CA2055946A1 - Chemical process - Google Patents
Chemical processInfo
- Publication number
- CA2055946A1 CA2055946A1 CA002055946A CA2055946A CA2055946A1 CA 2055946 A1 CA2055946 A1 CA 2055946A1 CA 002055946 A CA002055946 A CA 002055946A CA 2055946 A CA2055946 A CA 2055946A CA 2055946 A1 CA2055946 A1 CA 2055946A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- general formula
- stands
- compounds
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000001311 chemical methods and process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- -1 sulphonic acid ester Chemical class 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 206010011224 Cough Diseases 0.000 abstract description 22
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 22
- 230000000694 effects Effects 0.000 description 18
- 229960000278 theophylline Drugs 0.000 description 11
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 10
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 241000700198 Cavia Species 0.000 description 5
- 230000001813 broncholytic effect Effects 0.000 description 5
- 229960004126 codeine Drugs 0.000 description 5
- 229940125890 compound Ia Drugs 0.000 description 5
- 229960001340 histamine Drugs 0.000 description 5
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 241000282326 Felis catus Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- MKXZASYAUGDDCJ-NJAFHUGGSA-N dextromethorphan Chemical compound C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000000241 respiratory effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 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 3
- 108010058846 Ovalbumin Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229940124630 bronchodilator Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940092253 ovalbumin Drugs 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 229940075420 xanthine Drugs 0.000 description 3
- MVOYJPOZRLFTCP-UHFFFAOYSA-N 1-methyl-7H-xanthine Chemical compound O=C1N(C)C(=O)NC2=C1NC=N2 MVOYJPOZRLFTCP-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical class N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 235000020374 simple syrup Nutrition 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- RYQVRAILJXPCMZ-UHFFFAOYSA-N 3-methyl-7-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]purine-2,6-dione Chemical compound O1C(C)=NC(CN2C=3C(=O)NC(=O)N(C)C=3N=C2)=N1 RYQVRAILJXPCMZ-UHFFFAOYSA-N 0.000 description 1
- FOAAEWBAVWBKSD-UHFFFAOYSA-N 4-(7h-purin-2-ylmethyl)oxadiazole Chemical class N=1C=C2NC=NC2=NC=1CC1=CON=N1 FOAAEWBAVWBKSD-UHFFFAOYSA-N 0.000 description 1
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-Methylxanthine Natural products N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- IDCHQQSVJAAUQQ-UHFFFAOYSA-N N,N-diethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethanamine Chemical compound O1C(CCN(CC)CC)=NC(C=2C=CC=CC=2)=N1 IDCHQQSVJAAUQQ-UHFFFAOYSA-N 0.000 description 1
- 241001079660 Phanes Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 235000020438 lemon syrup Nutrition 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000007383 nerve stimulation Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229960003625 oxolamine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- PXZDWASDNFWKSD-UHFFFAOYSA-N prenoxdiazine Chemical compound C1CCCCN1CCC(ON=1)=NC=1CC(C=1C=CC=CC=1)C1=CC=CC=C1 PXZDWASDNFWKSD-UHFFFAOYSA-N 0.000 description 1
- 229960004202 prenoxdiazine Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000002023 wood Substances 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
- 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
- C07D473/08—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 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- 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
-
- 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
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A B S T R A C T
The present invention relates to compounds of the general formula I
and salts thereof - wherein R stands for hydrogen or C1-4 straighed or branched chain alkyl, which are prepared by a) reacting a compound of the general formula II
- wherein X stands for halogen or sulphonic acid ester - with a compound of the general formula III
- wherein R stands as given above - or b) reacting a salt of the compound of the general formula III - wherein R is as given above - with a compound of the general formula II - wherein X is halogen or sulphonic acid ester group.
The compounds of the formula I are used as cough relievers.
The present invention relates to compounds of the general formula I
and salts thereof - wherein R stands for hydrogen or C1-4 straighed or branched chain alkyl, which are prepared by a) reacting a compound of the general formula II
- wherein X stands for halogen or sulphonic acid ester - with a compound of the general formula III
- wherein R stands as given above - or b) reacting a salt of the compound of the general formula III - wherein R is as given above - with a compound of the general formula II - wherein X is halogen or sulphonic acid ester group.
