ZA200604281B - 8-[3-Amino-Piperidin-1-YL] -Xanthine, the production thereof and the use in the form of a DPP inhibitor - Google Patents
8-[3-Amino-Piperidin-1-YL] -Xanthine, the production thereof and the use in the form of a DPP inhibitor Download PDFInfo
- Publication number
- ZA200604281B ZA200604281B ZA200604281A ZA200604281A ZA200604281B ZA 200604281 B ZA200604281 B ZA 200604281B ZA 200604281 A ZA200604281 A ZA 200604281A ZA 200604281 A ZA200604281 A ZA 200604281A ZA 200604281 B ZA200604281 B ZA 200604281B
- Authority
- ZA
- South Africa
- Prior art keywords
- methyl
- cyano
- benzyl
- group
- pyridin
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- WNHHLYZOSOUUQW-UHFFFAOYSA-N 8-(3-aminopiperidin-1-yl)-3,7-dihydropurine-2,6-dione Chemical compound C1C(N)CCCN1C(N1)=NC2=C1C(=O)NC(=O)N2 WNHHLYZOSOUUQW-UHFFFAOYSA-N 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 title description 2
- -1 2,6-dicyanobenzyl Chemical group 0.000 claims description 176
- 150000001875 compounds Chemical class 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 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 description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 claims description 3
- 125000006508 2,6-difluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C(F)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 2
- 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006500 3-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC(F)(F)F)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 2
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 2
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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 claims description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 2
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Description
@® 86193pct 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP-IV inhibitor
The present invention relates to new substituted xanthines of general formula 0 =
RN N
A PN (1), 0“ >N~ N
NH, the tautomers, the enantiomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for preventing or treating illnesses or conditions connected with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV activity, particularly type | or type Il diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (1) or a physiologically acceptable sait thereof and processes for the preparation thereof.
Xanthine derivatives with an inhibiting effect on DPP-1V are already known from WO 02/068420, WO 02/02560, WO 03/004496, WO 03/024965, WO 04/018468, WO 04/048379, JP 2003300977 and EP 1 338 595.
In the above formula
R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro- benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
® ° a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group,
a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyi-4- cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4- methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5- fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro- benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or
2-cyano-4-bromobenzyl group, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy- benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy- benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group, a (benzo[1,3]dioxol-5-yl)methyi group, a [(4-cyano-benzo[1,3]dioxol-5-yl)methyl group,
a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl, 2-(3-cyclopropylmethoxy-phenyl)-2-oxo- ethyl or 2-(3-cyclobutyloxy-phenyli)}-2-oxo-ethyl group, a 2-ox0-2-[2-(pyndin-3-yl}-phenyl]-ethyl or 2-ox0-2-[2-(pyridin-4-yl}-phenyl]-ethyl group, a (3-cyano-naphthalen-1-yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4- dimethoxy-naphthalen-1-yl)methyl group, a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan- 2-yl)methyl, (5-cyano-furan-2-yl)methyi or (5-methoxycarbonyli-furan-2-yl)methyl group,
® ’ a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group,
a(3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyi, (5-cyano-pyridin-2- yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano- pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5- cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyt or (5-cyano-6-methoxy- pyridin-2-yl)methyl group,
a (6-phenyl-pyridin-2-yl)methyl or a ([2,2"bipyridinyl-6-yl)methyl group,
a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2- yl)methyl group,
a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methy! group,
a [(1-methyl-1H-benzotriazol-5-yl)methyl] group,
a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl, (2-methyl-quinolin-4- yl)methyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-4-methyi-quinolin-2-yl)methyl, (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl, (8-cyano-quinolin-2- yl)methyl, (6-amino-quinolin-2-yl)methyl, (8-amino-quinolin-2-yl)methyl, (4-methoxy- quinolin-2-yl)methyl, (6-methoxy-quinolin-2-yl)methyl, (6,7-dimethoxy-quinolin-2-
yl)methyl or (8-cyano-quinolin-7-yl)methyl group,
a (1-cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-1-yl)methyl- (4-cyano- isoquinolin-3-yl)methyl or [(4-(pyridin-2-yl)-isoquinolin-1-yljmethyl group,
a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl, (2-methyl-quinazolin-4-yl)methyl, (4,5-dimethyl-quinazolin-2-yl)methyl, (4-ethyl-quinazolin-2-yl)methyl, (4-cyclopropyil- quinazolin-2-yl)methyl, (2-phenyl-quinazolin-4-yl)methyl, (4-cyano-quinazolin-2-
* yl)methyl, (4-phenylamino-quinazolin-2-yl)methyl or (4-benzylamino-quinazolin-2- yl)methyt group, a (quinoxalin-5-yl)methyl- (quinoxalin-6-yl)methyl or (2,3-dimethyl-quinoxalin-6- yl)methyl group, or a ([1,5]naphthyridin-3-yl)methyl group, the tautomers, enantiomers, diastereomers, the mixtures and the salts thereof.
