WO2006029769A1 - Neue 3-methyl-7-butinyl-xanthine, deren herstellung und deren verwendung als arzneimittel - Google Patents
Neue 3-methyl-7-butinyl-xanthine, deren herstellung und deren verwendung als arzneimittel Download PDFInfo
- Publication number
- WO2006029769A1 WO2006029769A1 PCT/EP2005/009712 EP2005009712W WO2006029769A1 WO 2006029769 A1 WO2006029769 A1 WO 2006029769A1 EP 2005009712 W EP2005009712 W EP 2005009712W WO 2006029769 A1 WO2006029769 A1 WO 2006029769A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- group
- amino
- xanthine
- butyn
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 239000003814 drug Substances 0.000 title claims description 7
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 title abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims abstract description 27
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 phenylcarbonylmethyl Chemical group 0.000 claims description 218
- 150000001875 compounds Chemical class 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
- 229940075420 xanthine Drugs 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
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- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
- RDDABSKUGAUGTL-UHFFFAOYSA-N n-benzyl-2-methyl-2-nitropropan-1-amine Chemical compound [O-][N+](=O)C(C)(C)CNCC1=CC=CC=C1 RDDABSKUGAUGTL-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 230000001537 neural effect Effects 0.000 description 1
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- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
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- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
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- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- IUJDLCSUCFLYBT-HXUWFJFHSA-N tert-butyl n-[(2r)-1-[[7-but-2-ynyl-3-methyl-1-[(3-methylisoquinolin-1-yl)methyl]-2,6-dioxopurin-8-yl]-methylamino]propan-2-yl]carbamate Chemical compound C1=CC=C2C(CN3C(=O)N(C)C=4N=C(N(C=4C3=O)CC#CC)N(C)C[C@@H](C)NC(=O)OC(C)(C)C)=NC(C)=CC2=C1 IUJDLCSUCFLYBT-HXUWFJFHSA-N 0.000 description 1
- KXLZWLJKUVAJFJ-LJQANCHMSA-N tert-butyl n-[(2r)-1-[[7-but-2-ynyl-3-methyl-1-[(3-methylisoquinolin-1-yl)methyl]-2,6-dioxopurin-8-yl]amino]propan-2-yl]carbamate Chemical compound C1=CC=C2C(CN3C(=O)N(C)C=4N=C(NC[C@@H](C)NC(=O)OC(C)(C)C)N(C=4C3=O)CC#CC)=NC(C)=CC2=C1 KXLZWLJKUVAJFJ-LJQANCHMSA-N 0.000 description 1
- DASDOLSCWJUMPJ-SFHVURJKSA-N tert-butyl n-[(2s)-1-[[7-but-2-ynyl-1-[(2-cyanophenyl)methyl]-3-methyl-2,6-dioxopurin-8-yl]-methylamino]propan-2-yl]carbamate Chemical compound O=C1C=2N(CC#CC)C(N(C)C[C@H](C)NC(=O)OC(C)(C)C)=NC=2N(C)C(=O)N1CC1=CC=CC=C1C#N DASDOLSCWJUMPJ-SFHVURJKSA-N 0.000 description 1
- HUVANSSZPRYPNG-KRWDZBQOSA-N tert-butyl n-[(2s)-1-[[7-but-2-ynyl-1-[(2-cyanophenyl)methyl]-3-methyl-2,6-dioxopurin-8-yl]amino]propan-2-yl]carbamate Chemical compound O=C1C=2N(CC#CC)C(NC[C@H](C)NC(=O)OC(C)(C)C)=NC=2N(C)C(=O)N1CC1=CC=CC=C1C#N HUVANSSZPRYPNG-KRWDZBQOSA-N 0.000 description 1