The compounds of the formula I are used as cough relievers.
Description
CHEMICAL PROCESS ~5 ~9 ~
The present invention relates to novel 3H-purines of thP general formula I, pharmaceutically acceptable salts thereof, a process for the preparation of the novel compounds as well as pharmaceutical compositions containing compounds of the formula I and salts ther~of as active ingredient.
In the general formula I
R
o~,~ N
- H
R stands for C1_4 alkyl or hydrogen.
The compounds of the general formula I can be used for the treatment of the diseases of the respiratory organs. Various alkaloides and derivatives thereof, such as codeine among the morphine based compounds have been used for the treatment of the diseases of the respiratory system as a cough reliever.
These compounds show numerous side effects of central nervous system origin, therefore it was aimed to prepare new cough relievers having less side effect.
The present invention relates to novel 3H-purines of thP general formula I, pharmaceutically acceptable salts thereof, a process for the preparation of the novel compounds as well as pharmaceutical compositions containing compounds of the formula I and salts ther~of as active ingredient.
In the general formula I
R
o~,~ N
- H
R stands for C1_4 alkyl or hydrogen.
The compounds of the general formula I can be used for the treatment of the diseases of the respiratory organs. Various alkaloides and derivatives thereof, such as codeine among the morphine based compounds have been used for the treatment of the diseases of the respiratory system as a cough reliever.
These compounds show numerous side effects of central nervous system origin, therefore it was aimed to prepare new cough relievers having less side effect.
- 2 - 2~
Recently various 3,5 disubstituted-1,2,4-oxadiazoles have been prepared as novel cough relievers, and many of these have been used in human therapy (oxolamine, prenoxdiazine).
It has been also known that various xanthine derivatives were advantageously used for the treatment of the respiratory system due to their broncholytic activity. The best known representative of these compounds is theophylline. A new combination of 1,2,4~
oxadiazole ring and xanthine base is known, where cough relieving and broncholytic activity occu- simultaneously ~HU-PS Nos. 190.377 and 197.574).
It should be emphasized however, that though on the xanthtne derivatives used in therapy, the hydrogen of the N-1, N-7 and N-3 nitrogen atoms of the purine ring can be substituted by various groups, but common characteristic thereof is that N-3 is always substituted.
We have surprisingly found that the novel oxadiazolylmethyl-3H-purines of the general formula I
exhibit a~vantageous pharmacological properties, mainly for the treatment of the diseases of the respiratory organs and these properties are par~icularly advantageous in case of asthma bronchiale accompanied by cough attacks.
When determining the cough relieving activity of the compound of the formula Ia ,~N-O
,~ Cl~
H3~NJ~-N ~h3 ~ ~N~
I
H
as a reference compound the widely used cough reliever codeine and dextromethorphane have been used and when examining the broncholytic, antiasthmatic activity of the compound of the formula Ia the well known broncholytic theophylline has been used as reference.
The cough relieving activity of the compound of the formula Ia was examined on cats by inducing cough due to the electric stimulation of the nervous laryngeus superior (R. Domenjoz, Arch. Exp. Path., 1952, l~).
The test compound when administered i.v. and by gastric tube per os, the experiments show that compounds of the formula Ia exhibit a significant cough reliever activity both when using it ioV~ and p.o. The intensity of the activity is the same like the activity of the reference cough relievers, but the duration of activity surpasses that of the references both at i.v. and p.o.
administration (Table 1) Table 1 Cough reliever p.o. ED50 value~ on cats upon cough induced by electric nerve stimulation Compound Ia Cod~ine HCl dextrometho~- ¦
phane HBr p.o. EDso (+S.D-) 3.74 (~0-2) 4.33 (+0.1) 3.89 (~0-2) mg/kg p<O. 001 The cough reliever activity was examined on guirlea pig5 on reducing cough induced by 15 % citric acid spray (I.