Preferred are compounds of general formula 0 ~~
R. N
N
TY )— (la), 0” °N~ N
NH, wherein R is as hereinbefore defined, as well as their tautomers and salts.
Also preferred are compounds of general formula o ~~
R. N
N
TY )—N > (Ib), (9) N N 7,
NH, wherein Ris as hereinbefore defined, as well as their tautomers and salts.
According to the invention the compounds of general formula | are obtained by methods known per se, for example by the following methods:
C 5 a) reacting a compound of general! formula 0 =
SOs
A | )—= an, 0 N N wherein
R is as hereinbefore defined and
Z' denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy group, with 3-aminopiperidine, the enantiomers or the salts thereof.
The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, ethyleneglycol monomethylether, ethyleneglycol diethylether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Hiinig base), while these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180°C, but preferably at temperatures between -10 and 120°C. The reaction may, however, also be carried out without solvent or in an excess of the 3-aminopiperidine. b) deprotecting a compound of general formula
® lo} =
R. N
N
TY DN (i, 0” N~ °N 0
N—4 © wherein R is as hereinbefore defined.
The tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with bromotrimethyisilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80°C.
In the reactions described hereinbefore, any reactive groups present such as amino, alkytamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for an amino, alkylamino or imino group may be a formyl, acetyl, triflucroacety, ethoxycarbonyi, tert-butoxycarbonyl, benzyloxycarbony, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such ag trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alka metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethyisilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
C 7
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine, ethanolamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.
Moreover, the compounds of general formula | obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
C 8
Thus, for example, the cis/trans mixtures obtained may be separated by chromatography into their cis and trans isomers, the compounds of general formula obtained which occur as racemates may be separated by methods known per se (cf.
Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical enantiomers and compounds of general formula | with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be, for example, (+) or (-}-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula | obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
C 9
The compounds of general formulae 11 and Ill used as starting compounds are either known from the literature or may be prepared by methods known from the literature (see Examples | to XXV).
As already mentioned hereinbefore, the compounds of general formula | according to the invention and the physiologically acceptable salts thereof have valuable pharma- cological properties, particularly an inhibiting effect on the enzyme DPP-IV.
The biological properties of the new compounds were investigated as follows:
The ability of the substances and their corresponding salts to inhibit the DPP-IV activity can be demonstrated in an experiment in which an extract of the human colon carcinoma cell line Caco-2 is used as the DPP IV source. The differentiation of the cells in order to induce the DPP-IV expression was carried out in accordance with the description by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2" , which appeared in Proc. Natl. Acad. Sci. Vol. 90, pp. 5757-5761 (1993). The cell extract was obtained from cells solubilised in a buffer (10mM Tris
HCI, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4°C (to remove cell debris).
The DPP-IV assay was carried out as follows: 50 pi of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 uM, were placed in black microtitre plates. 20 pl of assay buffer (final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCl, 1 % DMSO) was pipetted in. The reaction was started by the addition of 30 p! of solubilised Caco-2 protein (final concentration 0.14 ug of protein per well). The test substances under investigation were typically added prediluted to 20 pl, while the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient temperature, the incubation period was 60 minutes. Then the fluorescence was measured in a Victor 1420 Multilabel Counter, with the excitation wavelength at 405 nm and the emission wavelength at 535 nm. Dummy values (corresponding to 0 %
C 10 activity) were obtained in mixtures with no Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100 % activity) were obtained in mixtures without any added substance. The potency of the test substances in question, expressed as ICs values, were calculated from dosage/activity curves consisting of 11 measured points in each case. The following results were obtained:
Compound DPP V inhibition 1 6 1(3) 6 1(4) 9 1(6) 2 1(7) 5 1(12) 2 1(21) 2 1(26) 2 1(30) 2 1(31) 3 1(38) 1 1(39) 2
The compounds prepared according to the invention are well tolerated as no toxic side effects could be detected in rats after the oral administration of 10 mg/kg of the compound of Example 1 (30), for example.