- GOVXVKUMGGGIDK-IBGZPJMESA-N tert-butyl n-[(2s)-1-[[7-but-2-ynyl-1-[(4-cyanoisoquinolin-3-yl)methyl]-3-methyl-2,6-dioxopurin-8-yl]-methylamino]propan-2-yl]carbamate Chemical compound C1=CC=CC2=C(C#N)C(CN3C(=O)N(C)C=4N=C(N(C=4C3=O)CC#CC)N(C)C[C@H](C)NC(=O)OC(C)(C)C)=NC=C21 GOVXVKUMGGGIDK-IBGZPJMESA-N 0.000 description 1
- KXLZWLJKUVAJFJ-IBGZPJMESA-N tert-butyl n-[(2s)-1-[[7-but-2-ynyl-3-methyl-1-[(3-methylisoquinolin-1-yl)methyl]-2,6-dioxopurin-8-yl]amino]propan-2-yl]carbamate Chemical compound C1=CC=C2C(CN3C(=O)N(C)C=4N=C(NC[C@H](C)NC(=O)OC(C)(C)C)N(C=4C3=O)CC#CC)=NC(C)=CC2=C1 KXLZWLJKUVAJFJ-IBGZPJMESA-N 0.000 description 1
- DRFGJMYBBHPBTM-SFHVURJKSA-N tert-butyl n-[(2s)-1-[[7-but-2-ynyl-3-methyl-2,6-dioxo-1-(quinoxalin-6-ylmethyl)purin-8-yl]-methylamino]propan-2-yl]carbamate Chemical compound N1=CC=NC2=CC(CN3C(=O)N(C)C=4N=C(N(C=4C3=O)CC#CC)N(C)C[C@H](C)NC(=O)OC(C)(C)C)=CC=C21 DRFGJMYBBHPBTM-SFHVURJKSA-N 0.000 description 1
- OEQRZPWMXXJEKU-LURJTMIESA-N tert-butyl n-[(2s)-1-oxopropan-2-yl]carbamate Chemical compound O=C[C@H](C)NC(=O)OC(C)(C)C OEQRZPWMXXJEKU-LURJTMIESA-N 0.000 description 1
- PPQLSSRBSIWJER-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-1-[(2-cyanophenyl)methyl]-3-methyl-2,6-dioxopurin-8-yl]-methylamino]-2-methylpropan-2-yl]carbamate Chemical compound O=C1C=2N(CC#CC)C(N(C)CC(C)(C)NC(=O)OC(C)(C)C)=NC=2N(C)C(=O)N1CC1=CC=CC=C1C#N PPQLSSRBSIWJER-UHFFFAOYSA-N 0.000 description 1
- NNKMLVFGXYNJPN-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-1-[(3-cyanophenyl)methyl]-3-methyl-2,6-dioxopurin-8-yl]-methylamino]-2-methylpropan-2-yl]carbamate Chemical compound O=C1C=2N(CC#CC)C(N(C)CC(C)(C)NC(=O)OC(C)(C)C)=NC=2N(C)C(=O)N1CC1=CC=CC(C#N)=C1 NNKMLVFGXYNJPN-UHFFFAOYSA-N 0.000 description 1
- KFCOZQLEZZNAEX-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-1-[(4-cyanophenyl)methyl]-3-methyl-2,6-dioxopurin-8-yl]-methylamino]-2-methylpropan-2-yl]carbamate Chemical compound O=C1C=2N(CC#CC)C(N(C)CC(C)(C)NC(=O)OC(C)(C)C)=NC=2N(C)C(=O)N1CC1=CC=C(C#N)C=C1 KFCOZQLEZZNAEX-UHFFFAOYSA-N 0.000 description 1
- DUSDZMYDYVNKLA-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-3-methyl-1-[(3-methylisoquinolin-1-yl)methyl]-2,6-dioxopurin-8-yl]amino]-2-methylpropan-2-yl]carbamate Chemical compound C1=CC=C2C(CN3C(=O)N(C)C=4N=C(NCC(C)(C)NC(=O)OC(C)(C)C)N(C=4C3=O)CC#CC)=NC(C)=CC2=C1 DUSDZMYDYVNKLA-UHFFFAOYSA-N 0.000 description 1
- OUMWEAJCOTXFCZ-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-2,6-dioxopurin-8-yl]-methylamino]-2-methylpropan-2-yl]carbamate Chemical compound C1=CC=CC2=NC(CN3C(=O)N(C)C=4N=C(N(C=4C3=O)CC#CC)N(C)CC(C)(C)NC(=O)OC(C)(C)C)=NC(C)=C21 OUMWEAJCOTXFCZ-UHFFFAOYSA-N 0.000 description 1
- KTSMXFPHIMAAPX-UHFFFAOYSA-N tert-butyl n-[1-[[7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-2,6-dioxopurin-8-yl]amino]-2-methylpropan-2-yl]carbamate Chemical compound C1=CC=CC2=NC(CN3C(=O)N(C)C=4N=C(NCC(C)(C)NC(=O)OC(C)(C)C)N(C=4C3=O)CC#CC)=NC(C)=C21 KTSMXFPHIMAAPX-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to novel substituted xanthines of the general formula
