Repaglinide administered. In yet another embodiment, the present compounds are used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione For example, the present compounds are administered in combination with a σ-glucosidase inhibitor such as miglitol or acarbose.
Bei einer anderen Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem Wirkstoff verabreicht, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, wie z.B. Tolbutamid, Glibenclamid, Glimepirid, Glipizid, Gliclazid oder Repaglinid. Bei noch einer anderen Ausführungsform werden die vorliegenden Verbindungen in Kombination mit einem antihyperlipidämischen Wirkstoff oder einem antilipidämischen Wirkstoff wie z.B. Cholestyramin, Colestipol, Clofibrat, Fenofibrat, Gemfibrozil, Lovastatin, Pravastatin, Simvastatin, Atorvastatin, Cerivastatin, Fluvastatin, Probucol, Ezetimibe oder Dextrothyroxin verabreicht. Bei einer weiteren Ausführungsform werden die vorliegenden Verbindungen in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z.B. in Kombination mit einem Sulphonylhamstoff und Metformin, einem Sulphonylhamstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulphonylhamstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht. Weiterhin können die erfindungsgemäßen Verbindungen in Kombination mit einem oder mehreren Antiadiposita oder appetitregulierenden Wirkstoffen verabreicht werden.
Solche Wirkstoffe können ausgewählt werden aus der Gruppe bestehend aus CART-In another embodiment, the present compounds are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide. In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or an antilipidemic agent, such as cholestyramine, colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine. In a further embodiment, the present compounds are used in combination with more than one of the aforementioned compounds, eg in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, Insulin and lovastatin, etc. administered. Furthermore, the compounds according to the invention can be administered in combination with one or more antiadipositas or appetite regulating active ingredients. Such agents may be selected from the group consisting of CART
Agonisten, NPY-Antagonisten, MC4-Agonisten, Orexin-Antagonisten, H3-Agonisten,Agonists, NPY antagonists, MC4 agonists, orexin antagonists, H3 agonists,
TNF-Agonisten, CRF-Agonisten, CRF BP-Antagonisten, Urocortin-Agonisten, ß3-TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3-
Agonisten, MSH (Melanocyt-stimulierendes Hormon)-Agonisten, CCK-Agonisten, Serotonin-Wiederaufnahme-Inhibitoren, gemischte Serotonin- und Noradrenalin-Agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonin and norepinephrine
Wiederaufnahme-Inhibitoren, 5HT-Modulatoren, MAO-Hemmer, Bombesin-Agonisten,Reuptake inhibitors, 5HT modulators, MAO inhibitors, bombesin agonists,
Galanin-Antagonisten, Wachstumshormon, Wachstumshormon freisetzendeGalanin antagonist, growth hormone, growth hormone releasing
Verbindungen, TRH-Agonisten, Modulatoren der Entkopplungsproteine 2 oder 3,Compounds, TRH agonists, modulators of decoupling proteins 2 or 3,
Leptin-Agonisten, Dopamin-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase- Inhibitoren, Antagonisten des Cannabinoid Rezeptors 1 , Modulatoren des dieLeptin agonists, dopamine agonists (bromocriptine, doprexin), lipase / amylase inhibitors, antagonists of the cannabinoid receptor 1, modulators of the
Acylierung stimulierende Protein (ASP), PPAR-Modulatoren, RXR-Modulatoren, hCNTF-Mimetika oder TR- ?-Agonisten.Acylation stimulating protein (ASP), PPAR modulators, RXR modulators, hCNTF mimetics or TR-? Agonists.
Bei einer Ausführungsform der Erfindung ist das Antiadipositum Leptin oder modifiziertes Leptin. Bei einer anderen Ausführungsform ist das Antiadipositum Dexamphetamin oderIn one embodiment of the invention, the anti-adiposity is leptin or modified leptin. In another embodiment, the anti-adiposity is dexamphetamine or
Amphetamin.Amphetamine.
Bei einer anderen Ausführungsform ist das Antiadipositum Fenfluramin oderIn another embodiment, the anti-adiposity is fenfluramine or
Dexfenfluramin.Dexfenfluramine.
Bei noch einer anderen Ausführungsform ist das Antiadipositum Sibutramin oder die mono- und bisdemethylierten Wirkmetabolite von Sibutramin.In yet another embodiment, the anti-adiposity is sibutramine or the mono- and bis-demethylated active metabolites of sibutramine.
Bei einer weiteren Ausführungsform ist das Antiadipositum Orlistat.In another embodiment, the anti-obesity agent is orlistat.
Bei einer anderen Ausführungsform ist das Antiadipositum Mazindol, Diethylpropion oder Phentermin.In another embodiment, the anti-obesity agent is mazindol, diethylpropion or phentermine.
Weiterhin können die vorliegenden Verbindungen in Kombination mit einem oder mehreren antihypertensiven Wirkstoffen verabreicht werden. Beispiele für antihypertensive Wirkstoffe sind Betabiocker wie Alprenolol, Atenol, Timolol, Pindolol,Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are beta blockers such as alprenolol, atenol, timolol, pindolol,
Propanolol und Metoprolol, ACE (Angiotensin Converting Enzym)-Hemmer wie z.B.Propranolol and metoprolol, ACE (Angiotensin Converting Enzyme) inhibitors, e.g.
Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Quinapril und Rampril,Benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril,
Calciumkanal-Blocker wie Nifedipin, Felodipin, Nicardipin, Isradipin, Nimodipin, Diltiazem und Verapamil, sowie Alphablocker wie Doxazosin, Urapidil, Prazosin undCalcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, as well as alpha-blockers such as doxazosin, urapidil, prazosin and
Terazosin. Weiterhin kann verwiesen werden auf Remington: The Science and
Practice of Pharmacy, 19. Auflage, Gennaro, Hrsg., Mack Publishing Co., Easton, PA,Terazosin. Further, reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, ed., Mack Publishing Co., Easton, PA,
1995.1995th
Es versteht sich, dass jede geeignete Kombination der erfindungsgemäßenIt is understood that any suitable combination of the invention
Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und 5 wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird.Compounds with one or more of the aforementioned compounds and optionally one or more further pharmacologically active substances are considered to fall within the scope of the present invention.
Die Wirksamkeit der Verbindungen wurde wie folgt getestet:The effectiveness of the compounds was tested as follows:
Biologisches Prüfmodell:Biological test model:
Die Prüfung der anorektischen Wirkung erfolgte an weiblichen NMRI Mäusen. Nach 10 17stündigem Futterentzug wurde über eine Schlundsonde das Testpräparat verabreicht. In Einzelhaltung und bei freiem Zugang zu Trinkwasser wurde den TierenThe anorectic effect was tested on female NMRI mice. After ten 17-hour feed withdrawal, the test preparation was administered via a gavage. In individual housing and with free access to drinking water was the animals
30 Minuten nach Präparatgabe Kondensmilch angeboten. DerCondensed milk is offered 30 minutes after preparation. Of the
Kondensmilchverbrauch wurde halbstündlich 7 Stunden lang bestimmt und dasCondensed milk consumption was determined every half hour for 7 hours and the
Allgemeinbefinden der Tiere beobachtet. Der gemessene Milchverbrauch wurde mit 15 den Vehikel-behandelten Kontrolltieren verglichen.
General condition of the animals observed. Measured milk consumption was compared with 15 vehicle-treated control animals.
Tabelle 1 : Anorektische Wirkung, gemessen als Reduktion des kumulierten Milchkonsums behandelter im Vergleich zu Kontrolltieren.Table 1: Anorectic effect, measured as a reduction of cumulated milk consumption treated compared to control animals.
Aus der Tabelle ist abzulesen, daß die Verbindungen der Formel I eine sehr gute anorektische Wirkung zeigen. In zwei gleichzeitig erschienenen Artikeln in Nature (Nature 400, 261-264, 1999; Nature 400, 265-269, 1999, siehe Anlage) wurde separat von zwei Arbeitsgruppen ein hochspezifischer Rezeptor für das Melanin-Concentrating-Hormone (MCH) beschrieben. MCH übernimmt wichtige Funktionen bei der Steuerung der Nahrungsaufnahme. Verbindungen die auf den MCH-Rezeptor wirken, besitzen daher eine anorektische Wirkung und sind zur Behandlung von Obesitas geeignet. Die Prüfung auf anorektische Wirkung der erfindungsgemäßen Verbindungen der Formel I wurde daher wie folgt durchgeführt.From the table it can be seen that the compounds of formula I show a very good anorexic effect. In two co-published articles in Nature (Nature 400, 261-264, 1999, Nature 400, 265-269, 1999, see attachment), a highly specific receptor for melanin-concentrating hormone (MCH) was separately described by two groups. MCH performs important functions in the control of food intake. Compounds which act on the MCH receptor therefore have an anorexic effect and are suitable for the treatment of obesity. The test for anorectic activity of the compounds of the formula I according to the invention was therefore carried out as follows.
Funktionelle Messungen zur Ermittlung von IC50-WertenFunctional measurements to determine IC50 values
Die Klonierung der cDNA für den humanen MCH-Rezeptor, Herstellung einer rekombinanten HEK293-Zellinie, welche den humanen MCH-Rezeptor exprimiert, sowie funktioneile Messungen mit der rekombinanten Zellinie erfolgten sinngemäß wie von Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001 ) beschrieben. Im
Unterschied zur Literaturstelle wurde jedoch für die Konstruktion des Expressionsvektors das Plasmid pEAKδ der Fa. EDGE Biosystems (USA) verwendet. Als Wirt für die Transfektion diente eine transformierte HEK-Zellinie namens „PEAK Stable Cells" (ebenfalls von EDGE Biosystems). Die funktionellen Messungen des zellulären Calciumflusses nach Agonistenzugabe (MCH) in Gegenwart von erfindungsgemässem Ligand erfolgten mit Hilfe des FLIPR-Gerätes der Fa. Molecular Devices (USA), unter Verwendung von Vorschriften des Geräteherstellers. Die Ergebnisse aus dem zellulären Assay sind in Tabelle 2 wiedergegeben. Tabelle 2:The cloning of the cDNA for the human MCH receptor, production of a recombinant HEK293 cell line expressing the human MCH receptor and functional measurements with the recombinant cell line were carried out analogously as described by Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). in the Difference to the literature, however, the plasmid pEAKδ Fa. EDGE Biosystems (USA) was used for the construction of the expression vector. The host used for the transfection was a transformed HEK cell line named "PEAK Stable Cells" (likewise from EDGE Biosystems) The functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligands according to the invention were carried out with the aid of the FLIPR apparatus of the company. Molecular Devices (USA), using equipment manufacturer's instructions The results from the cellular assay are reported in Table 2. TABLE 2
Die nachfolgend aufgeführten Beispiele und Herstellungsmethoden dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken. Beispiel 1 1 -[1 -(2-Dimethylamino-ethyl)-1 H-indol-5-yl]-3-(4-phenoxy-phenyl)-harnstoffThe following examples and preparation methods serve to illustrate the invention, but without limiting it. Example 1 1 - [1- (2-Dimethylamino-ethyl) -1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
Eine auf 0 °C gekühlte Lösung von 1-Dimethylamino-ethyl-5-aminoindol (6.30 g) in Dimethylformamid (50 mL) wurde mit Carbonyldiimidazol (5.12 g) versetzt. Nach 10 Minuten wurde 4-Aminodiphenylether (5.84 g) zugesetzt und die Reaktionsmischung für 2 Stunden auf 80 °C erhitzt. Nach dem Abkühlen wurde die Reaktion mit Ethylacetat verdünnt und mit Wasser gewaschen. Die organische Phase wurde über Magnesiumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel (Eluent: Dichlormethan/Methanol 9:1) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 414.15 (C25H26N402); MS (ESI): 415 (M+H+). A solution of 1-dimethylaminoethyl-5-aminoindole (6.30 g) in dimethylformamide (50 mL) cooled to 0 ° C was added with carbonyldiimidazole (5.12 g). After 10 minutes, 4-aminodiphenyl ether (5.84 g) was added and the reaction mixture heated to 80 ° C for 2 hours. After cooling, the reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol 9: 1). This gave the product with the molecular weight 414.15 (C 25 H 26 N 4 0 2 ); MS (ESI): 415 (M + H + ).
Beispiel 2Example 2
1 -(4-Butoxy-phenyl)-3-[1 -(2-dimethylamino-ethyl)-1 H-indol-5-yl]-hamstoff1- (4-Butoxy-phenyl) -3- [1- (2-dimethylamino-ethyl) -1H-indol-5-yl] -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 4-Butoxyanilin und 1- Dimethylamino-ethyl-5-aminoindol hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 394,52 (C23H3oN402); MS (ESI): 395 (M+H+).The compound was prepared as described in Example 1 from 4-butoxyaniline and 1-dimethylamino-ethyl-5-aminoindole. This gave the product with the molecular weight 394.52 (C 23 H 3 oN 4 0 2 ); MS (ESI): 395 (M + H + ).