Erdély, L. Tardos, Arzneim. Forsch. 1966, 617~. The 15 cough relievers were administered orally and the activity was measured one hour later. The compound of the formula Ia proved to be a significant cough reliever in this test as well and the intensity of the activity surpassed that of the reference cough relievers 20 (Table 2).
Table 2 ED50 values of cough relievers measured on guinea pigs 1 hour after the oral administration and the cough was induced by 15 ~ citric acid ~pray _ Compound Ia Codeine HC1 dextromethor phane HBr p.o. EDso (IS-D-) 3.04 (iO.10) 12,~4 ~I4.40) 5.26 (+1.72) mg/kg p<O . 001 _ _ 5 - 2~
The compound of the formula I does not show any hreathing depressing activity as opposed to the reference cough relievers, on the contrary the activity of the bronthoconstrictors is eliminated on the basis of both in vitro and in v.ivo experiments. The activity of the compound of the formula Ia on trachea smooth muscle of the guinea pig is similar to that of theophylline when examining the activity against histamine by accumu-lative dosage series (Table 3) Table 3 Inhibition of contracting activity of histamine on isolated trachea smooth muscle of guinea pigs 15 - Test compound p d 2' Emax%
_ Ia 5.48 (+1.42) 36 theophylline 5.38 (+1.24) 44 The inhibition of the increase of respiratory resistance induced by histamine was examined on cats (~.A. Wasserman~ D. W. Du Charme, Postaglandins, 1~77, 255).
The decrease of the increase of respiratory resistance induced by histamine administered i.v~ at a dosage of 3 ~glkg, was measured in 10-1~0 minute inter-vals for 4 mg/kg intraduodenal doses of the compound of the formula Ia and of theophylline. The compound of the formula Ia proved to be almost twice as active as theophylline and the activity lasted longer (Table 4).
Table 4 Decrease of the increase of tracheal resistance induced ~y histamine on cats upon 4 mg/kg intraduodenal doses __ _ _ _ Test compound Max. activity % Relative efficacy _ _ _ _ Ia 28.2 1.79 theophylline 15.7 1.00 The compound of the formula Ia shows a significant and favourable effect-on guinea pigs in preventing experimental asthma (anaphylaxis~. Guinea pigs were sensitized by a single i.v. dosage of 1 ~g/kg of ovalbumin (Andersson, Brattsand, Br. J. Pharmacol. 1982, 139), whereafter 40 days later the test compounds were administered i.v. in a dosage of 10 mg/kg, and the narcotized muscle relaxed and artificially breathed animals were intratracheally administered 3 mg/kg of ovalbumin. The prevention of l:he increase of the tracheal resistanca of the an:imals was measured in various intervals. The result-3 are shown in Table 5.
Records of guinea pig tests Groups: normal, compound Ia, theophylline Narcotization, preparation, artificial respiration after the administration o~ a muscle relaxant 1. measurement: injection of 10 mg/kg of active ingre-dient after 5 min and intratracheal provocation (0 min) 2. measurement: 3 min after intratracheal provocation 3. measurement: 6 min after intratracheal provocation 4. measurement: 12 min after intratracheal provocation 5. measurement: 24 min after intratracheal provocation 2 ~ ?~
Table 5 Resistance (R=Pa/ml/s) Changes on ~3enzi~ized guinea pig5 after intratracheal ovalbumin ()A) provocation 5(positive pressing respiration- 90/min and 3 ml volume) normal Ia ~heophylline Case number ~n): 6 6 6 8Ody weight: 635t40 731+36 716+18 after 10 mg/kg i.v.: 10.72~1.50 8.07+0.93 11.04+0.26 -3 min after OA:6.53+3.28 9.21+0.8412.87+1.06 ~ .20+~.74 1.14*0.771.~3~1.05 6 min after OA:11.81+1.939.41+0.9114.65+0.93 ~: 1.09'1.80 1.34+0.~63.51+1.04 2012 min after OA:16.32~2.1510.10+0.94 14.lB+0.54 ~: 5.60tl.0~ 2.03+0.443.14~0.65 24 min after OA:18.16+2.459.92+1.1114.11+0.51 `~: 7.44~1.55 1.85+0.643.07+0.39 ~: deviance from the value measured after 10 mg/kg i,v. (own control) (The normal group obtained physiological saline solution.) Table 5 shows that compound of the Foxmula Ia significantly reduces the experimental asthma on guinea pigs at an extent surpassing the activity of theophylli~e, i.e. the~trachPal resistance (R) incraase is inhibited.
