ZA200302914B - Novel anticholinergic agents that can be used as medicaments and method for the production thereof. - Google Patents
Novel anticholinergic agents that can be used as medicaments and method for the production thereof. Download PDFInfo
- Publication number
- ZA200302914B ZA200302914B ZA200302914A ZA200302914A ZA200302914B ZA 200302914 B ZA200302914 B ZA 200302914B ZA 200302914 A ZA200302914 A ZA 200302914A ZA 200302914 A ZA200302914 A ZA 200302914A ZA 200302914 B ZA200302914 B ZA 200302914B
- Authority
- ZA
- South Africa
- Prior art keywords
- denotes
- methyl
- fluorine
- general formula
- ethyl
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 15
- 239000000812 cholinergic antagonist Substances 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 8
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 30
- 239000011737 fluorine Chemical group 0.000 claims description 30
- 229910052731 fluorine Chemical group 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- -1 methyloxy, ethyloxy Chemical group 0.000 claims description 17
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- CTCCHKSGCBWINA-UHFFFAOYSA-N 2-methoxyethoxy hypofluorite Chemical compound COCCOOF CTCCHKSGCBWINA-UHFFFAOYSA-N 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 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 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 5
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 4
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 208000007101 Muscle Cramp Diseases 0.000 claims 2
- 208000005392 Spasm Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 101000800807 Homo sapiens Tumor necrosis factor alpha-induced protein 8 Proteins 0.000 claims 1
- 208000019255 Menstrual disease Diseases 0.000 claims 1
- 206010040741 Sinus bradycardia Diseases 0.000 claims 1
- 102100033649 Tumor necrosis factor alpha-induced protein 8 Human genes 0.000 claims 1
- 208000026723 Urinary tract disease Diseases 0.000 claims 1
- 239000000808 adrenergic beta-agonist Substances 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- 239000000043 antiallergic agent Substances 0.000 claims 1
- 230000003454 betamimetic effect Effects 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 claims 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000033764 rhythmic process Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 208000014001 urinary system disease Diseases 0.000 claims 1
- 210000001635 urinary tract Anatomy 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 11
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical class C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical group O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 4
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 3
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 3
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000026030 halogenation Effects 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Description
fo 02/32899 PCT/EP01/11226 74403pct.207
Novel anticholinergic agents that can be used as medicaments and method for the production thereof
The present invention relates to new anticholinergics of general formula 1 2 + R’
R~N’ X ) \| wH
A Oo 0 bye 7
R
6
R R3 1 wherein A. X - and the groups R1, R2, R3, R4, RS, R6 and R7 may have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments.
Anticholinergics may be used to therapeutic effect in a wide range of illnesses.
Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For treating these complaints, WO 92/16528 proposes anticholinergics which have a scopine, tropenol or tropine basic structure.
The underlying objective of WO 92/16528 is the preparation of anticholinergically effective compounds which are characterised by their long-lasting activity. To achieve this aim WQ 92/16528 discloses, inter alia, benzilic acid esters of scopine, tropenol or tropine.
For treating chronic diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals.
Moreover, giving an active substance at longer time intervals contributes to the wellbeing of the patient to a high degree. lt is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the
2 f ® 8200372914 patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.
In order to be used as a medicament taken once a day, the active substance to be given must meet particular requirements. First of all, the onset of the desired activity should take place relatively quickly after administration of the drug and ideally should have as constant an effect as possible over a subsequent fairly long period of time.
On the other hand, the duration of activity of the drug should not substantially exceed a period of about one day. Ideally, an active substance has an activity profile such that the preparation of a drug for administration once a day, which contains the active substance in therapeutically beneficial doses, can be deliberately controlled.
It has been found that the benzilic acid esters of scopine, tropenol and tropine disclosed in WO 92/16528 do not meet these stringent requirements. Because of their extremely long period of activity, which significantly exceeds the above-mentioned period of about one day, they cannot be used therapeutically for administration in a single dose per day.