Beispiel 3 1 -(1 -Methyl-2-pyrrolidin-1 -ylmethyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoffExample 3 1- (1-Methyl-2-pyrrolidin-1-ylmethyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 4-Aminodiphenylether und 1-Methyl-2-pyrrolidin-1 -ylmethyl-1 H-indol-5-ylamin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 440,55 (C27H2sN4O2); MS (ESI): 441 (M+H+).
1 -Methyl-2-pyrrolidin-1 -ylmethyl-1 H-indol-5-ylaminThe compound was prepared as described in Example 1 from 4-aminodiphenyl ether and 1-methyl-2-pyrrolidin-1-ylmethyl-1H-indol-5-ylamine. This gave the product of molecular weight 440.55 (C 27 H 2 sN 4 O 2 ); MS (ESI): 441 (M + H + ). 1-methyl-2-pyrrolidin-1-ylmethyl-1H-indol-5-ylamine
Eine Suspension von 1 -Methyl-5-nitro-2-pyrrolidin-1 -ylmethyl-1 H-indol (150 mg), Ethanol (2 mL) und Palladium(ll)-hydroxid auf Kohle (20%, 30 mg) wurde mit Ameisensäure (0,11 mL) versetzt und für 5 Minuten auf 60 °C erhitzt. Nach beendeter 5 Gasentwicklung wurde noch 20 Minuten gerührt und der Katalysator abfiltriert. Das Filtrat wurde eingeengt und zwischen gesättigter Natriumcarbonatlösung und Methyl- tert.-butylether verteilt. Die organische Phase wurde abgetrennt, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt so das Produkt mit dem Molekulargewicht 229,33 (C14H19N3); MS (ESI): 230 (M+H+).A suspension of 1-methyl-5-nitro-2-pyrrolidin-1-ylmethyl-1H-indole (150mg), ethanol (2mL) and palladium (II) hydroxide on carbon (20%, 30mg) treated with formic acid (0.11 mL) and heated to 60 ° C for 5 minutes. After completion of the gas evolution, the mixture was stirred for a further 20 minutes and the catalyst was filtered off. The filtrate was concentrated and partitioned between saturated sodium carbonate solution and methyl tert-butyl ether. The organic phase was separated, dried over magnesium sulfate and concentrated. This gave the product with the molecular weight 229.33 (C 14 H 19 N 3 ); MS (ESI): 230 (M + H + ).
1010
1 -Methyl-5-nitro-2-pyrrolidin-1 -ylmethyl-1 H-indol1-methyl-5-nitro-2-pyrrolidin-1-ylmethyl-1H-indole
Eine auf 0 °C gekühlte Lösung von (1-Methyl-5-nitro-1 H-indol-2-yl)-methanol (121 mg) in Dichlormethan (10 mL) und Triethylamin (0,17 mL) wurde tropfenweise mit Mesylchlorid (92 mg) versetzt. Nach 15 Minuten wurde Pyrrolidin (142 mg) zugesetztA solution of (1-methyl-5-nitro-1H-indol-2-yl) -methanol (121mg) in dichloromethane (10mL) and triethylamine (0.17mL) cooled to 0 ° C was added dropwise with mesyl chloride (92 mg). After 15 minutes, pyrrolidine (142 mg) was added
15 und die Lösung anschließend bei Raumtemperatur für eine Stunde gerührt. Die Reaktionslösung wurde mit gesättigter Natriumcarbonatlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde durch Chormoatographie an Kieselgel (Eluent: Ethylacetat / Triethylamin 99:1) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 259,31 (C14Hι7N302); MS (ESI):15 and the solution then stirred at room temperature for one hour. The reaction solution was washed with saturated sodium carbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by chormoatography on silica gel (eluent: ethyl acetate / triethylamine 99: 1). This gave the product with the molecular weight 259.31 (C 14 Hι 7 N 3 0 2 ); MS (ESI):
20 260 (M+H+).20 260 (M + H + ).
(1 -Methyl-5-nitro-1 H-indol-2-yl)-methanol(1-methyl-5-nitro-1H-indol-2-yl) -methanol
Zu einer auf 0 °C gekühlten Suspension von Lithiumaluminiumhydrid inTo a cooled to 0 ° C suspension of lithium aluminum hydride in
Tetrahydrofuran (50 mL) wurde innerhalb von 20 Minuten Schwefelsäure (96%ig, 0,64Tetrahydrofuran (50 mL) was added sulfuric acid (96%, 0.64.) Over 20 minutes
25 mL) getropft. Nach 20 Minuten wurde eine Lösung von 1-Methyl-5-nitro-1H-indol-2- carbonsäureethylester (1 ,85 g) in Tetrahydrofuran (40 mL) zugetropft. Nach 30 Minuten wurde Wasser (2 mL) zugegeben. Nach 30 Minuten wurde der entstandene Niederschlag abfiltriert und das Filtrat eingeengt. Das Rohprodukt wurde durch Chormoatographie an Kieselgel (Eluent: n-Heptan/Ethylacetat 3:2) gereinigt. Man25 mL). After 20 minutes, a solution of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (1.85 g) in tetrahydrofuran (40 mL) was added dropwise. After 30 minutes, water (2 mL) was added. After 30 minutes, the resulting precipitate was filtered off and the filtrate was concentrated. The crude product was purified by chormoatography on silica gel (eluent: n-heptane / ethyl acetate 3: 2). you
30 erhielt so das Produkt mit dem Molekulargewicht 206,20 (C10H10N2O3); MS (ESI): 207 (M+H+).
1 -Methyl-5-nitro-1 H-indol-2-carbonsäureethylester Eine Suspension von 5-Nitro-1 H-indol-2-carbonsäureethylester (2,34 g), Kaliumcarbonat (3,45 g), Methyliodid (2,13 g) und Acetonitril (30 mL) wurde für 6 Stunden bei 60 °C gehalten. Nach dem Abkühlen auf Raumtemperatur wurde Wasser zugesetzt und das ausgefallene Produkt durch Filtration isoliert. Man erhielt so das Produkt mit dem Molekulargewicht 248,24 (Cι2H12N2O4); MS (ESI): 249 (M+H+).30 thus obtained the product with the molecular weight 206.20 (C1 0 H1 0 N2O3); MS (ESI): 207 (M + H + ). Ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate A suspension of ethyl 5-nitro-1H-indole-2-carboxylate (2.34 g), potassium carbonate (3.45 g), methyl iodide (2, 13 g) and acetonitrile (30 mL) was kept at 60 ° C for 6 hours. After cooling to room temperature, water was added and the precipitated product was isolated by filtration. This gave the product with the molecular weight 248.24 (C 2 H 12 N 2 O 4 ); MS (ESI): 249 (M + H + ).
Beispiel 4Example 4
1 -[1 -(2-Dimethylamino-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)-hamstoff1 - [1- (2-Dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
Eine Lösung von 1-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-phenoxy- phenyl)-harnstoff (50 mg) in Dichlormethan (10 mL) und Eisessig (1 mL) wurde mit Zinkstaub (250 mg) versetzt. Nach 10 Minuten wurde das anorganische Material über Kieselgur abfiltriert. Das Filtrat wurde mit Natriumcarbonatlösung (10%ig) gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde in Dichlormethan (5 mL) und Ethanol (5 mL) aufgenommen und mit Dimethylformamiddimethylacetal (0,3 mL) und Ameisensäure (0,3 mL) versetzt. Die Mischung wurde mittels Heißluftfön erhitzt und dabei das Dichlormethan vertrieben. Die restliche Mischung wurde eingeengt und zwischen Dichlormethan und Natriumcarbonatlösung (10%ig) verteilt. Die organische Phase wurde abgetrennt, getrocknet und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 415,50 (C2 H25N5θ2); MS (ESI): 416 (M+H+). Schmelzpunkt des Hydrochlorids: 213-215 °C.A solution of 1- [4- (2-dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxyphenyl) -urea (50 mg) in dichloromethane (10 mL) and glacial acetic acid (1 mL). Zinc dust (250 mg) was added. After 10 minutes, the inorganic material was filtered through kieselguhr. The filtrate was washed with sodium carbonate solution (10%), dried over magnesium sulfate and concentrated. The residue was taken up in dichloromethane (5 mL) and ethanol (5 mL) and treated with dimethylformamide dimethyl acetal (0.3 mL) and formic acid (0.3 mL). The mixture was heated by means of a hot-air blower, thereby displacing the dichloromethane. The residual mixture was concentrated and partitioned between dichloromethane and sodium carbonate solution (10%). The organic phase was separated, dried and concentrated. The residue was purified by preparative HPLC. This gave the product with the molecular weight 415.50 (C 2 H 25 N 5 θ 2 ); MS (ESI): 416 (M + H + ). Melting point of the hydrochloride: 213-215 ° C.
1-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff Eine Lösung von 2-Dimethylaminoethylamin in Dimethylformamid (1M, 2 mL) und 1- (4-Fluor-3-nitro-phenyl)-3-(4-phenoxy-phenyl)-harnstoff (200 mg) wurde für 48
Stunden gerührt. Die Mischung wurde zwischen Dichlormethan und Natriumcarbonatlösung (10%ig) verteilt. Die organische Phase wurde getrocknet und eingeengt. Der Rückstand wurde aus Toluol umkristallisiert. Schmelzpunkt: 178-180 °C.1- [4- (2-Dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxyphenyl) -urea A solution of 2-dimethylaminoethylamine in dimethylformamide (1M, 2 mL) and 1- (4 Fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea (200 mg) was added for 48 Hours stirred. The mixture was partitioned between dichloromethane and sodium carbonate solution (10%). The organic phase was dried and concentrated. The residue was recrystallized from toluene. Melting point: 178-180 ° C.
1-(4-Fluor-3-nitro-phenyl)-3-(4-phenoxy-phenyl)-harnstoff1- (4-fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea
Zu einer Lösung von 4-Phenoxyanilin (2 mmol) in Dimethylformamid (20 mL) wurde 4-Fluor-3-nitrophenylisocyanat (2,2 mmol) gegeben. Nach zwei Tagen wurde die Reaktionsmischung zwischen Dichlormethan und gesättigter Natriumcarbonatlösung verteilt. Die organische Phase wurde getrocknet und eingeengt. Der Rückstand wurde durch Chromatographie an Kieselgel (Eluent: Ethylacetat/Dichlormethan 95:5) und anschließendes Umkristallisieren aus Ethylacetat/Hexan gereinigt. Schmelzpunkte 74- 176 °C.To a solution of 4-phenoxyaniline (2 mmol) in dimethylformamide (20 mL) was added 4-fluoro-3-nitrophenyl isocyanate (2.2 mmol). After two days, the reaction mixture was partitioned between dichloromethane and saturated sodium carbonate solution. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / dichloromethane 95: 5) followed by recrystallization from ethyl acetate / hexane. Melting points 74-176 ° C.
Beispiel 5Example 5
1 -[1 -(2-Dimethylamino-ethyl)-2-methyl-1 H-benzoimidazol-5-yl]-3-(4-isopropoxy- phenyl)-hamstoff1 - [1- (2-Dimethylamino-ethyl) -2-methyl-1H-benzoimidazol-5-yl] -3- (4-isopropoxyphenyl) -urea
1-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-isopropoxy-phenyl)-harnstoff1- [4- (2-dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-isopropoxy-phenyl) -urea
(75 mg) wurde wie im Beispiel 4 beschrieben mit Zinkstaub reduziert. Das(75 mg) was reduced as described in Example 4 with zinc dust. The
Reaktionsprodukt wurde in Methanol gelöst und mit Triethylorthoacetat (0,5 mL) undReaction product was dissolved in methanol and triethyl orthoacetate (0.5 mL) and
Eisessig (0,2 mL) versetzt. Die Mischung wurde für 5 Minuten zum Rückfluß erhitzt. Flüchtige Anteile wurden entfernt. Der Rückstand wurde zwischen Dichlormethan undGlacial acetic acid (0.2 mL) is added. The mixture was heated to reflux for 5 minutes. Volatile shares were removed. The residue was partitioned between dichloromethane and
Natriumcarbonatlösung verteilt. Die organische Phase wurde getrocknet und eingeengt. Der Rückstand wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 395,51
MS (ESI): 396 (M+H+).