The broncholytic and antiasthmatic activities of the compound of the Formula Ia are all the more remarkable that the compound of the Formula Ia has no undesired CNS and caxdial side effects which are characteristic for theophylline.
The compound of the Formula Ia has further fa~ourable toxicity data DLso>2000 mg/kg on mice when administered orally. Considering the toxicity of codeine, dextromethorphane and theophylline, which were used as controll the thereap~utic index of the compound of the Formula I is by one order of magnitude better than that of the reference compounds (Codeine.HCl DL50 on mice: 359.2 mg/kg p.o., dextromethorphane.HBr DL50 on mice: 165.9 mg/kg p.oO, theophylline DL50 on mice: 215 mg/kg p.o.). A special advantage of the compound of the Formula Ia is that it absorbs in the organism excellently and rapidly - in spite of the moderate water - solubility - without salt formation in case of oral administration.
The compounds of the Fonnula I according to the invention can preferably be prepared by reacting a compound of the general ~ormula II
N-o X- CH 2~N9~
- wherein X stands for halogen or sulphonic acid ester group -with xanthine of the formula III -~ 9 o H
R -i~ N~, wherein R stands as given above -in the presence of an organic solvent and/or diluent, preferably dimethylformamide or alcolhols, preferably butanol, and in the presence of an inorganic base, preferably alkali hydroxide or alkali carbonate, preférably potassium carbonate, or an alkali salt o the xanthine of the formula III, preferably a sodium or potassium salt thereof is reacted with a compound of t~e formula II in the presence of an organic solvent and/or diluent at a temperature of 20 to 150, preferably 40 to 10 100 C.
The compounds of the formula I are moderately acidic and the salts with alkali metals can be prepared by forming an aqueous solution of equimolar mixture of the compounds of the general formula I and alkali hydroxides, preferably sodium or potassium hydroxide, and by evaporating this mixture. The so ~ormed sodium or potassium salts are watersoluble.
The compounds of the general ormula I or salts thereof can be used as such or in pharmac~utical compositions. The pharmaceutical compositions can be used in the ~orm of syrups, tablets, coated tablets, 2 ~
capsules together with the usually used excipients. The pharmaceutical compositions can contain 0.2 to 100 per cent of active ingredients. The daily dosage depends on the age of the patient, on the method of administration and the aim thereof, as well of the weight of the patient, and it can vary between 1 to 500 mg. The further details of the invention are illustrated by the following examples without limiting the scope of the invention to the examples.
Example 1 3.32 g of 1-methyl-xanth:ine (K.A.Chkhidvadze, 0.
Magidson, Med. Prom. S.S.S.R.~ 1958, 16) and 1.45 g of potassium carbonate are .suspended in 40 ml of dimethyl-formamide, whereafter the mixture is stirred for 20 minutes at 85 C and at the same t~rmperature 3.43 g of 3-chloromethyl-5-methyl-1,2,4-oxadiazol2 are added drop-wise within 15 minutss ~J.Wood, German Publication No.
1,915,495) and the mixture is stirred at this tempera-ture for further 90 minutes. The mixture is filtered while hot, the filtrate is evaporated at reduced pressure and the residue is triturated with 15 ml of water and the solid product is filtered by suction and washed with water. 4.3 g of product are obtained and crystalliæed first from 38 ml of 10 % aqueous hydro-chloric acid and then 50 % aqueous ethanol clarifying with active charcoal. 3 g (60 %) of 3,7-dihydro-1-2 ~
methyl-7-[(5-methyl-1,2,4-oxadiazole-3-yl)-methyl]-3H
purine-2,6-dione are obtained ~ompound of the formula I), me~ting point: 243-245 C.
lH NMR ([D6]DMS0) ~=2.56 ~s, 3H, CH33; 3.13 (s, 3H, CH3); 5,65 (s, 2H, CH2); 8.1 ~s, lH, =(CH)-~; 12,16 ~b, lH, 4 NH).