The aim of the present invention is therefore to provide new anticholinergics which, by virtue of their activity profile, make it possible to prepare a drug for administration once a day. A further objective of the invention is to prepare compounds characterised by a relative rapid onset of activity. The invention further sets out to provide compounds which, after a rapid onset of activity, have as constant an activity as possible over a subsequent lengthy period of time. A further aim of the invention is to provide compounds whose duration of activity does not substantially exceed a period of about one day in therapeutically beneficial doses. Finally, the invention sets out to provide compounds which have an activity profile which ensures good control of the therapeutic effect (i.e. total therapeutic effect without side effects caused by a build-up of the substance in the body).
Surprisingly, it has been found that the above objectives are achieved by means of compounds of general formula 1 wherein the group R’ does not denote hydroxy.
Accordingly the present invention relates to compounds of general formula 1 1 2 + R -
A 0 0) ey fg
R’ 6
R R3 1 wherein
A denotes a double-bonded group selected from among
No Need NA
Hy H, © HH and pry
X~ denotes an anion with a single negative charge,
R1 and RZ denote C41-C4-alkyl, which may optionally be substituted by hydroxy or halogen;
R3, R4, RS and R8, which may be identical or different, denote hydrogen,
C1-C4-alkyl, C4-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R7 denotes hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene- halogen, halogen- C1-C4-alkyloxy, C1-C4-alkylene-OH, CF3, -C4-C4-alkylene- C1-C4-alkyloxy, -O-COC1-C4-alkyl, -0-COC1-C4-alkyl-halogen, -O-COCF; or halogen, while
NN if Adenotes 2 2
R1 and R2 denote methyl and
R3, R4 RS and R6 denote hydrogen,
R7 cannot also be hydrogen.
Preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among % d =¢ >A
H, H, , HH and Hy *H ;
X- denotes an anion with a single negative charge selected from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate, preferably bromide,
R1 and RZ which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3 R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chiorine, bromine, CN, CF, or NO,;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH,-F, -CH,-
CH,-F, -O-CH,-F, -O-CH,-CH,-F, -CH,-OH, -CH,-CH,-OH, CF;, -CH,-
OMe, -CH,-CH,-OMe, -CH,-OEt, -CH,-CH,-OEt, -O-COMe, -O-COEt, - 0O-COCF,, -O-COCF,, fluorine, chlorine or bromine.
Particularly preferred are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among
NN / \N / SA
C—C C=C and )
H,H, ' HH Hog H
X- denotes an anion with a single negative charge selected from among chloride, bromide and methanesulphonate, preferably bromide;
R1and RZ which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, RS and RS, which may be identical or different, denote hydrogen, methyl, } ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
R/ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine.
®
Preferred compounds of general formula 1 according to the invention are those wherein :
A denotes a double-bonded group selected from among
Ne J \N_/ \ /
H, H, GH and HH
X- denotes bromide;
R1 and RZ which may be identical or different denote a group selected from methyl and ethyl, preferably methyl,
R3. R4, R5 and R68, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine;
R7 denotes hydrogen, methyl or fluorine.
Of particular importance according to the invention are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among
Nord NA, —- and - :
HH H o H
X- denotes bromide,
R1 and R2 which may be identical or different denote methyl or ethyl, preferably methyl;
R3, R4, R5 and RS, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen;
R’ denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.
The invention relates to the compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
In the compounds of general formula 1 the groups R3, R4, RS and RS, provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the "-C- R7" group. Provided that none of the groups R3, R4,
R5 and RB denotes hydrogen, RS and RS are preferably linked in the para-position and R4 and RS are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R3 and R4 and one of the groups RS and
R6 denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R3, R4,
RS and R® denotes hydrogen, according to the invention the compounds of general formula 1 wherein the groups R3, R4, RS and RS have the same meaning are particularly preferred.
Of particular importance according to the invention are the compounds of general formula 1 wherein the ester-substituent on the nitrogen-bicyclic group is in the a- configuration. These compounds correspond to general formula 1-a 2 + R'
R~\’ X
H
A
0 0)
R’
R® 3
R 1-0.