1-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-isopropoxy-phenyl)-hamstoff Die Verbindung wurde wie im Beispiel 4 aus 1-(4-Fluor-3-nitro-phenyl)-3-(4- isopropoxy-phenyl)-hamstoff und 2-Dimethylaminoethylamin erhalten. Die Verbindung wurde ohne Reinigung weiter umgesetzt.Sodium carbonate solution distributed. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. This gave the product with a molecular weight of 395.51 MS (ESI): 396 (M + H + ). 1- [4- (2-Dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-isopropoxyphenyl) -urea The compound was prepared as described in Example 4 from 1- (4-fluoro-3-nitro-phenyl) phenyl) -3- (4-isopropoxyphenyl) urea and 2-dimethylaminoethylamine. The compound was reacted further without purification.
1-(4-Fluor-3-nitro-phenyl)-3-(4-isopropoxy-phenyl)-hamstoff1- (4-fluoro-3-nitro-phenyl) -3- (4-isopropoxy-phenyl) -hamstoff
Die Verbindung wurde wie im Beispiel 4 aus 4-Fluor-3-nitrophenylisocyanat und 4-The compound was prepared as in Example 4 from 4-fluoro-3-nitrophenyl isocyanate and 4-
Isopropoxyanilin erhalten. Schmelzpunkt: 170-172 °C.Isopropoxyanilin obtained. Melting point: 170-172 ° C.
Beispiel 6Example 6
1 -[1 -(1 -Ethyl-pyrrolidin-2-ylmethyl)-2-methyl-1 H-benzoimidazol-5-yl]-3-(4-isopropoxy- phenyl)-harnstoff1 - [1 - (1-Ethylpyrrolidin-2-ylmethyl) -2-methyl-1H-benzoimidazol-5-yl] -3- (4-isopropoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 5 beschrieben aus 1 -{4-[(1 -Ethyl-pyrrolidin-2- ylmethyl)-amino]-3-nitro-phenyl}-3-(4-isopropoxy-phenyl)-hamstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 435,57 (C25H33N5O2); MS (ESI): 436 (M+H+). Schmelzpunkt (Ethylacetat/Hexan): 185-187 °C. The compound was prepared as described in Example 5 from 1 - {4 - [(1-ethylpyrrolidin-2-ylmethyl) amino] -3-nitro-phenyl} -3- (4-isopropoxy-phenyl) -urea. This gave the product with the molecular weight 435.57 (C2 5 H 33 N 5 O 2); MS (ESI): 436 (M + H + ). Melting point (ethyl acetate / hexane): 185-187 ° C.
1 -{4-[(1 -Ethyl-pyrrolidin-2-ylmethyl)-amino]-3-nitro-phenyl}-3-(4-isopropoxy-phenyl)- harnstoff1 - {4 - [(1-Ethylpyrrolidin-2-ylmethyl) amino] -3-nitro-phenyl} -3- (4-isopropoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-isopropoxy-phenyl)-hamstoff und 1-Ethyl-pyrrolidin-2-yl-methylamin hergestellt und ohne weitere Reinigung weiter umgesetzt.The compound was prepared as described in Example 4 from 1- (4-fluoro-3-nitro-phenyl) -3- (4-isopropoxy-phenyl) -urea and 1-ethyl-pyrrolidin-2-yl-methylamine and without further Cleaning further implemented.
Beispiel 7Example 7
1 -(4-lsopropoxy-phenyl)-3-[2-methyl-1 -(2-piperidin-1 -yl-ethyl)-1 H-benzoimidazol-5-yl]- hamstoff
1- (4-Isopropoxy-phenyl) -3- [2-methyl-1- (2-piperidine-1-yl-ethyl) -1H-benzoimidazol-5-yl] -urea
Die Verbindung wurde wie im Beispiel 5 beschrieben aus 1-(4-lsopropoxy-phenyl)-3- [3-nitro-4-(2-piperidin-1-yl-ethylamino)-phenyl]-hamstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 435,57 (C^sHssN^); MS (ESI): 436 (M+H+).The compound was prepared as described in Example 5 from 1- (4-isopropoxy-phenyl) -3- [3-nitro-4- (2-piperidin-1-yl-ethylamino) -phenyl] -urea. This gave the product with the molecular weight 435.57 (C ^ sHssN ^); MS (ESI): 436 (M + H + ).
1-(4-lsopropoxy-phenyl)-3-[3-nitro-4-(2-piperidin-1-yl-ethylamino)-phenyl]-hamstoff Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-isopropoxy-phenyl)-harnstoff und 1-(2-Aminoethyl)piperidin hergestellt (60 °C, 4 h). Schmelzpunkt (Ethylacetat): 157-159 °C.1- (4-isopropoxy-phenyl) -3- [3-nitro-4- (2-piperidin-1-yl-ethylamino) -phenyl] -urea The compound was prepared as described in Example 4 from 1- (4-fluoro 3-nitro-phenyl) -3- (4-isopropoxy-phenyl) -urea and 1- (2-aminoethyl) -piperidine (60 ° C, 4 h). Melting point (ethyl acetate): 157-159 ° C.
Beispiel 8Example 8
1 -(4-lsopropoxy-phenyl)-3-[2-methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-benzoimidazol-5- yl]-hamstoff1 - (4-isopropoxy-phenyl) -3- [2-methyl-1- (2-morpholin-4-yl-ethyl) -1H-benzoimidazol-5-yl] -urea
Die Verbindung wurde wie im Beispiel 5 beschrieben aus 1-(4-lsopropoxy-phenyl)-3- [4-(2-morpholin-4-yl-ethylamino)-3-nitro-phenyl]-hamstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 437,55 (C24H31N5O3); MS (ESI): 438 (M+H+).The compound was prepared as described in Example 5 from 1- (4-isopropoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethylamino) -3-nitro-phenyl] -urea. This gave the product with the molecular weight 437.55 (C 2 4H31N 5 O 3 ); MS (ESI): 438 (M + H + ).
1-(4-lsopropoxy-phenyl)-3-[4-(2-morpholin-4-yl-ethylamino)-3-nitro-phenyl]-harnstoff Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-isopropoxy-phenyl)-hamstoff und 1-(2-Aminoethyl)morpholin hergestellt (60 °C, 4 h). Schmelzpunkt (Ethylacetat): 191-193 °C.
Beispiel 91- (4-isopropoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethylamino) -3-nitro-phenyl] -urea The compound was prepared as described in Example 4 from 1- (4-fluoro 3-nitro-phenyl) -3- (4-isopropoxyphenyl) -urea and 1- (2-aminoethyl) morpholine (60 ° C, 4h). Melting point (ethyl acetate): 191-193 ° C. Example 9
1 -(4-lsopropoxy-phenyl)-3-[2-methyl-1 -(2-pyrrolidin-1-yl-ethyl)-1 H-benzoimidazol-5-yl]- harnstoff1- (4-isopropoxy-phenyl) -3- [2-methyl-1- (2-pyrrolidin-1-yl-ethyl) -1H-benzoimidazol-5-yl] -urea
Die Verbindung wurde wie im Beispiel 5 beschrieben aus 1-[3-Nitro-4-(2-pyrrolidin-1- yl-ethylamino)-phenyl]-3-(4-phenoxy-phenyl)-harnstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 455,56 (C27H29N5θ2); MS (ESI): 456 (M+H+).The compound was prepared as described in Example 5 from 1- [3-nitro-4- (2-pyrrolidin-1-yl-ethylamino) -phenyl] -3- (4-phenoxy-phenyl) -urea. This gave the product of molecular weight 455.56 (C 27 H 29 N 5 O 2 ); MS (ESI): 456 (M + H + ).
1 -[3-N itro-4-(2-pyrrol id in- 1 -yl-ethylamino)-phenyl]-3-(4-phenoxy-phenyl)-hamstoff Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1 -(4-Fluor-3-nitro-phenyl)-3- (4-phenoxy-phenyl)-hamstoff und und 1-(2-Aminoethyl)pyrrolidin hergestellt (60 °C, 5 h). Schmelzpunkt (Ethylacetat/Hexan): 179-181 °C.1 - [3-N itro-4- (2-pyrrole id in 1 -yl-ethylamino) -phenyl] -3- (4-phenoxy-phenyl) -urea The compound was prepared as described in Example 4 from 1 - ( 4-fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea and 1- (2-aminoethyl) pyrrolidine (60 ° C, 5 h). Melting point (ethyl acetate / hexane): 179-181 ° C.
Beispiel 10Example 10
1 -[2-Methyl-1 -(2-dimethylamino-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1 - [2-Methyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 5 beschrieben aus 1-[4-(2-Dimethylamino- ethylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 429,53 (C25H27N5θ2); MS (ESI): 430 (M+H+).The compound was prepared as described in Example 5 from 1- [4- (2-dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea. This gave the product with the molecular weight 429.53 (C 25 H 27 N 5 θ2); MS (ESI): 430 (M + H + ).
Beispiel 11Example 11
1 -(4-Phenoxy-phenyl)-3-[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-benzoimidazol-5-yl]-harnstoff
1- (4-Phenoxy-phenyl) -3- [1- (2-pyrrolidin-1-yl-ethyl) -1H-benzoimidazol-5-yl] -urea
Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-[3-Nitro-4-(2-pyrrolidin-1- yl-ethylamino)-phenyl]-3-(4-phenoxy-phenyl)-hamstoff hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 441 ,54 (C26H27N5O2); MS (ESI): 442 (M+H+).The compound was prepared as described in Example 4 from 1- [3-nitro-4- (2-pyrrolidin-1-yl-ethylamino) -phenyl] -3- (4-phenoxy-phenyl) -urea. This gave the product with the molecular weight 441, 54 (C26H27N 5 O 2 ); MS (ESI): 442 (M + H + ).
Beispiel 12Example 12
1 -[2-Benzyl-1 -(2-dimethylamino-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1 - [2-Benzyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
1-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff (75 mg) wurde wie im Beispiel 4 beschrieben reduziert. Das Rohprodukt wurde mit Phenylessigsäure (0,33 mmol) aktiviert mit HATU (0,33 mmol) und Diisopropylamin (0,7 mmol) in Dimethylformamid (1 ,5 mL) für drei Stunden behandelt. Das Reaktionsgemisch wurde zwischen Dichlormethan und Natriumcarbonatlösung (10%ig) verteilt. Die organische Phase wurde getrocknet und eingeengt. Der Rückstand wurde in Trifluoressigsäure (1 mL), Wasser (1 mL) und Acetonitril (0,5 mL) für fünf Minuten zum Rückfluß erhitzt. Flüchtige Anteile wurden evaporiert und der Rückstand durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 505,63 (C31H31N5O2); MS (ESI): 506 (M+H+).1- [4- (2-Dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea (75 mg) was reduced as described in Example 4. The crude product was treated with phenylacetic acid (0.33 mmol) activated with HATU (0.33 mmol) and diisopropylamine (0.7 mmol) in dimethylformamide (1.5 mL) for three hours. The reaction mixture was partitioned between dichloromethane and sodium carbonate solution (10%). The organic phase was dried and concentrated. The residue was refluxed in trifluoroacetic acid (1 mL), water (1 mL) and acetonitrile (0.5 mL) for five minutes. Volatiles were evaporated and the residue was purified by preparative HPLC. This gave the product with the molecular weight 505.63 (C 31 H 3 1N5O 2); MS (ESI): 506 (M + H + ).
Beispiel 13
1 -[1 -(2-Dimethylamino-ethyl)-2-phenyl-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- hamstoffExample 13 1 - [1- (2-Dimethylamino-ethyl) -2-phenyl-1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
1 -[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff (50 mg) wurde wie im Beispiel 4 beschrieben reduziert. Nach Filtration über Kieselgur wurde das Filtrat mit Benzaldehyd (0,2 mL) versetzt. Die Reaktionsmischung wurde mit Natriumcarbonatlösung (10%ig) gewaschen, getrocknet und mit Mangandioxid (0,5 g) versetzt. Nach 15 Minuten wurde das anorganische Material abfiltriert und das Filtrat eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 491 ,60 (C30H29N5O2); MS (ESI): 492 (M+H+).1 - [4- (2-Dimethylamino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea (50 mg) was reduced as described in Example 4. After filtration through kieselguhr, the filtrate was treated with benzaldehyde (0.2 mL). The reaction mixture was washed with sodium carbonate solution (10%), dried and treated with manganese dioxide (0.5 g). After 15 minutes, the inorganic material was filtered off and the filtrate was concentrated. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 491, 60 (C 30 H 29 N 5 O 2 ); MS (ESI): 492 (M + H + ).