Example 2 A solution is prepared from 3.5 g of 1-methyl-xanthine and 8.14 ml of 10 % sodium hydroxide solution by shaking and a solid material precipitates ~rom the mixture very soon. The water is distilled off at reduced pressure and the ~races of water are removed ~rom the residue by toluene azeotrope distillation. The obtained l-methyl-xanthine sodium salt is suspended in dimethyl-formamide, reacted with 3-chloromQthyl-5-methyl-1,2,~-oxadiazole according to example 1 and worked up to a compound of the formula Ia with the same yield.
Example 3 Tablets: Compound Ia 2.0 g Starch 97.0 g Calcium-phosphate 100.0 g Magnesium-stearate 1.0 g Total: 200.0 g - 12 2~
The powdered mixture is converted to 1000 pieces of 200 mg tablet by method known per se, so that each tablet contains 2 mg of active component.
Example 4 Syru~: Compound Ia ~.o g Lemon syrup 200.0 ml Benzoic acid solution 20.0 ml Water 100.0 ml Sugar syrup 1000.0 ml The active component is dissolved in water while hot, 500 ml of sugar syrup is added and the other components are supplemented to lO00 ml by adding a sugar.
syrup. Each ml of the syrup solution co~tains 4 mg of active component.
Recently various 3,5 disubstituted-1,2,4-oxadiazoles have been prepared as novel cough relievers, and many of these have been used in human therapy (oxolamine, prenoxdiazine).
It has been also known that various xanthine derivatives were advantageously used for the treatment of the respiratory system due to their broncholytic activity. The best known representative of these compounds is theophylline. A new combination of 1,2,4~
oxadiazole ring and xanthine base is known, where cough relieving and broncholytic activity occu- simultaneously ~HU-PS Nos. 190.377 and 197.574).
It should be emphasized however, that though on the xanthtne derivatives used in therapy, the hydrogen of the N-1, N-7 and N-3 nitrogen atoms of the purine ring can be substituted by various groups, but common characteristic thereof is that N-3 is always substituted.
We have surprisingly found that the novel oxadiazolylmethyl-3H-purines of the general formula I
exhibit a~vantageous pharmacological properties, mainly for the treatment of the diseases of the respiratory organs and these properties are par~icularly advantageous in case of asthma bronchiale accompanied by cough attacks.
When determining the cough relieving activity of the compound of the formula Ia ,~N-O
,~ Cl~
H3~NJ~-N ~h3 ~ ~N~
I
H
as a reference compound the widely used cough reliever codeine and dextromethorphane have been used and when examining the broncholytic, antiasthmatic activity of the compound of the formula Ia the well known broncholytic theophylline has been used as reference.
The cough relieving activity of the compound of the formula Ia was examined on cats by inducing cough due to the electric stimulation of the nervous laryngeus superior (R. Domenjoz, Arch. Exp. Path., 1952, l~).
The test compound when administered i.v. and by gastric tube per os, the experiments show that compounds of the formula Ia exhibit a significant cough reliever activity both when using it ioV~ and p.o. The intensity of the activity is the same like the activity of the reference cough relievers, but the duration of activity surpasses that of the references both at i.v. and p.o.
administration (Table 1) Table 1 Cough reliever p.o. ED50 value~ on cats upon cough induced by electric nerve stimulation Compound Ia Cod~ine HCl dextrometho~- ¦
phane HBr p.o. EDso (+S.D-) 3.74 (~0-2) 4.33 (+0.1) 3.89 (~0-2) mg/kg p<O. 001 The cough reliever activity was examined on guirlea pig5 on reducing cough induced by 15 % citric acid spray (I.