According to the invention, the following compounds are of particular importance: - tropenol 2,2-diphenylpropionate-methobromide; - scopine 2,2-diphenylpropionate-methobromide; - scopine 2-fluoro-2,2-diphenylacetate-methobromide; - tropenol 2-fluoro-2,2-diphenylacetate-methobromide;
Unless otherwise stated, the alkyl groups are straight-chained or branched alkyl groups having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases the abbreviations Me, Et,
Prop or Bu are used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions propy! and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propy! includes n-propyl and iso- propyl, butyl includes iso-butyl, sec.butyl and tert.-butyl, etc.
Unless otherwise stated, the alkylene groups are branched and unbranched double- bonded alkyl! bridges having 1 to 4 carbon atoms. The following are mentioned by way of example: methylene, ethylene, propylene or butylene.
Unless otherwise stated, the alkylene-halogen groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or
4 » 7 trisubstituted, preferably monosubstituted, by a halogen. Accordingly, unless otherwise stated, the alkylene-OH groups are branched and unbranched double- bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a hydroxy.
Unless otherwise stated, the term alkyloxy groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples of these include: methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO-, EtO-, PropO- or BuO- are used in some cases to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, the definitions propyloxy and butyloxy include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyioxy, butyloxy includes iso-butyloxy, sec.butyloxy and tert.-butyloxy, etc. In some cases, within the scope of the present invention, the term alkoxy is used instead of the term alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy may also be used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy
Unless otherwise stated, the term alkylene-alkyloxy groups denotes branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group.
Unless otherwise stated, the term -O-CO-alkyl groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an ester group. The alkyl groups are linked directly to the carbonyl carbon of the ester group.
The term -O-CO-alkyl-halogen group should be understood in the same way. The group -O-CO-CF3 denotes trifluoroacetate.
Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are the preferred halogens.
The group CO denotes a carbonyl group.
The compounds according to the invention may partly be prepared, as illustrated below, analogously to procedures which are already known from the prior art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained using methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalysed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.
®
RY Re
R
. 1 lo] 1 1
NC [) 3 NT Ry x
R® fe = RZ—X ) NW 5 P= +H \ AW
A OH A 0.__0O A SNA
Xo) R ) R® ¥ R® 2 4 1
Diagram 1:
Starting from the compounds of formula 2 the esters of general formula 4 may be obtained by reacting the carboxylic acid derivatives of formula 3, wherein R may denote chlorine or a C1-C4-alkyloxy group, for example. When R denotes C1-C4- alkyloxy this reaction may be carried out, for example, in a sodium melt at elevated temperature, preferably at about 50-150°C, most preferably at about 90-100°C at low pressure, preferably below 500mbar, most preferably below 75mbar. Alternatively, instead of the derivatives 3 wherein R denotes C1-C4-alkyloxy, the corresponding acid chlorides (R equals Cl) may be used.
The compounds of formula 4 thus obtained may be converted into the target compounds of formula 1 by reacting the compounds R2-X, wherein R2 and X may be as hereinbefore defined. This synthesis step may also be carried out analogously to the examples of synthesis disclosed in WO 92/16528.
Alternatively to the procedure illustrated in Diagram 1 for synthesising the compounds of formula 4 , the derivatives 4 in which the nitrogen bicyclic group is a scopine derivative may be obtained by oxidation (epoxidation) of compounds of formula 4 wherein the nitrogen-bicyclic group is a tropenyl group. This may be done as follows, according to the invention.
Compound 4, wherein A denotes -CH=CH-, is suspended in a polar organic solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide , and then heated to a temperature of about 30-90°C, preferably 40-70°C. Then a suitable oxidising agent is added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The preferred oxidising agent is vanadium pentoxide mixed with HpO»2, most preferably HpO2-urea complex combined with vanadium pentoxide. The mixture is worked up in the usual way. The products may be purified by crystallisation or chromatography, depending on their crystallisation tendencies.
Alternatively, the compounds of formula 4 wherein R7 denotes halogen may also be obtained by the method shown in Diagram 2.
R' R'
N N
EN wH MN nH
A o__0O A o__0O “bye “Fe 7.
RE OH Cs RS R Co 5 4 (with R7 Halogen)
Diagram 2:
For this, the benzilic acid esters of formula 5 [verb missing (are converted?)] , using suitable halogenating reagents, into the compounds 4 wherein RY’ denotes halogen.