- DPP-IV dipropyl-peptidase-IV
- their preparation their use for the prevention or treatment of diseases or conditions which are associated with increased DPP-IV activity or which can be prevented or alleviated by reducing DPP-IV activity, in particular diabetes Mellitus type I or type II, the medicament containing a compound of the general formula (I) or a physiologically acceptable salt thereof and processes for their preparation.
- R 1 is an arylmethyl or arylethyl group, a heteroarylmethyl or heteroarylethyl group,
- a arylprop-2-enyl or 2-enyl group Heteroarylprop-in which the Propenylkette by 1 to 4 fluorine atoms or a cyano, C- ⁇ - 3 may be substituted alkyloxy-carbonyl or nitro group,
- R 2 is a Ci. 4- alkyl group, which may be straight or branched, and
- X is a -CHbCHa group, which may be replaced by one or two C 1 . 3 -alkyl groups, which may be the same or different, may be substituted,
- aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups which may be mono-, di- or trisubstituted independently of one another by R h , where the substituents may be identical or different and R h is a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, Ci -3 alkoxy carbonyl, aminosulphonyl, methylsulphonyl, acetylamino, methylsulfonylamino , C 1 - 3 - alkyl, cyclopropyl, ethenyl, ethynyl, phenyl, morpholinyl, hydroxy, Ci -3 represents alkyloxy, difluoromethoxy or trifluoromethoxy group, or two R h on two adjacent carbon atoms of the Aromatic compounds together form a C 3-5 al
- heteroaryl groups can be mono- or disubstituted by R h , where the substituents can be identical or different and R h is defined as mentioned above,
- alkyl, alkenyl and alkynyl groups may be straight-chain or branched, their tautomers, enantiomers, diastereomers, their mixtures, their prodrugs and their salts.
- amino and imino groups mentioned in the definition of the abovementioned radicals may be substituted by an in vivo cleavable radical.
- Such groups are described, for example, in WO 98/46576.
- a cleavable by an imino or amino group in vivo radical is for example a hydroxy group, an acyl group such as optionally substituted by fluorine, chlorine, bromine or iodine atoms, by Ci -3 alkyl or C 3 alkoxy mono- or disubstituted phenyl carbonyl, whereby the substituents may be the same or different, a pyridinoyl group or a Ci- 16 alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a Ci_i 6 -alkoxycarbonyl or Ci- 1 6-Alkyicarbonyloxy distr in which hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl
- saturated alkyl and alkoxy moieties containing more than 2 carbon atoms mentioned in the preceding and following definitions also include their branched isomers, for example the isopropyl, tert-butyl, isobutyl, etc. group. one.