Erdély, L. Tardos, Arzneim. Forsch. 1966, 617~. The 15 cough relievers were administered orally and the activity was measured one hour later. The compound of the formula Ia proved to be a significant cough reliever in this test as well and the intensity of the activity surpassed that of the reference cough relievers 20 (Table 2).
Table 2 ED50 values of cough relievers measured on guinea pigs 1 hour after the oral administration and the cough was induced by 15 ~ citric acid ~pray _ Compound Ia Codeine HC1 dextromethor phane HBr p.o. EDso (IS-D-) 3.04 (iO.10) 12,~4 ~I4.40) 5.26 (+1.72) mg/kg p<O . 001 _ _ 5 - 2~
The compound of the formula I does not show any hreathing depressing activity as opposed to the reference cough relievers, on the contrary the activity of the bronthoconstrictors is eliminated on the basis of both in vitro and in v.ivo experiments. The activity of the compound of the formula Ia on trachea smooth muscle of the guinea pig is similar to that of theophylline when examining the activity against histamine by accumu-lative dosage series (Table 3) Table 3 Inhibition of contracting activity of histamine on isolated trachea smooth muscle of guinea pigs 15 - Test compound p d 2' Emax%
_ Ia 5.48 (+1.42) 36 theophylline 5.38 (+1.24) 44 The inhibition of the increase of respiratory resistance induced by histamine was examined on cats (~.A. Wasserman~ D. W. Du Charme, Postaglandins, 1~77, 255).
The decrease of the increase of respiratory resistance induced by histamine administered i.v~ at a dosage of 3 ~glkg, was measured in 10-1~0 minute inter-vals for 4 mg/kg intraduodenal doses of the compound of the formula Ia and of theophylline. The compound of the formula Ia proved to be almost twice as active as theophylline and the activity lasted longer (Table 4).
Table 4 Decrease of the increase of tracheal resistance induced ~y histamine on cats upon 4 mg/kg intraduodenal doses __ _ _ _ Test compound Max. activity % Relative efficacy _ _ _ _ Ia 28.2 1.79 theophylline 15.7 1.00 The compound of the formula Ia shows a significant and favourable effect-on guinea pigs in preventing experimental asthma (anaphylaxis~. Guinea pigs were sensitized by a single i.v. dosage of 1 ~g/kg of ovalbumin (Andersson, Brattsand, Br. J. Pharmacol. 1982, 139), whereafter 40 days later the test compounds were administered i.v. in a dosage of 10 mg/kg, and the narcotized muscle relaxed and artificially breathed animals were intratracheally administered 3 mg/kg of ovalbumin. The prevention of l:he increase of the tracheal resistanca of the an:imals was measured in various intervals. The result-3 are shown in Table 5.
Records of guinea pig tests Groups: normal, compound Ia, theophylline Narcotization, preparation, artificial respiration after the administration o~ a muscle relaxant 1. measurement: injection of 10 mg/kg of active ingre-dient after 5 min and intratracheal provocation (0 min) 2. measurement: 3 min after intratracheal provocation 3. measurement: 6 min after intratracheal provocation 4. measurement: 12 min after intratracheal provocation 5. measurement: 24 min after intratracheal provocation 2 ~ ?~
Table 5 Resistance (R=Pa/ml/s) Changes on ~3enzi~ized guinea pig5 after intratracheal ovalbumin ()A) provocation 5(positive pressing respiration- 90/min and 3 ml volume) normal Ia ~heophylline Case number ~n): 6 6 6 8Ody weight: 635t40 731+36 716+18 after 10 mg/kg i.v.: 10.72~1.50 8.07+0.93 11.04+0.26 -3 min after OA:6.53+3.28 9.21+0.8412.87+1.06 ~ .20+~.74 1.14*0.771.~3~1.05 6 min after OA:11.81+1.939.41+0.9114.65+0.93 ~: 1.09'1.80 1.34+0.~63.51+1.04 2012 min after OA:16.32~2.1510.10+0.94 14.lB+0.54 ~: 5.60tl.0~ 2.03+0.443.14~0.65 24 min after OA:18.16+2.459.92+1.1114.11+0.51 `~: 7.44~1.55 1.85+0.643.07+0.39 ~: deviance from the value measured after 10 mg/kg i,v. (own control) (The normal group obtained physiological saline solution.) Table 5 shows that compound of the Foxmula Ia significantly reduces the experimental asthma on guinea pigs at an extent surpassing the activity of theophylli~e, i.e. the~trachPal resistance (R) incraase is inhibited.