The reaction of halogenation to be carried out according to Diagram 2 is already sufficiently well known in the art.
The benzilic acid esters of formula 5 may be obtained in accordance with or analogously to methods known in the art (see e.g. WO 92/16528).
As shown in Diagram 1, the intermediate products of general formula 4 are of crucial importance. Accordingly, in another aspect, the present invention relates to the intermediates of formula 4
R'
N
A 0 0 7
R
R® 3
R 4 wherein
A denotes a double-bonded group selected from among eo Nod NA, - : = and ;
H, H, H H H o H
®
R1 denotes C1-C4-alkyl, which may optionally be substituted by hydroxy or halogen;
R3, R4, RS and RE, which may be identical or different, denote hydrogen, C4-C4- alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
RY denotes hydrogen, C4-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene- halogen, halogen- C1-C4-alkyloxy, C4-C4-alkylene-OH, CF3, - C1-C4- alkylene- C1-C4-alkyloxy, -0-COC4-C4-alkyl, -O-COC4-C4-alkyl- halogen, -O-COCF3 or halogen, while
NN /
C—C if A denotes Hay H, ,
R1 denotes methyl and
R3, R4, R5 and R6 denote hydrogen,
R7 cannot be n-propyl.
Preferred are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among \o old Ny
HH, © HH ed oN
R1 which may be identical or different denotes a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, RS and RS, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN,
CF3 or NO2;
RY denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH,-F, - CH,-
CH,-F, -O- CH,-F, -O- CH,- CH,-F, - CH,-OH, - CH,- CH,-OH, CF3, -CH,-OMe, - CH,- CH,-OMe, - CH,-OEt, - CH,- CH,-OEt, -O-COMe, -O-COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine.
Particularly preferred are compounds of general formula 1, whérein
A denotes a double-bonded group selected from among
Nel Nod | NA,
H, H, Hf/ and AVA
®
R1 which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyi;
R3, R4, RO and RS, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
RY denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine.
Preferred compounds of general formula 1 according to the invention are those wherein 70 A denotes a double-bonded group selected from among
Na Nord | NA,
H, H, , H H and HH ;
R1 which may be identical or different denote a group selected from methyl and ethyl, preferably methyl;
R3, R4, RS and RS, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine;
R7 denotes hydrogen, methyl or fluorine.
Of particular importance according to the invention are compounds of general formula 1 wherein
A denotes a double-bonded group selected from among
NN. /
G=¢ and NA
H o H
R1 which may be identical or different denote methyl or ethyl, preferably methyl;
R3, R4 RS and R6, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen,
R7 denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.
As in the compounds of general formula 1 , in the intermediates of formula 4 , the groups R3, R4, RS and RS, provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the "-C- R7" group.
Provided that none of the groups R3, R4, RS and R® denotes hydrogen, R3 and RS are preferably linked in the para-position and R4 and RO are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R3 and R4 and one of the groups RS and R® denotes hydrogen, the other group in each
Claims (12)
1) Compounds of general formula 1 RZ + R' - ’ A oO 0] &7 R® 3 R 1 : wherein
A denotes a double-bonded group selected from among o=c NA - and ; HH H og H
X- denotes an anion with a single negative charge preferably selected . from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate;
R1andR2 which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine;
R3, R4, RS and R68, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3or NO;
R7 denotes methyl, ethyl, methyloxy, ethyloxy, -CHx-F, -CH,-CH.-F, -O-CHz-F, -O-CH2-CH2-F, -CH,-OH, -CH,-CH,-OH, CF, -CH-- OMe, -CH,-CH,-OMe, -CH,-OEt, -CH,-CH,-OEt, -O-COMe, -O- COE, -O-COCF3, -0O-COCFs3, fluorine, chlorine or bromine,
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
2) Compounds of general formula 1, according to claim 1,
wherein A denotes a double-bonded group selected from among © =NDED SHEET
®
2) Compounds of general formula 1 according to claim 1,
wherein
A denotes a double-bonded group selected from among
Ns Ned NA HH, © HH and ov X- denotes an anion with a single negative charge selected from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate;