Beispiel 14 1-[2-Ethyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- hamstoffExample 14 1- [2-Ethyl-1- (2-pyrrolidin-1-yl-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
1-[4-(2-Pyrrolidino-ethylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff wurde wie im Beispiel 4 beschrieben reduziert. Das Rohprodukt wurde analog Beispiel 5 mit Triethylorthopropionat umgesetzt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 469,59 (C28H3ιN5θ2); MS (ESI): 470 (M+H+).
Beispiel 151- [4- (2-Pyrrolidino-ethylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea was reduced as described in Example 4. The crude product was reacted analogously to Example 5 with triethyl orthopropionate. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 469.59 (C 28 H 3 ιN 5 θ2); MS (ESI): 470 (M + H + ). Example 15
1 -[2-Methyl-1 -(2-piperidin-1 -yl-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1 - [2-Methyl-1 - (2-piperidine-1-yl-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
1 -[2-Methyl-1 -(2-piperidin-1 -yl-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- hamstoff wurde wie im Beispiel 4 beschrieben reduziert. Das Rohprodukt wurde wie im Beispiel 5 beschrieben mit Triethylorthoacetat umgesetzt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 469,59 (C28H3ιN5θ2); MS (ESI): 470 (M+H+).1 - [2-Methyl-1- (2-piperidine-1-yl-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea was reduced as described in Example 4. The crude product was reacted as described in Example 5 with triethyl orthoacetate. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 469.59 (C 28 H 3 ιN 5 θ 2 ); MS (ESI): 470 (M + H + ).
1-[2-Methyl-1-(2-piperidin-1-yl-ethyl)-1 H-benzoimidazol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1- [2-Methyl-1- (2-piperidin-1-yl-ethyl) -1H-benzoimidazol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-phenoxy-phenyl)-hamstoff und 1-(2-Aminoethyl)piperidin hergestellt (60 °C, 4 h). Schmelzpunkt (Ethylacetat/Hexan): 163-165 °C.The compound was prepared as described in Example 4 from 1- (4-fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea and 1- (2-aminoethyl) piperidine (60 ° C, 4 H). Melting point (ethyl acetate / hexane): 163-165 ° C.
Beispiel 16Example 16
1 -[1 -(1 -Ethyl-pyrrolidin-2-ylmethyl)-2-methyl-1 H-benzoimidazol-5-yl]-3-(4-phenoxy- phenyl)-hamstoff1 - [1- (1-Ethylpyrrolidin-2-ylmethyl) -2-methyl-1H-benzoimidazol-5-yl] -3- (4-phenoxyphenyl) -urea
1-{4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-3-nitro-phenyl}-3-(4-phenoxy-phenyl)- hamstoff wurde wie im Beispiel 4 beschrieben reduziert. Das Rohprodukt wurde wie im Beispiel 5 beschrieben mit Triethylorthoacetat umgesetzt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 469,59 (C28H3iN5θ2); MS (ESI): 470 (M+H+). 1- {4 - [(1-Ethylpyrrolidin-2-ylmethyl) amino] -3-nitro-phenyl} -3- (4-phenoxy-phenyl) -urea was reduced as described in Example 4. The crude product was reacted as described in Example 5 with triethyl orthoacetate. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 469.59 (C 28 H 3 iN 5 θ 2 ); MS (ESI): 470 (M + H + ).
1-{4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-3-nitro-phenyl}-3-(4-phenoxy-phenyl)- hamstoff Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-phenoxy-phenyl)-harnstoff und C-(1-Ethyl-pyrrolidin-2-yl)-methylamin hergestellt (60 °C, 4 h). Schmelzpunkt (Ethylacetat/Hexan): 129-132 °C.1- {4 - [(1-Ethylpyrrolidin-2-ylmethyl) -amino] -3-nitro-phenyl} -3- (4-phenoxy-phenyl) -urea The compound was prepared as described in Example 4 from 1- (4-Fluoro-3-nitro-phenyl) -3- (4-phenoxy-phenyl) -urea and C- (1-ethyl-pyrrolidin-2-yl) -methylamine (60 ° C., 4 h). Melting point (ethyl acetate / hexane): 129-132 ° C.
Beispiel 17 1 -(2-Dimethylaminomethyl-1 H-benzoimidazol-5-yl)-3-(4-phenoxy-phenyl)-hamstoffExample 17 1 - (2-Dimethylaminomethyl-1H-benzoimidazol-5-yl) -3- (4-phenoxyphenyl) -urea
1-[4-(2,4-Dimethoxy-benzylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-hamstoff (75 mg) wurde wie im Beispiel 4 beschrieben reduziert. Das Reduktionsprodukt wurde mit Dimethylaminoessigsäure (1 mmol), HATU (1 mmol) und Diisopropylamin (2 mmol) in Dimethylformamid (3 mL) umgesetzt. Nach drei Stunden wurde die Mischung zwischen Ethylacetat und Natriumcarbonatlösung verteilt. Die organische Phase wurde getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Zwischenprodukt (N-{2-Amino-5-[3-(4-phenoxy-phenyl)- ureido]-phenyl}-2-dimethylamino-acetamid) mit dem Molekulargewicht 419.49 (C23H25N5O3); MS (ESI): 420 (M+H+).
Dieses Material wurde mit Pivalinsäure zum Rückfluß erhitzt und anschliessend flüchtige Anteile im Hochvakuum entfernt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 401.47 (C23H23N5O2); MS (ESI): 402 (M+H+).1- [4- (2,4-Dimethoxy-benzylamino) -3-nitro-phenyl] -3- (4-phenoxyphenyl) -urea (75 mg) was reduced as described in Example 4. The reduction product was reacted with dimethylaminoacetic acid (1 mmol), HATU (1 mmol) and diisopropylamine (2 mmol) in dimethylformamide (3 mL). After three hours, the mixture was partitioned between ethyl acetate and sodium carbonate solution. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC. This gave the intermediate (N- {2-amino-5- [3- (4-phenoxy-phenyl) - ureido] -phenyl} -2-dimethylamino-acetamide) with the molecular weight 419.49 (C23H25N5O 3); MS (ESI): 420 (M + H + ). This material was heated to reflux with pivalic acid and then volatiles were removed under high vacuum. The crude product was purified by preparative HPLC. This gave the product with a molecular weight of 401.47 (C 23 H 23 N 5 O 2); MS (ESI): 402 (M + H + ).
1-[4-(2,4-Dimethoxy-benzylamino)-3-nitro-phenyl]-3-(4-phenoxy-phenyl)-harnstoff Die Verbindung wurde wie im Beispiel 4 beschrieben aus 1-(4-Fluor-3-nitro-phenyl)-3- (4-phenoxy-phenyl)-hamstoff und 2,4-Dimethoxybenzylamin (60 °C, 12 h) hergestellt. Schmelzpunkt (Ethylacetat): 214-216 °C.1- [4- (2,4-Dimethoxybenzylamino) -3-nitro-phenyl] -3- (4-phenoxy-phenyl) -urea The compound was prepared as described in Example 4 from 1- (4-fluoro-3 -nitro-phenyl) -3- (4-phenoxyphenyl) -urea and 2,4-dimethoxybenzylamine (60 ° C, 12 h). Melting point (ethyl acetate): 214-216 ° C.
Beispiel 18Example 18
1-[1-(2-Dimethylamino-ethyl)-2,3-dimethyl-1 H-indol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1- [1- (2-dimethylamino-ethyl) -2,3-dimethyl-1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 1-(2-Dimethylamino-ethyl)- 2,3-dimethyl-l H-indol-5-ylamin und 4-Phenoxyanilin hergestellt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 442,57 (C27H3oN4O3); MS (ESI): 443 (M+H+).The compound was prepared as described in Example 1 from 1- (2-dimethylamino-ethyl) -2,3-dimethyl-1H-indol-5-ylamine and 4-phenoxyaniline. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 442.57 (C 27 H 3 oN 4 O 3 ); MS (ESI): 443 (M + H + ).
1 -(2-Dimethylamino-ethyl)-2,3-dimethyl-1 H-indol-5-ylamin Die Verbindung wurde wie im Beispiel 3 durch Hydrierung von [2-(2,3-Dimethyl-5- nitro-indol-1-yl)-ethyl]-dimethyl-amin erhalten. Man erhielt so das Produkt mit dem Molekulargewicht 231 ,34 (C14H2ιN3); MS (ESI): 232 (M+H+).1- (2-Dimethylamino-ethyl) -2,3-dimethyl-1H-indol-5-ylamine The compound was prepared as in Example 3 by hydrogenation of [2- (2,3-dimethyl-5-nitroindole) 1-yl) -ethyl] -dimethyl-amine. This gave the product with the molecular weight 231, 34 (C 14 H 2 ιN 3 ); MS (ESI): 232 (M + H + ).
[2-(2,3-Dimethyl-5-nitro-indol-1-yl)-ethyl]-dimethyl-amin[2- (2,3-Dimethyl-5-nitro-indol-1-yl) -ethyl] -dimethyl-amine
2, 3-Dimethyl-5-nitro-1 H-indol (1 g) in Tetrahydrofuran (10 mL) wurden bei 0 °C mit2,3-Dimethyl-5-nitro-1H-indole (1 g) in tetrahydrofuran (10 mL) was stirred at 0 ° C
Natriumhydrid (50%ig in Öl; 0,8 g) versetzt. Nach 30 Minuten bei Raumtemperatur
wurde Dimethylaminoethylchlorid (Hydrochlorid; 1 ,1 g) zugesetzt und dann für zwei Stunden auf 65 °C erhitzt. Die abgekühlte Reaktionslösung wurde mit Dichlormethan extrahiert. Die organische Phase wurde getrocknet und eingeengt. Das Rohprodukt wurde durch Chormoatographie an Kieselgel (Eluent: Dichlormethan/Methanol 9:1) gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 261 ,33 (C14H19N3O2); MS (ESI): 262 (M+H+).Sodium hydride (50% in oil, 0.8 g). After 30 minutes at room temperature Dimethylaminoethyl chloride (hydrochloride, 1.1 g) was added and then heated to 65 ° C for two hours. The cooled reaction solution was extracted with dichloromethane. The organic phase was dried and concentrated. The crude product was purified by chormoatography on silica gel (eluent: dichloromethane / methanol 9: 1). This gave the product of molecular weight 261, 33 (C 14 H 19 N 3 O 2 ); MS (ESI): 262 (M + H + ).
Beispiel 19Example 19
1 -[1 -(2-Dimethylamino-ethyl)-2-methyl-1 H-indol-5-yl]-3-(4-phenoxy-phenyI)-hamstoff1 - [1- (2-Dimethylamino-ethyl) -2-methyl-1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 1-(2-Dimethylamino-ethyl)-2- methyl-1 H-indol-5-ylamin und 4-Phenoxyanilin hergestellt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 428,54 (C26H28N4O3); MS (ESI): 428 (M+H+).The compound was prepared as described in Example 1 from 1- (2-dimethylamino-ethyl) -2-methyl-1H-indol-5-ylamine and 4-phenoxyaniline. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 428.54 (C 26 H 28 N 4 O 3 ); MS (ESI): 428 (M + H + ).
1 -(2-Dimethylamino-ethyl)-2-methyl-1 H-indol-5-ylamin1- (2-dimethylamino-ethyl) -2-methyl-1H-indol-5-ylamine
Die Verbindung wurde wie im Beispiel 3 beschrieben durch Hydrierung von [2-(2- Methyl-5-nitro-indol-1-yl)-ethyl]-dimethyl-amin erhalten. Man erhielt so das Produkt mit dem Molekulargewicht 217,32 (C13Hι9N3); MS (ESI): 218 (M+H+).The compound was obtained as described in Example 3 by hydrogenation of [2- (2-methyl-5-nitro-indol-1-yl) -ethyl] -dimethyl-amine. This gave the product with the molecular weight 217.32 (C 13 Hι 9 N 3 ); MS (ESI): 218 (M + H + ).
[2-(2-Methyl-5-nitro-indol-1-yl)-ethyl]-dimethyl-amin Die Verbindung wurde wie im Beispiel 18 aus 2-Methyl-5-nitro-1 H-indol und Dimethylaminoethylchlorid (Hydrochlorid) hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 247,30 (C13H17N3O2); MS (ESI): 248 (M+H+). Tabelle 3: Beispiele der Formel I
[2- (2-Methyl-5-nitro-indol-1-yl) -ethyl] -dimethyl-amine The compound was prepared as in Example 18 from 2-methyl-5-nitro-1H-indole and dimethylaminoethyl chloride (hydrochloride). produced. This gave the product with the molecular weight 247.30 (C 13 H 17 N 3 O 2 ); MS (ESI): 248 (M + H + ). Table 3: Examples of the formula I
worin der Teil Xi die Bedeutungwhere the part Xi is the meaning
hat und x2 die Bedeutunghas and x 2 the meaning
hat und x2 in der nachfolgenden Tabelle in der Spalte, die mit "Anilin" bezeichnet ist, wiedergegeben wird.