The broncholytic and antiasthmatic activities of the compound of the Formula Ia are all the more remarkable that the compound of the Formula Ia has no undesired CNS and caxdial side effects which are characteristic for theophylline.
The compound of the Formula Ia has further fa~ourable toxicity data DLso>2000 mg/kg on mice when administered orally. Considering the toxicity of codeine, dextromethorphane and theophylline, which were used as controll the thereap~utic index of the compound of the Formula I is by one order of magnitude better than that of the reference compounds (Codeine.HCl DL50 on mice: 359.2 mg/kg p.o., dextromethorphane.HBr DL50 on mice: 165.9 mg/kg p.oO, theophylline DL50 on mice: 215 mg/kg p.o.). A special advantage of the compound of the Formula Ia is that it absorbs in the organism excellently and rapidly - in spite of the moderate water - solubility - without salt formation in case of oral administration.
The compounds of the Fonnula I according to the invention can preferably be prepared by reacting a compound of the general ~ormula II
N-o X- CH 2~N9~
- wherein X stands for halogen or sulphonic acid ester group -with xanthine of the formula III -~ 9 o H
R -i~ N~, wherein R stands as given above -in the presence of an organic solvent and/or diluent, preferably dimethylformamide or alcolhols, preferably butanol, and in the presence of an inorganic base, preferably alkali hydroxide or alkali carbonate, preférably potassium carbonate, or an alkali salt o the xanthine of the formula III, preferably a sodium or potassium salt thereof is reacted with a compound of t~e formula II in the presence of an organic solvent and/or diluent at a temperature of 20 to 150, preferably 40 to 10 100 C.
The compounds of the formula I are moderately acidic and the salts with alkali metals can be prepared by forming an aqueous solution of equimolar mixture of the compounds of the general formula I and alkali hydroxides, preferably sodium or potassium hydroxide, and by evaporating this mixture. The so ~ormed sodium or potassium salts are watersoluble.
The compounds of the general ormula I or salts thereof can be used as such or in pharmac~utical compositions. The pharmaceutical compositions can be used in the ~orm of syrups, tablets, coated tablets, 2 ~
capsules together with the usually used excipients. The pharmaceutical compositions can contain 0.2 to 100 per cent of active ingredients. The daily dosage depends on the age of the patient, on the method of administration and the aim thereof, as well of the weight of the patient, and it can vary between 1 to 500 mg. The further details of the invention are illustrated by the following examples without limiting the scope of the invention to the examples.
Example 1 3.32 g of 1-methyl-xanth:ine (K.A.Chkhidvadze, 0.
Magidson, Med. Prom. S.S.S.R.~ 1958, 16) and 1.45 g of potassium carbonate are .suspended in 40 ml of dimethyl-formamide, whereafter the mixture is stirred for 20 minutes at 85 C and at the same t~rmperature 3.43 g of 3-chloromethyl-5-methyl-1,2,4-oxadiazol2 are added drop-wise within 15 minutss ~J.Wood, German Publication No.
1,915,495) and the mixture is stirred at this tempera-ture for further 90 minutes. The mixture is filtered while hot, the filtrate is evaporated at reduced pressure and the residue is triturated with 15 ml of water and the solid product is filtered by suction and washed with water. 4.3 g of product are obtained and crystalliæed first from 38 ml of 10 % aqueous hydro-chloric acid and then 50 % aqueous ethanol clarifying with active charcoal. 3 g (60 %) of 3,7-dihydro-1-2 ~
methyl-7-[(5-methyl-1,2,4-oxadiazole-3-yl)-methyl]-3H
purine-2,6-dione are obtained ~ompound of the formula I), me~ting point: 243-245 C.
lH NMR ([D6]DMS0) ~=2.56 ~s, 3H, CH33; 3.13 (s, 3H, CH3); 5,65 (s, 2H, CH2); 8.1 ~s, lH, =(CH)-~; 12,16 ~b, lH, 4 NH).