R1 and R2 which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine;
R3, R4, RS and RS, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chiorine, bromine, CN, CF, or NO,;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH,-F, -CH,-
CH,-F, -O-CH,-F, -O-CH,-CH,-F, -CH,-OH, -CH,-CH,-OH, CF,, -CH,- OMe, -CH,-CH,-OMe, -CH,-OEt, -CH,-CH,-OEt, -O-COMe, -O-COEt, - O-COCF;, -O-COCF,, fluorine, chlorine or bromine, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
3) Compounds of general formula 1, according to one of claims 1 or 2,
wherein
A denotes a double-bonded group selected from among
Ne Nod NA H, H, ) H H and Hy *H ; X- denotes an anion with a single negative charge selected from among chloride, bromide and methanesulphonate;
R1and RZ which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine;
R3, R4, RS and RS, which may be identical or different, denote hydrogen, methyl,
ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
RY denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3 or fluorine,
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
° BRO03/ 2914 4) Compounds of general formula 1, according to one of claims 1, 2 or 3, wherein A denotes a double-bonded group selected from among % J = H,H, = HH @nd \y . X- denotes bromide; : R1and R2 which may be identical or different denote a group selected from methyl and ethy!, R3 R
4 R5 and RS, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine; RY denotes hydrogen, methyl or fluorine,
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
5) Compounds of general formula 1, according to one of claims 1 to 4, wherein A denotes a double-bonded group selected from among Y= aa NA = an .
Hon H oH X- denotes bromide;
R1 and RZ which may be identical or different denote methyl or ethyl,
R3, R4, RS and R8, which may be identical or different, denote hydrogen or fluorine; R7 denotes hydrogen, methyl or fluorine,
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
6) Use of a compound of general formula 1 according to one of claims 1 to 5 as a medicament.
7) Use of a compound of general formula 1 according to one of claims 1 to 5 for preparing a medicament for treating diseases in which anticholinergics may develop a therapeutic benefit.
8) Use of a compound of general formula 1 according to one of claims 1 to 5 for preparing a medicament for the treatment of asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract and menstrual disorders.
9) Pharmaceutical preparations containing as active substance one or more compounds of general formula 1 according to one of claims 1 to 5 or the : physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
N 10) Pharmaceutical preparations according to claim 9, characterised in that they contain, in addition to one or more of the compounds of formula 1, at least one further active substance which is selected from among the betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists and steroids.
11) Process for preparing a compound of general formula 1 1 2 + R - ) \| wH A 0) 0] : 7 R 6 R R® 1 wherein A, X - and the groups R1, R2, R3, R4, RS, R6 and R” may have the meanings given in claims 1 to 5, characterised in that in a first step a compound of general formula 3 R 0 ha R’ & R® 3 R™ 3 wherein the groups R3, R4, RS, RS and R” may have the meanings given in claims 1 to 5 and R denotes chlorine or a C1-C4-alkyloxy , is reacted with a compound of formula 2 R' N’ NW! A OH 4 wherein A and R1 may have the meanings given in claims 1 to 5, to obtain a compound of formula 4
JR
N . H A Oo 0] “yh R’ C3 R® 3 R* 4 wherein A and the groups R1, R3, R4, RS, R6 and RY may have the meanings given in claims 1 to 5, and this is then quatemised by reacting a compound R2-X, wherein R2 and X may have the meanings given in claims 1 to 5 to obtain a compound of formula 1.
12) Intermediate products of general formula 4 rR N’ \ \| wH A 0 0 Rr’ R™ 4 wherein A and the groups R1, R3, R4, RS, RS and R7 may have the meanings given in claims 1 to 5, while NN / Hy Hi if Adenotes 2 2, R1 denotes methyl and
R3. R4, RS and R6 denote hydrogen, R/ cannot be n-propyl.
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DE4003270A1 (en) * | 1990-02-03 | 1991-08-08 | Boehringer Ingelheim Kg | NEW SPEED GASES AND THEIR USE IN MEDICINE PREPARATIONS |
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