- R 1 has the meaning of a 2-cyanobenzyl, 3-cyanobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl , 2-cyano-4-fluorobenzyl, 2-cyano-5-fluorobenzyl, 2-cyano-6-fluorobenzyl, 4-cyano-3-fluorobenzyl, 4-cyano-3-nitrobenzyl, 3,5-dimethoxybenzyl -, 2-cyano-3-methoxybenzyl, 2-cyano-4-methoxybenzyl, 2-cyano-5-methoxybenzyl, 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl -, 5-cyanofuranylmethyl, oxazolylmethyl, isoxazolylmethyl, 5-methoxycarbonylthienylmethyl, pyridin
- R 1 is defined as mentioned above,
- R 2 is a methyl or ethyl group
- X is a -CH 2 CH 2 group, which may optionally be substituted by one or two methyl or ethyl groups, where the substituents may be identical or different
- R 1 represents a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, quinolinonylmethyl, imidazoquinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinazolinonylmethyl, quinoxalinylmethyl, phenanthridinylmethyl , Naphthyridinylmethyl, Benzonaphthiridinylmethyl, Imidazopyridinylmethyl- or Benzotriazolylmethyl distr, each by one or two fluorine, chlorine, bromine or one or two cyano, nitro, amino, Ci- 3 alkyl, Ci_ 3 - Alkyloxy, phenyl and morpholinyl groups, where the substituents are the same or different,
- R 2 is a methyl group
- X is a -CH 2 CH 2 group which may optionally be substituted by one or two methyl groups, their tautomers, enantiomers, diastereomers, their mixtures and their salts.
- R 1 is a benzyl group substituted with one or two cyano groups or a methoxy and a cyano group, or
- R 2 is a methyl group
- X represents a -CH (CH 3 ) -CH 2 -group, a -CH 2 -CH (CH 3 ) -group or a -CH 2 -C (CH 3 ) 2 - group,
- R 1 is a cyano group-substituted benzyl group or
- a pyridinylmethyl isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl or naphthyridinylmethyl group, each of which may be substituted by a cyano or methyl group,
- R 2 is a methyl group and X is a -CH (CH 3 ) -CH 2 - group, a -CH 2 -CH (CH 3 ) group or a -CH 2 -C (CH 3 ⁇ - group, wherein each of the right-standing carbon atom with the terminal amino group linked, mean
- the compounds of the general. Formula I according to known methods, for example by the following methods: a) reaction of a compound of the general formula
- R 1 is defined as mentioned above and
- Z 1 is a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulfinyl, sulfonyl or sulfonyloxy group such as.
- B. represents a chlorine, bromine or iodine atom, a methanesulfonyl, trifluoromethanesulfonyloxy or methanesulfonyloxy group,
- R 2 and X are defined as mentioned above and NPG represents a protected or masked amino functionality, derivatives or salts thereof.
- the amino function can also be masked in the form of a carboxy group or a derivative thereof, which are named after a so-called Curtius, Schmidt or
- Hofmann degradation can be converted to the amino function (see, inter alia, J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4th Edition, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1992 and therein cited literature).
- the reaction is conveniently carried out in a solvent such.
- a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane optionally in the presence of an inorganic or tertiary organic base, for.
- Sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base e.g.
- organic bases can also serve as a solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a catalyst based on palladium or copper Temperatures between -20 and 18O 0 C, but preferably at temperatures between -10 and 120 0 C performed.
- a reaction accelerator such as an alkali metal halide or a catalyst based on palladium or copper
- the reaction can also be carried out without solvent in an excess of piperidine derivative under conventional heating or in microwave oven.
- R 1 , R 2 and X are defined as mentioned above and NPG represents a protected or masked amino functionality.
- Possible protective groups or maskings of the amino function have already been mentioned under a).
- the amino group is protected with a tert-butoxycarbonyl or phthalyl radical.
- the cleavage of the tert-butoxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 0 C.
- an acid such as trifluoroacetic acid or hydrochloric acid
- bromotrimethylsilane or iodotrimethylsilane optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 0 C.
- Phttrelylrestes is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine, ethanolamine or n-butylamine in a Wegs ⁇ medium such as methanol, ethanol, isopropanol, toluene, toluene / water or dioxane at temperatures between 20 and 120 0 C.