BeiName Anilin SummenMol[M+H]+ spiel formel gewicht and x 2 is reproduced in the following table in the column labeled "aniline". For Name Anilin SumMol [M + H] + play formula weight
53 1-[1-(2- C24H32N4O3 424,55 42553 1- [1- (2-C24H32N4O3 424.55 425
Dimethylamino- ethyl)-1 H-indol-5-yl]-Dimethylaminoethyl) -1H-indol-5-yl] -
3-(4-isobutoxy-3- methoxy-phenyl)- hamstoff3- (4-isobutoxy-3-methoxy-phenyl) -urea
54 1-[1-(2- C24H32N4O2 408,55 40954 1- [1- (2-C24H32N4O2 408.55 409
Dimethylamino- ethyl)-1 H-indol-5-yl]-Dimethylaminoethyl) -1H-indol-5-yl] -
3-(4-isobutoxy-2- methyl-phenyl)- harnstoff3- (4-isobutoxy-2-methylphenyl) urea
55 1-[1-(2- C25H34N4O2 422,58 42355 1- [1- (2-C25H34N4O2 422.58 423
Dimethylamino- ethyl)-1 H-indol-5-yl]-Dimethylaminoethyl) -1H-indol-5-yl] -
3-(4-isobutoxy-2,5- dimethyl-phenyl)- harnstoff3- (4-isobutoxy-2,5-dimethylphenyl) urea
56 1-(3,5-Dichloro-4- C23H28CI2N4Q 463,41 463 isobutoxy-phenyl)-3- [1 -(2-dimethylamino- ethyl)-1H-indol-5-yl]- hamstoff56 1- (3,5-dichloro-4-C23H28C12N4Q 463.41 463 isobutoxy-phenyl) -3- [1- (2-dimethylamino-ethyl) -1H-indol-5-yl] -urea
57 1-[1-(2- C23H29N5O4 439,52 44057 1- [1- (2-C23H29N5O4 439.52 440
Dimethylamino- ethyl)-1H-indol-5-yl]-Dimethylaminoethyl) -1H-indol-5-yl] -
3-(4-isobutoxy-3- nitro-phenyl)- hamstoff3- (4-isobutoxy-3-nitro-phenyl) -urea
58 1-[1-(2- C24H32N4O2 408,55 40958 1- [1- (2-C24H32N4O2 408.55 409
Dimethylamino- ethyl)-1H-indol-5-yl]-Dimethylaminoethyl) -1H-indol-5-yl] -
3-(4-isobutoxy-3- methyl-phenyl)- harnstoff
3- (4-isobutoxy-3-methylphenyl) urea
Der Molekülionenpeak ([M+H]+) wurde ESI-Massenspektren entnommen.The molecular ion peak ([M + H] + ) was taken from ESI mass spectra.
Die Beispiele 20 - 51 und 71 -109 wurden analog zu Beispiel 1 hergestellt.Examples 20-51 and 71-109 were prepared analogously to Example 1.
Synthese der Beispiele 52 - 70Synthesis of Examples 52-70
1-(2-Dimethylamino-ethyl)-1H-indol-5-ylamin (0,25 mmol) in Dimethylformamid (1 mL) wurde bei 0 °C mit Carbonyldiimidazol (0,25 mmol) versetzt. Nach einer Stunde bei Raumtemperatur wurde die Reaktionslösung wieder auf 0 °C gekühlt und das entsprechende Aminophenol (0,25 mmol) zugesetzt. Nach 15 Stunden bei1- (2-Dimethylamino-ethyl) -1H-indol-5-ylamine (0.25 mmol) in dimethylformamide (1 mL) was added carbonyldiimidazole (0.25 mmol) at 0 ° C. After one hour at room temperature, the reaction solution was recooled to 0 ° C and the corresponding aminophenol (0.25 mmol) added. After 15 hours at
Raumtemperatur wurden Cäsiumcarbonat (0,5 mmol) und Isobutyliodid (0,5 mmol) zugesetzt und für zwei Stunden auf 80 °C erwärmt. Die Reaktionslösungen wurden filtriert und das Filtrat mit Natriumhydrogencarbonat (5%ig) und Natriumchloridlösung (5%ig) gewaschen. Die organische Phase wurde getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem in der Tabelle 3 angegebenen Molekulargewicht und dem angegebenen Molekülionenpeak im Massenspektrum.
Vorstufen der Beispiele 20-51Cesium carbonate (0.5 mmol) and isobutyl iodide (0.5 mmol) were added at room temperature and heated to 80 ° C for two hours. The reaction solutions were filtered and the filtrate was washed with sodium bicarbonate (5%) and sodium chloride solution (5%). The organic phase was dried and concentrated. The crude product was purified by preparative HPLC. This gave the product with the molecular weight indicated in Table 3 and the molecular ion peak in the mass spectrum. Precursors of Examples 20-51
Eine Mischung von 4-Fluor-nitrobenzol (0,35 mmol), Kaliumcarbonat (0,7 mmol), das entsprechende Amin und Dimethylformamid (1 mL) wurde für drei Stunden auf 100 °C erwärmt. Die Reaktionslösung wurde filtriert und mit Natriumchloridlösung (5%ig) gewaschen. Die organische Phase wurde getrocknet und eineengt. Das alsA mixture of 4-fluoro-nitrobenzene (0.35 mmol), potassium carbonate (0.7 mmol), the corresponding amine and dimethylformamide (1 mL) was heated to 100 ° C for three hours. The reaction solution was filtered and washed with sodium chloride solution (5%). The organic phase was dried and concentrated. That as
Rohprodukt erhaltene 4-Nitroanilin wurde in Eisessig (1 mL) gelöst und ZinkstaubCrude product obtained 4-nitroaniline was dissolved in glacial acetic acid (1 mL) and zinc dust
(0,25 g) zugesetzt. Nach drei Stunden Reaktionszeit wurde die Reaktionslösung mit(0.25 g) was added. After three hours of reaction, the reaction solution was washed with
Ethylacetat (10 mL) verdünnt, filtriert und das Filtrat mit Natriumchloridlösung (5%ig) gewaschen. Das Filtrat wurde getrocknet und eingeengt. Das als Rohprodukt erhaltene 4-substituierte Anilin wurde ohne weitere Reinigung weiter umgesetzt.Ethyl acetate (10 mL), filtered and the filtrate washed with sodium chloride solution (5%). The filtrate was dried and concentrated. The crude 4-substituted aniline was further reacted without further purification.
Folgende 4-Nitroaniline wurden hergestellt:The following 4-nitroanilines were prepared:
1-(4-Nitro-phenyl)-azocan1- (4-nitro-phenyl) -azocan
Cyclohexyl-methyl-(4-nitro-phenyl)-aminCyclohexyl-methyl- (4-nitro-phenyl) -amine
1-(4-Nitro-phenyl)-pyrrolidin 2,5-Dimethyl-1-(4-nitro-phenyl)-pyrrolidin1- (4-nitro-phenyl) -pyrrolidine 2,5-dimethyl-1- (4-nitro-phenyl) -pyrrolidine
1-(4-Nitro-phenyl)-1 ,2,3,6-tetrahydro-pyridin1- (4-nitro-phenyl) -1,2,3,6-tetrahydro-pyridine
2,6-Dimethyl-4-(4-nitro-phenyl)-morpholin2,6-dimethyl-4- (4-nitro-phenyl) -morpholine
4-(4-Nitro-phenyl)-thiomorpholin4- (4-nitro-phenyl) -thiomorpholin
2-Methyl-1-(4-nitro-phenyl)-piperidin 2-Ethyl-1 -(4-nitro-phenyl)-piperidin2-Methyl-1- (4-nitro-phenyl) -piperidine 2-ethyl-1- (4-nitro-phenyl) -piperidine
3-Methyl-1-(4-nitro-phenyl)-piperidin3-methyl-1- (4-nitro-phenyl) -piperidine
3,3-Dimethyl-1-(4-nitro-phenyl)-piperidin3,3-dimethyl-1- (4-nitro-phenyl) -piperidine
3,5-Dimethyl-1-(4-nitro-phenyl)-piperidin3,5-dimethyl-1- (4-nitro-phenyl) -piperidine
1-(4-Nitro-phenyl)-4-phenyl-piperidin 4-Methyl-1 -(4-nitro-phenyl)-piperidin1- (4-nitro-phenyl) -4-phenyl-piperidine 4-methyl-1- (4-nitro-phenyl) -piperidine
2-(4-Nitro-phenyl)-1 ,2,3,4-tetrahydro-isochinolin2- (4-nitro-phenyl) -1,2,3,4-tetrahydro-isoquinoline
1 -(4-Nitro-phenyl)-azepan1- (4-nitro-phenyl) -azepane
Benzyl-methyl-(4-nitro-phenyl)-aminBenzyl-methyl- (4-nitro-phenyl) -amine
Methyl-(4-nitro-phenyl)-phenethyl-amin Butyl-methyl-(4-nitro-phenyl)-aminMethyl (4-nitro-phenyl) -phenethyl-amine Butyl-methyl- (4-nitro-phenyl) -amine
Benzyl-butyl-(4-nitro-phenyl)-aminBenzyl-butyl- (4-nitro-phenyl) -amine
Dibutyl-(4-nitro-phenyl)-amin
(4aR,8aS)-2-(4-Nitro-phenyl)-decahydro-isochinolin 2-Methyl-1-(4-nitro-phenyl)-pyrrolidin 5-Ethyl-2-methyl-1-(4-nitro-phenyl)-piperidin Methyl-(4-nitro-phenyl)-pyridin-3-ylmethyl-amin 3-(4-Nitro-phenyl)-3-aza-bicyclo[3.2.2]nonan 2-lsopropyl-1-(4-nitro-phenyl)-pyrrolidin 2-lsobutyl-1-(4-nitro-phenyl)-pyrrolidin 1-(4-Nitro-phenyl)-3-phenyl-pyrrolidin 1-(4-Nitro-phenyl)-3-trifluormethyl-piperidin (4aR,8aR)-2-(4-Nitro-phenyl)-dekahydro-isochinolinDibutyl (4-nitro-phenyl) -amine (4aR, 8aS) -2- (4-nitro-phenyl) -decahydro-isoquinoline 2-Methyl-1- (4-nitro-phenyl) -pyrrolidine 5-ethyl-2-methyl-1- (4-nitro-phenyl ) -piperidine Methyl- (4-nitro-phenyl) -pyridin-3-ylmethyl-amine 3- (4-nitro-phenyl) -3-aza-bicyclo [3.2.2] nonane 2-isopropyl-1- (4- nitro-phenyl) -pyrrolidine 2-isobutyl-1- (4-nitro-phenyl) -pyrrolidine 1- (4-nitro-phenyl) -3-phenyl-pyrrolidine 1- (4-nitro-phenyl) -3-trifluoromethyl- piperidine (4aR, 8aR) -2- (4-nitro-phenyl) decahydro-isoquinoline
(1S,5R)-1 ,3,3-Trimethyl-6-(4-nitro-phenyl)-6-aza-bicyclo[3.2.1]octan(1S, 5R) -1,3,3-trimethyl-6- (4-nitro-phenyl) -6-aza-bicyclo [3.2.1] octane
Alle oben aufgeführten 4-Nitroaniline zeigten den erwarteten Molekülionenpeak imAll the 4-nitroanilines listed above showed the expected molecular ion peak in
ESI-Massenspektrum.ESI mass spectrum.