In view of their ability to inhibit DPP-IV activity, the compounds of general formula according to the invention and the corresponding pharmaceutically acceptable salts thereof are suitable for influencing any conditions or diseases which can be affected by the inhibition of the DPP-IV activity. It is therefore to be expected that the compounds according to the invention will be suitable for the prevention or treatment of diseases or conditions such as type | and type li diabetes mellitus, pre-diabetes, reduced glucose tolerance or changes in the fasting blood sugar, diabetic
Claims (8)
1. Compounds of general formula 0 = Ran N J Wa (n, 0“ >N~ N NH, wherein R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro- benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group, a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4- cyano-benzyl, 3-nitro-4-cyano-benzyl|, 2-cyano-3-methoxy-benzyl, 2-cyano-4- methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5- fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro- benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy- benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy- benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzy! or 3,4-dimethoxy-6-fluoro-benzyl group,
® 2 a (benzo[1,3]dioxol-5-yl)methyl group, a [(4-cyano-benzo[1,3]dioxol-5-yl)methyl group,
a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl, 2-(3-cyclopropylmethoxy-phenyl)-2-oxo- ethyl or 2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl group, a 2-oxo0-2-[2-(pyridin-3-yl}-phenyl]-ethyl or 2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group,
a (3-cyano-naphthalen-1-yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4- dimethoxy-naphthalen-1-yl)methyl group,
a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan- 2-yl)methyl, (5-cyano-furan-2-yl)methyl or (5-methoxycarbonyl-furan-2-yl)methyl group,
a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group,
a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2- yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano- pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5- cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or (5-cyano-6-methoxy- pyridin-2-yl)methyl group, a (6-phenyl-pyridin-2-yl)methyl or a ([2,2bipyridinyl-6-yl)methyl group, a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyi-pyrimidin-2- yl)methyl group,
® : a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, a [(1-methyl-1H-benzotriazol-5-yl)methyl] group, a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl, (2-methyl-quinolin-4- yl)methyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-4-methyl-quinolin-2-yl)methyl, (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl, (8-cyano-quinolin-2- yh)methyl, (6-amino-quinolin-2-yl)methyl, (8-amino-quinolin-2-yl)methyl, (4-methoxy- quinolin-2-yl)methyl, (6-methoxy-quinolin-2-yl)methyl, (6,7-dimethoxy-quinolin-2- yl)methyl or (8-cyano-quinolin-7-yl)methyl group, a (1-cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-1-yl)methyl- (4-cyano- isoquinolin-3-yl)methyl or [(4-(pyridin-2-yl)-isoquinolin-1 -yllmethyl group, 16 a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl, (2-methyl-quinazolin-4-yl)methyl, (4,5-dimethyl-quinazolin-2-yl)methyl, (4-ethyl-quinazolin-2-yl)methyl, (4-cyclopropyl- quinazolin-2-yl)methyl, (2-phenyl-quinazolin-4-yl)methyl, (4-cyano-quinazolin-2- yl)methyl, (4-phenylamino-quinazolin-2-yl)methy! or (4-benzylamino-quinazolin-2- yl)methyl group, a (quinoxalin-5-yl)methyl- (quinoxalin-6-yl)methyl or (2,3-dimethyl-quinoxalin-6- yl)methyl group, or a ([1,5]naphthyridin-3-yl)methyl group, the tautomers, enantiomers, diastereomers, the mixtures and the salts thereof.
2. A compound of general formula
@® 74 0 = Ran N PY PN (la), i "A NH, wherein R is defined as in claim 1, and the tautomers and salts thereof.
3. A compound of general formula jo = Ro N N TY >) m, 0~ °N~ N NH, wherein Ris defined as in claim 1, and the tautomers and salts thereof.
4. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 3 with inorganic or organic acids.
5. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 3 or a physiologically acceptable salt according to claim 4, optionally together with one or more inert carriers and/or diluents.
6. Use of a compound according to at least one of claims 1 to 4 for preparing a pharmaceutical composition which is suitable for treating type | and Il diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis.
® .
7. Process for preparing a pharmaceutical composition according to claim 5, characterised in that a compound according to at least one of claims 1 to 4 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
8. Process for preparing the compounds of general formula | according to claims 1 to 4, characterised in that a) a compound of general formula 0 = R<N N IL Xp—= w 0“ °N" N wherein R is defined as in claim 1 and Z" denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group, is reacted with 3-aminopiperidine, the enantiomers or the salts thereof, or b) a compound of general formula 0 = Ry N N TY DN (my, 0~ °N~ N [0] N—4 © wherein R is defined as in claim 1, is deprotected,
and/or any protecting groups used during the reaction are then cleaved and/or the compounds of general formula | thus obtained are resolved into their enantiomers and/or diastereomers and/or the compounds of formula | thus obtained are converted into their salts, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004008112A DE102004008112A1 (en) | 2004-02-18 | 2004-02-18 | New 8-aminopiperidinyl-xanthine derivatives, useful for treating e.g. diabetes, arthritis and osteoporosis, are inhibitors of dipeptidylpeptidase-IV |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200604281B true ZA200604281B (en) | 2007-10-31 |
Family
ID=34813493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200604281A ZA200604281B (en) | 2004-02-18 | 2006-05-26 | 8-[3-Amino-Piperidin-1-YL] -Xanthine, the production thereof and the use in the form of a DPP inhibitor |
Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN1980930B (en) |
| AR (1) | AR115411A2 (en) |
| DE (1) | DE102004008112A1 (en) |
| UA (1) | UA87835C2 (en) |
| ZA (1) | ZA200604281B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20090938A1 (en) * | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL |
| DE102008010661A1 (en) * | 2008-02-22 | 2009-09-03 | Dr. Felix Jäger und Dr. Stefan Drinkuth Laborgemeinschaft OHG | Preparing pyridin-2-boronic acid compounds, useful e.g. to treat multiple myeloma, comprises preparing a pyridin-2-borate compound, purifying the pyridin-2-borate compound; and hydrolyzing the purified pyridin-2-borate compound |
| CN102311448B (en) * | 2010-07-07 | 2014-02-19 | 中国科学院广州生物医药与健康研究院 | Thieno-pyrimidone DPP-IV (dipeptidyl peptidase) inhibitor |
| EP2731947B1 (en) * | 2011-07-15 | 2019-01-16 | Boehringer Ingelheim International GmbH | Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes |
| CN103450201B (en) * | 2012-05-30 | 2017-04-12 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine |
| CN103709163B (en) * | 2012-09-29 | 2016-12-21 | 齐鲁制药有限公司 | Xanthine derivative, Preparation Method And The Use |
| CN103319483B (en) * | 2012-10-19 | 2016-08-03 | 药源药物化学（上海）有限公司 | A kind of preparation method of important intermediate of linagliptin |
| CN106008507B (en) * | 2013-01-23 | 2017-11-28 | 成都苑东生物制药股份有限公司 | Xanthine derivative |
| CN106188058B (en) * | 2015-05-29 | 2020-11-06 | 江苏天士力帝益药业有限公司 | Xanthine derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100883277B1 (en) * | 2001-02-24 | 2009-02-12 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | Pharmaceutical composition comprising xanthine derivative and process for the preparation thereof |
-
2004
- 2004-02-18 DE DE102004008112A patent/DE102004008112A1/en not_active Withdrawn
-
2005
- 2005-02-12 CN CN2005800054231A patent/CN1980930B/en active Active
- 2005-02-12 UA UAA200609881A patent/UA87835C2/en unknown
-
2006
- 2006-05-26 ZA ZA200604281A patent/ZA200604281B/en unknown
-
2019
- 2019-05-22 AR ARP190101358A patent/AR115411A2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| UA87835C2 (en) | 2009-08-25 |
| DE102004008112A1 (en) | 2005-09-01 |
| CN1980930B (en) | 2012-11-21 |
| CN1980930A (en) | 2007-06-13 |
| AR115411A2 (en) | 2021-01-13 |
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