- a primary amine such as methylamine, ethylamine, ethanolamine or n-butylamine
- a Harrisons ⁇ medium such as methanol, ethanol, isopropanol, toluene, toluene / water or dioxane at temperatures between 20 and 120 0 C.
- any reactive groups present such as amino, alkylamino or imino groups, may be protected during the reaction by conventional protective groups which are split off again after the reaction.
- protective radicals for an amino, alkylamino or imino group are the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups and the amino group additionally the phthalyl group into consideration.
- the optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for.
- an aqueous solvent for.
- Example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or Kalium ⁇ hydroxide or aprotic, z.
- B. in the presence of iodotrimethylsilane, at temperatures between .0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
- the cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, by hydrogenolysis, eg. B. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of a potu ⁇ re such as hydrochloric acid at temperatures between 0 and 100 c C, but preferably at room temperatures between 20 and 60 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
- a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
- cleavage of a tert-butyl or tert-Butoxycarbonylrestes preferably takes place by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
- an acid such as trifluoroacetic acid or hydrochloric acid
- iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
- Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 0 C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 0 C.
- an acid such as hydrochloric acid
- a solvent such as acetic acid
- sodium hydroxide optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 0 C.
- the cleavage of a phthalyl radical is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, ethanolamine, isopropanol, toluene, toluene / water or dioxane at temperatures between 20 and 12O 0 C.
- a primary amine such as methylamine, ethylamine or n-butylamine
- a solvent such as methanol, ethanol, ethanolamine, isopropanol, toluene, toluene / water or dioxane at temperatures between 20 and 12O 0 C.
- the resulting cis / trans mixtures can be chromatographed into their cis and trans isomers, the compounds of general formula I which are obtained in racemates can be prepared by methods known per se (see Allinger NL and US Pat Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I having at least two asymmetric carbon atoms due to their physicochemical differences according to known methods, for.
- the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or derivatives such.
- esters or amides-forming optically active substance in particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative obtained in this way, for. Due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
- Particularly common, optically active acids are, for. B.
- the D and L forms of tartaric acid or dibenzoyltartaric acid, di-Op-toluoyl-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
- optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
- the compounds of the formula I obtained can be converted into their salts, in particular for the pharmaceutical application, into their physiologically tolerated salts with inorganic or organic acids.
- suitable acids include hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, benzoic, fumaric, succinic, lactic, citric, tartaric and maleic acids.
- novel compounds of the formula I thus obtained can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerated salts.
- suitable bases are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the compounds of the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibiting action on the enzyme DPP-IV.
- the cell extract was analyzed from in buffer (10 mM Tris HCl, 0.15M NaCl, 0.04% aprotinin, 0.5% Nonidet-P40, pH 8.0) solubilized cells by centrifugation at 35,000g for 30 minutes at 4 ° C (to remove cell debris).
- the DPP-IV assay was performed as follows:
- the compounds prepared according to the invention are well tolerated since, for example after oral administration of 10 mg / kg of the compound of Example 2 (4), no changes in the behavior of the animals could be observed in rats.
- the compounds of the general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which are caused by an inhibition of the DPP-IV Activity can be influenced. It is therefore to be expected that the compounds according to the invention for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes mellitus, prediabetes, diminution of glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or Neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance, metabolic syndrome, dyslipidaemias of various genesis, arthritis, atherosclerosis and related diseases, adiposity, allograft transplantation, and calcitonin-induced osteoporosis.
- diseases or conditions such as type 1 and type 2 diabetes mellitus, prediabetes, diminution of glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or Neuropathies), metabolic acidos
- these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells.
- the substances are further suited to improve or restore the functionality of pancreatic cells, in addition to increase the number and size of pancreatic B cells.