Folgende 4-substituierte Aniline wurden hergestellt:The following 4-substituted anilines were prepared:
4-Azocan-1 -yl-phenylamin4-azocan-1-yl-phenylamine
N-Cyclohexyl-N-methyl-benzol-1 ,4-diaminN-cyclohexyl-N-methylbenzene-1,4-diamine
4-Pyrrolidin-1 -yl-phenylamin4-pyrrolidin-1-yl-phenylamine
4-(2,5-Dimethyl-pyrrolidin-1-yl)-phenylamin 4-(3,6-Dihydro-2H-pyridin-1-yl)-phenylamin4- (2,5-Dimethyl-pyrrolidin-1-yl) -phenylamine 4- (3,6-dihydro-2H-pyridin-1-yl) -phenylamine
4-(2,6-Dimethyl-morpholin-4-yl)-phenylamin4- (2,6-dimethyl-morpholin-4-yl) -phenylamine
4-Thiomorpholin-4-yl-phenylamin4-thiomorpholin-4-yl-phenylamine
4-(2-Methyl-piperidin-1-yl)-phenylamin4- (2-methyl-piperidin-1-yl) -phenylamine
4-(2-Ethyl-piperidin-1-yl)-phenylamin 4-(3-Methyl-piperidin-1 -yl)-phenylamin4- (2-Ethyl-piperidin-1-yl) -phenylamine 4- (3-methylpiperidin-1-yl) -phenylamine
4-(3,3-Dimethyl-piperidin-1-yl)-phenylamin4- (3,3-dimethyl-piperidin-1-yl) -phenylamine
4-(3,5-Dimethyl-piperidin-1 -yl)-phenylamin4- (3,5-dimethyl-piperidin-1-yl) -phenylamine
4-(4-Phenyl-piperidin-1-yl)-phenylamin4- (4-phenyl-piperidin-1-yl) -phenylamine
4-(4-Methyl-piperidin-1-yl)-phenylamin 4-(3,4-Dihydro-1 H-isochinolin-2-yl)-phenylamin4- (4-Methyl-piperidin-1-yl) -phenylamine 4- (3,4-dihydro-1H-isoquinolin-2-yl) -phenylamine
4-Azepan-1 -yl-phenylamin4-Azepan-1-yl-phenylamine
N-Benzyl-N-methyl-benzol-1 ,4-diamin
N-Methyl-N-phenethyl-benzol-1 ,4-diaminN-benzyl-N-methylbenzene-1,4-diamine N-methyl-N-phenethylbenzene-1,4-diamine
N-Butyl-N-methyl-benzol-1 ,4-diaminN-butyl-N-methylbenzene-1,4-diamine
N-Benzyl-N-butyl-benzol-1 ,4-diaminN-benzyl-N-butylbenzene-1,4-diamine
N,N-Dibutyl-benzol-1 ,4-diamin 5 (4aR,8aS)-4-(Octahydro-isochinolin-2-yl)-phenylaminN, N-dibutylbenzene-1,4-diamine 5 (4aR, 8aS) -4- (octahydroisoquinolin-2-yl) -phenylamine
4-(2-Methyl-pyrrolidin-1-yl)-phenylamin4- (2-methyl-pyrrolidin-1-yl) -phenylamine
4-(5-Ethyl-2-methyl-piperidin-1-yl)-phenylamin4- (5-ethyl-2-methyl-piperidin-1-yl) -phenylamine
N-Methyl-N-pyridin-3-ylmethyl-benzol-1 ,4-diaminN-methyl-N-pyridin-3-ylmethylbenzene-1,4-diamine
4-((1 S,5R)-1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-phenylamin 10 4-(3-Aza-bicyclo[3.2.2]non-3-yl)-phenylamin4 - ((1S, 5R) -1, 3,3-trimethyl-6-azabicyclo [3.2.1] oct-6-yl) -phenylamine 10 4- (3-azabicyclo [3.2.2] non-3-yl) -phenylamine
4-(2-lsopropyl-pyrrolidin-1-yl)-phenylamin4- (2-isopropyl-pyrrolidin-1-yl) -phenylamine
4-(2-lsobutyl-pyrrolidin-1-yl)-phenylamin4- (2-isobutyl-pyrrolidin-1-yl) -phenylamine
4-(3-Phenyl-pyrrolidin-1 -yl)-phenylamin4- (3-phenylpyrrolidin-1-yl) -phenylamine
4-(3-Trifluormethyl-piperidin-1-yl)-phenylamin 15 (4aR,8aR)-4-(Octahydro-isochinolin-2-yl)-phenylamin .4- (3-trifluoromethylpiperidin-1-yl) -phenylamine 15 (4aR, 8aR) -4- (octahydro-isoquinolin-2-yl) -phenylamine.
Alle oben aufgeführten 4-substituierten Aniline zeigten den erwartetenAll the above listed 4-substituted anilines showed the expected
Molekülionenpeak im ESI-Massenspektrum.Molecular ion peak in the ESI mass spectrum.
Beispiel 110 20 [1 -(2-Dimethylamino-ethyl)-1 H-indol-5-yl]-carbaminsäure-4-phenoxy-phenylesterExample 110 20 [1- (2-Dimethylamino-ethyl) -1H-indol-5-yl] -carbamic acid 4-phenoxy-phenyl ester
Die Verbindung wurde analog Beispiel 1 durch Reaktion des durch Carbonyl- diimidazol aktivierten Indolamins mit deprotoniertem 4-Phenoxyphenol hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 415,50 (C25H25N3O3); MS (ESI): 25 416 (M+H+).The compound was prepared analogously to Example 1 by reaction of the carbonyl diimidazole activated indoleamine with deprotonated 4-phenoxyphenol. This gave the product with the molecular weight 415.50 (C 25 H 25 N 3 O 3 ); MS (ESI): 25,416 (M + H + ).
Beispiel 111Example 111
1 -(2-lmidazol-1 -ylmethyl-1 -methyl-1H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff
1 - (2-imidazol-1-ylmethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea
1-(2-Hydroxymethyl-1-methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff (0,2 g) und Triethylamin (0,16 mL) in Dichlormethan (4 mL) wurden bei 0 °C mit Mesylchlorid (47 μL) versetzt. Nach 10 Minuten wurde Imidazol (185 mg) zugesetzt . Nach 12 Stunden wurde die Reaktionslösung mit Natriumchloridlösung gewaschen, getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC gereinigt. Man erhielt so das Produkt mit dem Molekulargewicht 437,51 (C26H23N5O2); MS (ESI): 438 (M+H+).1- (2-Hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxyphenyl) -urea (0.2 g) and triethylamine (0.16 mL) in dichloromethane (4 mL) were added at 0 ° C with mesyl chloride (47 μL). After 10 minutes, imidazole (185 mg) was added. After 12 hours, the reaction solution was washed with sodium chloride solution, dried and concentrated. The crude product was purified by preparative HPLC. This gave the product with the molecular weight 437.51 (C 26 H 23 N 5 O 2 ); MS (ESI): 438 (M + H + ).
1-(2-Hydroxymethyl-1-methyl-1H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -hamstoff
(5-Amino-1-methyl-1H-indol-2-yl)-methanol wurde wie im Beispiel 1 beschrieben mit 4- Phenoxyanilin und Carbonyldiimidazol umgesetzt. Man erhielt so das Produkt mit dem Molekulargewicht 387,44 (C23H2iN3θ3); MS (ESI): 388 (M+H+).(5-Amino-1-methyl-1H-indol-2-yl) -methanol was reacted as described in Example 1 with 4-phenoxyaniline and carbonyldiimidazole. This gave the product with the molecular weight 387.44 (C 23 H 2 iN 3 θ 3 ); MS (ESI): 388 (M + H + ).
(5-Amino-1-methyl-1H-indol-2-yl)-methanol(5-amino-1-methyl-1H-indol-2-yl) -methanol
(1-Methyl-5-nitro-1H-indol-2-yl)-methanol wurde wie im Beispiel 3 beschrieben hydriert. Man erhielt so das Produkt mit dem Molekulargewicht 176,22 (C10H12N2O); MS (ESI): 177 (M+H+).(1-Methyl-5-nitro-1H-indol-2-yl) -methanol was hydrogenated as described in Example 3. This gave the product of molecular weight 176.22 (C 10 H 12 N 2 O); MS (ESI): 177 (M + H + ).
Beispiel 112Example 112
1-[1-Methyl-2-(2-methyl-4,5-dihydro-imidazol-1-ylmethyl)-1H-indol-5-yl]-3-(4-phenoxy- phenyl)-harnstoff1- [1-Methyl-2- (2-methyl-4,5-dihydroimidazol-1-ylmethyl) -1H-indol-5-yl] -3- (4-phenoxyphenyl) urea
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxymethyl-1- methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff und 2-Methyl-4,5-dihydro-
imidazol hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 453,55 (C27H27N5O2); MS (ESI): 454 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea and 2-methyl-4,5- dihydro- imidazole produced. This gave the product with the molecular weight 453.55 (C27H27N5O2); MS (ESI): 454 (M + H + ).
Beispiel 113 5 1 -(2-Cyclohexylaminomethyl-1 -methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoffExample 113 5 1- (2-Cyclohexylaminomethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxymethyl-1- methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff und Cyclohexylamin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 468,60 (C29H32N4θ2); MS (ESI): 10 469 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea and cyclohexylamine. This gave the product with the molecular weight 468.60 (C 29 H 32 N 4 θ 2 ); MS (ESI): 10,469 (M + H + ).
Beispiel 114Example 114
1 -[2-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-1 -methyl-1 H-indol-5-yl]-3-(4-phenoxy- phenyl)-hamstoff1 - [2- (3-Dimethylamino-pyrrolidin-1-ylmethyl) -1-methyl-1H-indol-5-yl] -3- (4-phenoxyphenyl) -urea
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxymethyl-1- methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-harnstoff und 3-Dimethylamino-pyrrolidin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 483,62 (C29H33N5O2); MS (ESI): 484 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea and 3-dimethylaminopyrrolidine. This gave the product with the molecular weight 483.62 (C29H33N5O2); MS (ESI): 484 (M + H + ).
2020
Beispiel 115Example 115
1 -[2-(4-Hydroxy-piperidin-1-ylmethyl)-1 -methyl-1 H-indol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff
1 - [2- (4-Hydroxy-piperidin-1-ylmethyl) -1-methyl-1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxy methyl-1 • methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff und 4-Hydroxy-piperidin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 470,58 (C28H3oN4O3); MS (ESI): 471 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxy-methyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea and 4-hydroxy-piperidine. This gave the product with the molecular weight 470.58 (C 28 H 3 oN 4 O 3 ); MS (ESI): 471 (M + H + ).
Beispiel 116Example 116
1 -[1 -Methyl-2-(4-phenyl-piperidin-1 -ylmethyl)-1 H-indol-5-yl]-3-(4-phenoxy-phenyl)- harnstoff1 - [1-Methyl-2- (4-phenyl-piperidine-1-ylmethyl) -1H-indol-5-yl] -3- (4-phenoxy-phenyl) -urea
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxymethyl-1- methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-harnstoff und 4-Phenylpiperidin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 530,68 (C3 H34N4O2); MS (ESI): 531 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxyphenyl) urea and 4-phenylpiperidine. This gave the product with the molecular weight 530.68 (C 3 H 3 4N 4 O 2 ); MS (ESI): 531 (M + H + ).
Beispiel 117
N-(1-{1-Methyl-5-[3-(4-phenoxy-phenyl)-ureido]-1H-indol-2-ylmethyl}-pyrrolidin-3-yl)-Example 117 N- (1- {1-methyl-5- [3- (4-phenoxy-phenyl) -ureido] -1H-indol-2-ylmethyl} -pyrrolidin-3-yl) -
acetamid
acetamide
Die Verbindung wurde wie im Beispiel 111 beschrieben aus 1-(2-Hydroxymethyl-1- methyl-1 H-indol-5-yl)-3-(4-phenoxy-phenyl)-hamstoff und Pyrrolidin-3-yl-acetamid hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 497,60 (C29H3iN5O3); MS (ESI): 498 (M+H+).The compound was prepared as described in Example III from 1- (2-hydroxymethyl-1-methyl-1H-indol-5-yl) -3- (4-phenoxy-phenyl) -urea and pyrrolidin-3-yl-acetamide , This gave the product with the molecular weight 497.60 (C 29 H 3iN 5 O 3 ); MS (ESI): 498 (M + H + ).
Beispiel 118 1-(4-Phenoxy-phenyl)-3-(2-pyrrolidin-1-ylmethyl-benzofuran-5-yl)-hamstoffExample 118 1- (4-Phenoxy-phenyl) -3- (2-pyrrolidin-1-ylmethyl-benzofuran-5-yl) -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 2-Pyrrolidin-1-ylmethyl- benzofuran-5-ylamin und 4-Phenoxyanilin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 427,51 (C26H25N3O3); MS (ESI): 428 (M+H+).The compound was prepared as described in Example 1 from 2-pyrrolidin-1-ylmethyl-benzofuran-5-ylamine and 4-phenoxyaniline. This gave the product with the molecular weight 427.51 (C 26 H 25 N 3 O 3 ); MS (ESI): 428 (M + H + ).