- glucagon-like peptides such as GLP-1 and GLP-2 and their linkage with DPP-IV inhibition, it is expected that the compounds of the present invention will be useful, inter alia, to achieve a sedative or anxiolytic effect
- catabolic states after surgery or hormonal stress responses can be favorably influenced or the mortality and morbidity after myocardial infarction can be reduced.
- the compounds of the invention are also diuretics or antihypertensives and suitable for the prevention and treatment of acute renal failure.
- the compounds according to the invention can be used for the treatment of inflammatory diseases of the respiratory tract.
- they are suitable for the prevention and treatment of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as in pancreatitis.
- IBS irritable bowel syndrome
- Crohn's disease Crohn's disease or ulcerative colitis
- pancreatitis pancreatitis
- DPP-IV inhibitors and thus also the compounds according to the invention can be used for the treatment of infertility or for improving fertility in humans or in mammalian organisms, in particular if the infertility is associated with insulin resistance or with the poly ⁇ Cystic ovarian syndrome is.
- these substances are suitable for influencing sperm motility and thus can be used as contraceptives for use in men.
- the substances are suitable for influencing deficiency states of growth hormone associated with shortage growth, as well as being useful for all indications in which growth hormone can be used.
- the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow 's disease, etc.
- they can be used in viral diseases as well, for example in HIV infections, for the stimulation of blood formation, in benign prostatic hyperplasia, in gingivitis, and for the treatment of neuronal defects and neurodegenerative diseases such as, for example, Alzheimer's disease.
- Compounds described are also to be used for the therapy of tumors, in particular for the modification of tumor invasion as well as metastatization.
- T-cell lymphomas examples are the use in T-cell lymphomas, acute lymphoblastic leukemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas.
- Other indications include stroke, ischemia of various origins, Parkinson's disease and migraine.
- other indications include follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephaly lomyelitis, glomerulonephritides, lipodystrophies, as well as psychosomatic, depressive and neuropsychiatric disorders of various genesis.
- the compounds according to the invention can also be used in combination with other active substances.
- Therapeutics suitable for such combination include e.g. Antidiabetics such as metformin, sulfonylureas (eg glibenclamide, tolbutamide, glimepiride), nateglinides, repaglinide, thiazolidinediones (eg rosiglitazone, pioglitazone), PPAR-gamma agonists (eg Gl 262570) and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), PPAR-gamma / alpha / delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, 11ß-HSD inhibitors, FGF19 agonists or mimetics, alpha-glucosidase inhibitors (eg, acarbose, voglibose), other
- SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances that affect deregulated glucose production in the liver, e.g. Inhibitors of Glucqse 6-phosphatase or fructose 1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA reductase inhibitors (eg simvastatin, atorvastatin) , Fibrates (eg Bezafibrat, Feno ⁇ fibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol resorption inhibitors such as eze
- Antagonists or ⁇ 3 agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor possible.
- a combination with drugs for influencing the high blood pressure such as, for example, all antagonists or ACE inhibitors, diuretics, ⁇ -blockers, Ca antagonists and others or combinations thereof, is suitable.
- the dosage required to achieve a corresponding effect is expediently when intravenously administered 1 to 100 mg, preferably 1 to 30 mg, and when administered orally 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times daily.
- the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, e.g.
- lactose cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, into common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
- Example III 1 -r (3-Methyl-isoquinolin-1-yl) methyl-3-methyl-7- (2-butyne-1-vn-8-r2- (tert-butoxycarbonylamino) -2-methyl- propylamino-xanthine
- Example IX tert -Butyl r2- (benzylmethyl-aminoV1, 1-dimethyl-ethyll-carbamate
- a mixture of 34.41 g of N 1 -benzyl-N 1 , 2-dimethyl-propane-1, 2-diamine in 280 ml of ethanol, 25.20 ml of triethylamine and 39.20 g of pyrocarbonic acid di-tert-butyl ester is stirred for two hours at room temperature.
- the solvent is then distilled off and the residue is purified by chromatography on silica gel with cyclohexane / ethyl acetate (100: 0 to 66:34) as eluent.
- 1 drag core contains:
- the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone,
- Hydroxypropylmethylcellulose and half of the stated amount of magnesium Stearate mixed On a tableting machine compacts are produced with a diameter of about 13 mm Jerusalem ⁇ , these are ground on a suitable machine through a sieve with 1, 5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
- the dragee cores produced in this way are coated with a film which consists essentially of hydroxypropylmethylcellulose.
- the finished film dragees are shined with beeswax. Dragee weight: 245 mg.
- Composition 1 tablet contains: Active substance 100.0 mg
- Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening the wet mass (2.0 mm mesh size) and dried in a rack drier at 50 0 C er ⁇ is sieved neut (1, 5 mm mesh size) and mixed into the lubricant. The ready to use mixture is made into tablets. Tablet weight: 220 mg Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.
- the active substance mixed with milk sugar, corn starch and silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve of 1.5 mm mesh size.
- the dried at 45 0 C granules are rubbed again through the same sieve and mixed with the specified amount of magnesium stearate. From the mixture tablets are pressed.
- Hard gelatin capsules with 150 mq active ingredient 1 capsule contains:
- the active ingredient is mixed with the excipients, through a sieve of
- the final mixture is filled into size 1 hard gelatin capsules.
- Capsule shell hard gelatin capsule size 1.
- 1 suppository contains:
- Active ingredient 150.0 mg of polyethylene glycol 1500 550.0 mg
- the active ingredient After melting the suppository mass, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
- 100 ml suspension contain: active ingredient 1, 00 g
- Carboxymethylcellulose Na salt 0.10 g of methyl p-hydroxybenzoate 0.05 g of propyl p-hydroxybenzoate 0.01 g
- Dest. Water is heated to 70 0 C.
- p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring. 5 ml of suspension contain 50 mg of active ingredient.
- composition active ingredient 10.0 mg
- Active ingredient 50 0 mg
- the active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 10 ml ampoules.
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Abstract
Description
Claims
Priority Applications (3)
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CA002576294A CA2576294A1 (en) | 2004-09-14 | 2005-09-09 | Novel 3-methyl-7-butinyl-xanthines, production thereof, and use thereof as medicaments |
EP05781895A EP1797093B1 (de) | 2004-09-14 | 2005-09-09 | Neue 3-methyl-7-butinyl-xanthine, deren herstellung und deren verwendung als arzneimittel |
JP2007531650A JP2008513390A (ja) | 2004-09-14 | 2005-09-09 | 新規3−メチル−7−ブチニル−キサンチン、その製造方法及び医薬組成物としての使用 |
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DE102004044221A DE102004044221A1 (de) | 2004-09-14 | 2004-09-14 | Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004044221.5 | 2004-09-14 |
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US (1) | US7495002B2 (de) |
EP (1) | EP1797093B1 (de) |
JP (1) | JP2008513390A (de) |
CA (1) | CA2576294A1 (de) |
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WO2014045266A1 (en) | 2012-09-24 | 2014-03-27 | Ulf Eriksson | Treatment of type 2 diabetes and related conditions |
EP4364796A2 (de) | 2013-03-15 | 2024-05-08 | Boehringer Ingelheim International GmbH | Verwendung von linagliptin in der kardio- und renoprotektiven antidiabetischen therapie |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
WO2018104263A1 (en) | 2016-12-06 | 2018-06-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
WO2024091863A1 (en) | 2022-10-25 | 2024-05-02 | Starrock Pharma Llc | Combinatorial, and rotational combinatorial therapies for obesity and other diseases |
Also Published As
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JP2008513390A (ja) | 2008-05-01 |
CA2576294A1 (en) | 2006-03-23 |
EP1797093A1 (de) | 2007-06-20 |
DE102004044221A1 (de) | 2006-03-16 |
US7495002B2 (en) | 2009-02-24 |
US20060079541A1 (en) | 2006-04-13 |
EP1797093B1 (de) | 2012-05-30 |
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