2-Pyrrolidin-1 -ylmethyl-benzofuran-5-ylamin2-pyrrolidin-1-ylmethyl-benzofuran-5-ylamine
Die Verbindung wurde wie im Beispiel 3 beschrieben durch Hydrierung von 1-(5-Nitro- benzofuran-2-ylmethyl)-pyrrolidin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 216,29 (Cι3H16N2O); MS (ESI): 217 (M+H+).The compound was prepared as described in Example 3 by hydrogenation of 1- (5-nitrobenzofuran-2-ylmethyl) -pyrrolidine. This gave the product with a molecular weight of 216.29 (C 3 H 16 N 2 O); MS (ESI): 217 (M + H + ).
1-(5-Nitro-benzofuran-2-ylmethyl)-pyrrolidin1- (5-nitro-benzofuran-2-ylmethyl) -pyrrolidine
Die Verbindung wurde wie im Beispiel 3 beschrieben aus (5-Nitro-benzofuran-2-yl)- methanol hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 246,27 (C13H14N203); MS (ESI): 247 (M+H+).
(5-Nitro-benzofuran-2-yl)-methanolThe compound was prepared as described in Example 3 from (5-nitro-benzofuran-2-yl) - methanol. This gave the product with the molecular weight 246.27 (C 13 H 14 N 2 0 3 ); MS (ESI): 247 (M + H + ). (5-Nitro-benzofuran-2-yl) -methanol
Die Verbindung wurde wie im Beispiel 3 beschrieben durch Reduktion von 5-Nitro- benzofuran-2-carbonsäuremethylester hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 193,16 (C9H7NO4); MS (ESI): 194 (M+H+).The compound was prepared as described in Example 3 by reduction of methyl 5-nitrobenzofuran-2-carboxylate. This gave the product with the molecular weight 193.16 (C 9 H 7 NO 4 ); MS (ESI): 194 (M + H + ).
Beispiel 119 1-(4-Phenoxy-phenyl)-3-(2-pyrrolidin-1-ylmethyl-benzo[b]thiophen-5-yl)-hamstoffExample 119 1- (4-phenoxyphenyl) -3- (2-pyrrolidin-1-ylmethyl-benzo [b] thiophen-5-yl) -urea
Die Verbindung wurde wie im Beispiel 1 beschrieben aus 2-Pyrrolidin-1-ylmethyl- benzo[b]thiophen-5-ylamin und 4-Phenoxyanilin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 443,57 (C26H25N3O2S); MS (ESI): 444 (M+H+).The compound was prepared as described in Example 1 from 2-pyrrolidin-1-ylmethyl-benzo [b] thiophen-5-ylamine and 4-phenoxyaniline. This gave the product with the molecular weight 443.57 (C 26 H 25 N 3 O 2 S); MS (ESI): 444 (M + H + ).
2-Pyrrolidin-1-ylmethyl-benzo[b]thiophen-5-ylamin2-pyrrolidin-1-ylmethyl-benzo [b] thiophen-5-ylamine
Die Verbindung wurde wie im Beispiel 3 beschrieben durch Hydrierung von 1-(5-Nitro- benzo[b]thiophen-2-ylmethyl)-pyrrolidin hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 232,35 (Cι3Hι6N2S); MS (ESI): 233 (M+H+).The compound was prepared as described in Example 3 by hydrogenating 1- (5-nitrobenzo [b] thiophen-2-ylmethyl) -pyrrolidine. This gave the product with the molecular weight 232.35 (C 3 Hι 6 N 2 S); MS (ESI): 233 (M + H + ).
1-(5-Nitro-benzo[b]thiophen-2-ylmethyl)-pyrrolidin1- (5-nitro-benzo [b] thiophen-2-ylmethyl) -pyrrolidine
Die Verbindung wurde wie im Beispiel 3 beschrieben aus (5-Nitro-benzo[b]thiophen-2- yl)-methanol hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 262,33 (C13Hι4N2O2S); MS (ESI): 263 (M+H+).The compound was prepared as described in Example 3 from (5-nitro-benzo [b] thiophen-2-yl) -methanol. This gave the product with the molecular weight 262.33 (C 13 Hι 4 N 2 O 2 S); MS (ESI): 263 (M + H + ).
(5-Nitro-benzo[b]thiophen-2-yl)-methanol(5-nitro-benzo [b] thiophen-2-yl) -methanol
Die Verbindung wurde wie im Beispiel 3 beschrieben durch Reduktion von 5-Nitro- benzo[b]thiophene-2-carbonsäuremethylester hergestellt. Man erhielt so das Produkt mit dem Molekulargewicht 209,23 (C9H7NO3S); MS (ESI): 210 (M+H+).
Generell wurden alle beschriebenen basischen Verbindungen entweder als freie Base erhalten oder in Form eines Salzes einer der folgenden Säuren: Ameisensäure, Trifluoressigsäure oder Chlorwasserstoff.
The compound was prepared as described in Example 3 by reduction of methyl 5-nitrobenzo [b] thiophene-2-carboxylate. This gave the product with the molecular weight 209.23 (C 9 H 7 NO 3 S); MS (ESI): 210 (M + H + ). In general, all the basic compounds described were obtained either as the free base or in the form of a salt of one of the following acids: formic acid, trifluoroacetic acid or hydrogen chloride.
Claims
1. Verbindungen der Formel I,1. Compounds of the formula I,
worin bedeutenin which mean
A (CrC8)-Alkyl, (C0-C8)-Alkylen-Aryl;A (-C 8) -alkyl, (C 0 -C 8) -alkylene-aryl;
3-12 gliedriger mono- oder bicyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, N02, CF3, OCF3, CN, (C C6)-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH, O-(C C6)-Alkyl, S-(C C6)-Alkyl, oder NHCO(C C6)-Alkyl tragen kann;3-12 membered mono- or bicyclic ring, which may contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, N0 2 , CF 3 , OCF 3 , CN, (CC 6) -alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH, O- (CC 6) -alkyl, S- (CC 6) alkyl, or NHCO ( CC 6 ) alkyl can carry;
X eine Bindung, C(R8)(R9), C(OR10)(R11), O, N(R12), S, SO, SO2, CO;X is a bond, C (R 8) (R 9), C (OR 10) (R 11), O, N (R 12), S, SO, SO 2 , CO;
R8, R9, R10, R11 , R12 unabhängig voneinander H, (CrC6)-Alkyl;R 8, R 9, R 10, R 11, R 12 independently of one another are H, (C 1 -C 6 ) -alkyl;
D N, C(R41);D N, C (R41);
N, C(R42);N, C (R42);
G N, C(R43);G N, C (R43);
N, C(R44); R1, R2, R3, R41, R42, R43, R44 unabhängig voneinanderN, C (R44); R1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C C6)-Alkyl, (C C4)- Alkoxyalkyl, S-(C C6)-Alkyl, (C C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)- Cycloalkyl, O-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkenyl, O-(C3-C8)-H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (CC 6) alkyl, (CC 4) - alkoxyalkyl, S- (CC 6) alkyl, (CC 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 3 -C 8 ) -cycloalkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, O- ( C 3 -C 8 ) -
Cycloalkenyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, -O-(C0-C8)-Alkylen- Aryl, S-Aryl, N(R13)(R14), S02-CH3, COOH, COO-(C C6)-Alkyl, CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21 ), ein 5-7 gliedriger Heterocyclus mit 1-4 Heteroatomen;Cycloalkenyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, -O- (C 0 -C 8 ) -alkylene-aryl, S-aryl, N (R 13) (R 14) , S0 2 -CH 3 , COOH, COO- (CC 6 ) -alkyl, CON (R 15) (R 16), N (R 17) CO (R 18), N (R 19) SO 2 (R 20), CO (R 21), a 5-7 membered heterocycle having 1-4 heteroatoms;
R13, R14 unabhängig voneinander H, (CrC6)-Alkyl,R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl,
oder R13 und R14 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;or R 13 and R 14 together with the nitrogen atom to which they are attached form a 5-6 membered ring, in the case of the 6-membered ring a CH 2 group being replaced by O or S;
R15, R16 unabhängig voneinander H, (Cι-C6)-Alkyl, oder R15 und R16 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, or R 15 and R 16 form, together with the nitrogen atom to which they are bonded, a 5-6 membered ring, where in the case of the 6-membered ring a CH 2 - Group can be replaced by O or S;
R17, R19 unabhängig voneinander H, (CrC6)-Alkyl;R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (CrC6)-Alkyl, Aryl;R18, R20, R21 are independently (C 1 -C 6 ) -alkyl, aryl;
B N(R24), O;B N (R24), O;
R24 H, (C C6)-Alkyl;R24 H, (CC 6) alkyl;
R5 H, (C C6)-Alkyl;R5 H, (CC 6) alkyl;
W N, C(R25); R25 H, (Cι-C6)-Alkyl, Aryl, eine Bindung zu Y;WN, C (R25); R 25 is H, (C 1 -C 6 ) -alkyl, aryl, a bond to Y;
T N, C(R26);T N, C (R26);
R26 H, (CrCβ)-AIkyl, Aryl, (C0-C8)-Alkylen-Aryl, eine Bindung zu Y;R 26 is H, (C 1 -C 6) -alkyl, aryl, (C 0 -C 8 ) -alkylene-aryl, a bond to Y;
U O, S, N(R27), -C(R30)=N-, -N=C(R31 )-;U O, S, N (R27), -C (R30) = N-, -N = C (R31) -;
R27, R30, R31 unabhängig voneinander H, (CrC6)-Alkyl, eine Bindung zu Y;R 27, R 30, R 31 independently of one another are H, (C 1 -C 6 ) -alkyl, a bond to Y;
Y (Cι-C8)-Alkylen, worin ein oder mehrere Kohlenstoffatome durch O, S,Y (C 1 -C 8 ) -alkylene, in which one or more carbon atoms are substituted by O, S,
SO, SO2, C(R32)(R33), CO, C(R34)(OR35) oder N(R36) ersetzt sein können;(OR35), or N (R36) may be replaced SO, SO 2, C (R32) (R33), CO, C (R34);
R32, R33, R34, R35, R36 unabhängig voneinander H, (Cι-C6)-Alkyl, Aryl;R32, R33, R34, R35, R36 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl;
R6, R7 unabhängig voneinander H, (CrC^-Alkyl, (C3-C7)-Cycloalkyl,R6, R7 independently of one another H, (CrC ^ alkyl, (C 3 -C 7) cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 3-8 gliedrigen Ring, worin ein oder mehrere Kohlenstoffatome durch O, N oder S ersetzt sein können und der 3-8 gliedrige Ring weitere Substituenten wie (Cι-C6)-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH, O-(C C6)-Alkyl oder NHCO(C C6)-or R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 3-8 membered ring in which one or more carbon atoms may be replaced by O, N or S and the 3-8 membered ring may have further substituents such as (Cι-C6) alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH, O- (CC 6) alkyl or NHCO (CC 6) -
Alkyl tragen kann;Can carry alkyl;
R37, R38, R39, R40 unabhängig voneinander H, (d-C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (C 1 -C 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze. and their physiologically acceptable salts.
2. Verbindungen der Formel I, gemäß Anspruch 1 , dadurch gekennzeichnet, daß darin bedeuten2. Compounds of formula I, according to claim 1, characterized in that mean
A (C2-C7)-Alkyl, (C0-C3)-Alkylen-Aryl; 4-10 gliedriger mono- oder bicyclischer Ring, der ein oder mehrereA (C 2 -C 7 ) -alkyl, (C 0 -C 3 ) -alkylene-aryl; 4-10 membered mono- or bicyclic ring containing one or more
Heteroatome aus der Gruppe N, O und S enthalten kann und der 4-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO2, CF3,(CrC6)- Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), O-td-Ce^Alkyl, oder NHCO(C1-C6)-Alkyl tragen kann;Heteroatoms from the group N, O and S may contain and the 4-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , (CrC 6 ) - alkyl, aryl, CON (R37) (R38), N (R39) (R40), O-td-Ce ^ alkyl, or NHCO (C 1 -C 6 ) alkyl;
X eine Bindung, C(R8)(R9), O, N(R12), S, S02;X is a bond, C (R8) (R9), O, N (R12), S, S0 2 ;
R8, R9, R12 unabhängig voneinander H, (C C6)-Alkyl;R8, R9, R12 independently of one another are H, (CC 6 ) -alkyl;
D N, C(R41);D N, C (R41);
E N, C(R42);E N, C (R42);
G N, C(R43);G N, C (R43);
L N, C(R44); wobei die Gesamtzahl der durch D, E, G und L definiertenL N, C (R44); where the total number of defined by D, E, G and L.
Stickstoffatome 0, 1 oder 2 beträgt;Nitrogen atom is 0, 1 or 2;
R1 , R2, R3, R41 , R42, R43, R44 unabhängig voneinanderR1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, Br, CF3, NO2, 0-(C C6)-Alkyl, (C C6)-Alkyl, (C3-C8)-Cycloalkyl, 0-(C3-C8)-Cycloalkyl, (C2-C6)-Alkinyl, (C0-C8)-Alkylen-Aryl, -O-(C0-C3)- Alkylen-Aryl, S-Aryl, N(R13)(R14), SO2-CH3, COO-(C C6)-Alkyl, CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21);H, F, Cl, Br, CF 3 , NO 2 , 0- (CC 6 ) -alkyl, (CC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, 0- (C 3 -C 8 ) - Cycloalkyl, (C 2 -C 6 ) -alkynyl, (C 0 -C 8 ) -alkylene-aryl, -O- (C 0 -C 3 ) -alkylene-aryl, S-aryl, N (R 13) (R 14) , SO 2 -CH 3 , COO- (CC 6 ) -alkyl, CON (R 15) (R 16), N (R 17) CO (R 18), N (R 19) SO 2 (R 20), CO (R 21);
R13, R14 unabhängig voneinander H, (C C6)-Alkyl, oder R13 und R14 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch 0 oder S ersetzt sein kann;R 13, R 14 independently of one another are H, (CC 6 ) -alkyl, or R 13 and R 14 together with the nitrogen atom to which they are attached form a 5-6 membered ring, in the case of the 6-membered ring a CH 2 group being replaced by O or S;
R15, R16 unabhängig voneinander H, (CrC6)-Alkyl, oder R15 und R16 bilden zusammen mit dem Stickstoff atom, an das sie gebunden sind, einen 5-6 gliedrigen Ring, wobei im Falle des 6-Rings eine CH2- Gruppe durch O oder S ersetzt sein kann;R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, or R 15 and R 16 together with the nitrogen atom to which they are attached form a 5-6 membered ring, with a CH 2 group in the case of the 6-membered ring can be replaced by O or S;
R17, R19 unabhängig voneinander H, (C C6)-Alkyl;R17, R19 independently of one another are H, (CC 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (CrC6)-Alkyl, Aryl;R18, R20, R21 are independently (C 1 -C 6 ) -alkyl, aryl;
B N(R24), O;B N (R24), O;
R24 H, (CrC6)-Alkyl;R 24 is H, (C 1 -C 6 ) -alkyl;
R5 H, (C C6)-Alkyl;R5 H, (CC 6) alkyl;
W N, C(R25);W N, C (R25);
R25 H, (C C6)-Alkyl, Aryl;R 25 is H, (CC 6 ) -alkyl, aryl;
T C(R26);T C (R26);
R26 H, (C C6)-Alkyl, Aryl, eine Bindung zu Y;R26 H, (CC 6) alkyl, aryl, a bond to Y;
U O, S, N(R27), -N=C(R31)-;U O, S, N (R 27), -N = C (R 31) -;
R27, R31 unabhängig voneinander H, (Cι-C6)-Alkyl, eine Bindung zu Y; Y (C C4)-Alkylen, worin ein Kohlenstoffatom durch SO2, C(R32)(R33), CO oder N(R36) ersetzt sein kann;R 27, R 31 independently of one another are H, (C 1 -C 6 ) -alkyl, a bond to Y; Y (CC 4 ) alkylene, wherein a carbon atom may be replaced by SO 2 , C (R 32) (R 33), CO or N (R 36);
R32, R33, R36 unabhängig voneinander H, (CrC6)-Alkyl, Aryl;R32, R33, R36 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl;
R6, R7 unabhängig voneinander H, (Cι-C6)-Alkyl, (C3-C7)-Cycloalkyl,R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7 gliedrigen Ring, worin ein oder mehrereor R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 4-7 membered ring wherein one or more
Kohlenstoffatome durch O, N oder S ersetzt sein können und der 4-7 gliedrige Ring weitere Substituenten wie (CrCβJ-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH oder NHCO(C C6)-Alkyl tragen kann;Carbon atoms can be replaced by O, N or S and the 4-7 membered ring further substituents such as (CrCβJ-alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH or NHCO (CC 6 ) -Alkyl can carry;
R37, R38, R39, R40 unabhängig voneinander H, (C C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (CC 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
3. Verbindungen der Formel I, gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß darin bedeuten3. Compounds of formula I, according to claim 1 or 2, characterized in that mean
A (C3-C7)-Alkyl, (C0-C2)-Alkylen-Aryl; 5-10 gliedriger mono- oder bicyclischer Ring, der 0, 1 oder 2A (C 3 -C 7 ) -alkyl, (C 0 -C 2 ) -alkylene-aryl; 5-10 membered mono- or bicyclic ring, the 0, 1 or 2
Heteroatome aus der Gruppe N, O und S enthalten kann und der 5-10 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO2, CF3, (C C6)- Alkyl, Aryl, O-(Cι-C6)-Alkyl oder NHCO(C C6)-Alkyl tragen kann;Heteroatoms from the group N, O and S may contain and the 5-10 membered ring further substituents such as F, Cl, Br, NO 2 , CF 3 , (CC 6 ) - alkyl, aryl, O- (C 1 -C 6 ) Alkyl or NHCO (CC 6 ) alkyl;
X eine Bindung, C(R8)(R9), 0, N(R12);X is a bond, C (R8) (R9), O, N (R12);
R8, R9, R12 unabhängig voneinander H, (CrCe)-Alkyl; D N, C(R41);R 8, R 9, R 12 independently of one another are H, (C 1 -C 6) -alkyl; DN, C (R41);
E N, C(R42);E N, C (R42);
G N, C(R43);G N, C (R43);
L N, C(R44); wobei die Gesamtzahl der durch D, E, G und L definierten Stickstoffatome 0 oder 1 beträgt;L N, C (R44); wherein the total number of nitrogen atoms defined by D, E, G and L is 0 or 1;
R1 , R2, R3, R41 , R42, R43, R44 unabhängig voneinanderR1, R2, R3, R41, R42, R43, R44 independently
H, F, Cl, CF3, NO2, O-(C C6)-Alkyl, (C C6)-Alkyl, O-(C3-C8)-Cycloalkyl, (C0-C2)-Alkylen-Aryl, -O-(C0-C3)-Alkylen-Aryl, N(R13)(R14), COO-(C1-C6)~ Alkyl, CON(R15)(R16), N(R17)CO(R18), N(R19)SO2(R20), CO(R21);H, F, Cl, CF 3 , NO 2 , O- (CC 6 ) -alkyl, (CC 6 ) -alkyl, O- (C 3 -C 8 ) -cycloalkyl, (C 0 -C 2 ) -alkylene Aryl, -O- (C 0 -C 3 ) -alkylene-aryl, N (R 13) (R 14), COO- (C 1 -C 6 ) -alkyl, CON (R 15) (R 16), N (R 17) CO (R18), N (R19) SO 2 (R20), CO (R21);
R13, R14 unabhängig voneinander H, (CrC6)-Alkyl,R 13, R 14 independently of one another are H, (C 1 -C 6) -alkyl,
R15, R16 unabhängig voneinander H, (CrCβJ-Alkyl,R15, R16 independently of one another H, (CrCβJ-alkyl,
R17, R19 unabhängig voneinander H, (C-ι-C6)-Alkyl;R 17, R 19 independently of one another are H, (C 1 -C 6 ) -alkyl;
R18, R20, R21 unabhängig voneinander (CrC6)-Alkyl, Aryl;R18, R20, R21 are independently (C 1 -C 6 ) -alkyl, aryl;
B N(R24);B N (R24);
R24 H, (C C6)-Alkyl;R24 H, (CC 6) alkyl;
R5 H, (d-Ce^Alkyl;R5 H, (d-Ce ^ alkyl;
W N, C(R25); R25 H, (C C6)-Alkyl;WN, C (R25); R 25 is H, (CC 6 ) -alkyl;
T C(R26);T C (R26);
R26 H, (C C6)-Alkyl, eine Bindung zu Y;R26 H, (CC 6 ) alkyl, a bond to Y;
U O, S, N(R27);U O, S, N (R27);
R27 H, (C C6)-Alkyl, eine Bindung zu Y;R27 is H, (CC 6 ) alkyl, a bond to Y;
Y (CrC3)-Alkylen, worin ein Kohlenstoffatom durch SO2, C(R32)(R33) oderY (CrC 3 ) -alkylene, wherein a carbon atom by SO 2 , C (R 32) (R 33) or
CO ersetzt sein kann;CO can be replaced;
R32, R33 unabhängig voneinander H, (C-ι-C6)-Alkyl, Aryl;R32, R33 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl;
R6, R7 unabhängig voneinander H, (Cι-C6)-Alkyl, (C3-C7)-Cycloalkyl,R 6, R 7 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl,
oder R6 und Y oder R6 und R7 bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5 oder 6 gliedrigen Ring, worin ein oder mehrereor R6 and Y or R6 and R7 together with the nitrogen atom to which they are attached form a 5 or 6 membered ring wherein one or more
Kohlenstoffatome durch O oder N ersetzt sein können und der 5 oder 6 gliedrige Ring weitere Substituenten wie (C CöJ-Alkyl, Aryl, CON(R37)(R38), N(R39)(R40), OH oder NHCO(Cι-C6)-Alkyl tragen kann;Carbon atoms can be replaced by O or N and the 5 or 6 membered ring further substituents such as (CC ö J-alkyl, aryl, CON (R37) (R38), N (R39) (R40), OH or NHCO (-C-C 6 ) alkyl can carry;
R37, R38, R39, R40 unabhängig voneinander H, (C C6)-Alkyl;R37, R38, R39, R40 independently of one another are H, (CC 6 ) -alkyl;
sowie deren physiologisch verträgliche Salze.and their physiologically acceptable salts.
4. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3. 4. Medicament comprising one or more of the compounds according to one or more of claims 1 to 3.
5. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 und ein oder mehrere anorektische Wirkstoffe.5. A pharmaceutical composition containing one or more of the compounds according to one or more of claims 1 to 3 and one or more anorectic agents.
5 6. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung der Obesitas.5 6. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the prophylaxis or treatment of obesity.
10 7. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung des Typ II Diabetes.10 7. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the prophylaxis or treatment of type II diabetes.
15 8. Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 in8. Compounds according to one or more of claims 1 to 3 in
Kombination mit mindestens einem weiteren anorektischen Wirkstoff zur Anwendung als Medikament zur Prophylaxe oder Behandlung der Obesitas.Combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of obesity.
20 9. Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 in20 9. Compounds according to one or more of claims 1 to 3 in
Kombination mit mindestens einem weiteren anorektischen Wirkstoff zur Anwendung als Medikament zur Prophylaxe oder Behandlung des Typ II Diabetes.Combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of type II diabetes.
25 10. Verfahren zur Herstellung eines Arzneimittels enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß der Wirkstoff mit einem pharmazeutisch geeigneten Träger vermischt wird und diese Mischung in eine für die Verabreichung geeignete Form gebracht wird.25 10. A process for the preparation of a medicament comprising one or more of the compounds according to one or more of claims 1 to 3, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture is brought into a suitable form for administration.
30 30
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PCT/EP2002/008686 WO2003015769A1 (en) | 2001-08-17 | 2002-08-03 | Aminoalkyl-substituted aromatic bicyclic compounds, method for the production thereof and their use as medicaments |
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HR (1) | HRP20040149A2 (en) |
HU (1) | HUP0401329A2 (en) |
IL (1) | IL160424A0 (en) |
MX (1) | MXPA04001307A (en) |
NO (1) | NO20040678L (en) |
PA (1) | PA8553001A1 (en) |
PE (1) | PE20030333A1 (en) |
PL (1) | PL366794A1 (en) |
RU (1) | RU2004107654A (en) |
UY (1) | UY27417A1 (en) |
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AR043477A1 (en) | 2005-08-03 |
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BR0211989A (en) | 2004-09-28 |
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GT200200165A (en) | 2003-05-22 |
CN1555260A (en) | 2004-12-15 |
MXPA04001307A (en) | 2004-05-20 |
US20030212070A1 (en) | 2003-11-13 |
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HRP20040149A2 (en) | 2004-08-31 |
RU2004107654A (en) | 2005-09-10 |
IL160424A0 (en) | 2004-07-25 |
KR20040043197A (en) | 2004-05-22 |
ZA200401221B (en) | 2004-10-27 |
NO20040678L (en) | 2004-05-13 |
UY27417A1 (en) | 2002-11-29 |
PA8553001A1 (en) | 2003-02-28 |
PL366794A1 (en) | 2005-02-07 |
PE20030333A1 (en) | 2003-04-24 |
WO2003015769A1 (en) | 2003-02-27 |
US20040198733A1 (en) | 2004-10-07 |
US20040198731A1 (en) | 2004-10-07 |
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