Example 2 A solution is prepared from 3.5 g of 1-methyl-xanthine and 8.14 ml of 10 % sodium hydroxide solution by shaking and a solid material precipitates ~rom the mixture very soon. The water is distilled off at reduced pressure and the ~races of water are removed ~rom the residue by toluene azeotrope distillation. The obtained l-methyl-xanthine sodium salt is suspended in dimethyl-formamide, reacted with 3-chloromQthyl-5-methyl-1,2,~-oxadiazole according to example 1 and worked up to a compound of the formula Ia with the same yield.
Example 3 Tablets: Compound Ia 2.0 g Starch 97.0 g Calcium-phosphate 100.0 g Magnesium-stearate 1.0 g Total: 200.0 g - 12 2~
The powdered mixture is converted to 1000 pieces of 200 mg tablet by method known per se, so that each tablet contains 2 mg of active component.
Example 4 Syru~: Compound Ia ~.o g Lemon syrup 200.0 ml Benzoic acid solution 20.0 ml Water 100.0 ml Sugar syrup 1000.0 ml The active component is dissolved in water while hot, 500 ml of sugar syrup is added and the other components are supplemented to lO00 ml by adding a sugar.
syrup. Each ml of the syrup solution co~tains 4 mg of active component.
Claims (8)
1. Process for the preparation of the compounds of the general formula I
and salts thereof - wherein R stands for hydrogen or C1-4 straight or branched chain alkyl, which comprises a) reacting a compound of the general formula II
- wherein X stands for halogen or sulphonic acid ester group - with a compound of the general formula III
- wherein R stands as given above - or b) reacting a salt of the compound of the general formula III - wherein R is as given above - with a compound of the general formula II - wherein X is halogen or sulphonic acid ester group.
and salts thereof - wherein R stands for hydrogen or C1-4 straight or branched chain alkyl, which comprises a) reacting a compound of the general formula II
- wherein X stands for halogen or sulphonic acid ester group - with a compound of the general formula III
- wherein R stands as given above - or b) reacting a salt of the compound of the general formula III - wherein R is as given above - with a compound of the general formula II - wherein X is halogen or sulphonic acid ester group.
2. A process according to process a) of claim 1, which comprises conducting the reaction in the presence of a base.
3. Process a) or b) according to claim 1, which comprises conducting the reaction in an organic solvent and/or in a diluent.
4. Process b) according to claim 1, which comprises using an alkali metal salt of the compound of the general formula III - wherein R is as given above.
5. Compounds of the general formula I - wherein R
stands for hydrogen or C1-4 straight or branched alkyl and salts thereof.
stands for hydrogen or C1-4 straight or branched alkyl and salts thereof.
6. 3,7-Dihydro-1-methyl-7-[(5-methyl-1,2,4-oxa-diazole-3-yl)-methyl]-3H-purine-2,6-dione.
7. Pharmaceutical composition comprising one or more compound(s) of the general formula I - wherein R is as given in claim 1 - and/or a salt thereof together with one or more pharmaceutically acceptable carrier(s) or excipient(s).
8. Process for preparing a pharmaceutical composition, which comprises admixing one or more compound(s) of the general formula I and/or salts thereof - wherein R is as given in claim 1 - with one or more pharmaceutically acceptable carrier(s) or excipient(s) and converting the mixture to a pharma-ceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU7236/90 | 1990-11-22 | ||
| HU907236A HU206884B (en) | 1990-11-22 | 1990-11-22 | Process for producing purin derivatives and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2055946A1 true CA2055946A1 (en) | 1992-05-23 |
Family
ID=10972253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002055946A Abandoned CA2055946A1 (en) | 1990-11-22 | 1991-11-21 | Chemical process |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0488079A1 (en) |
| JP (1) | JPH05262770A (en) |
| KR (1) | KR920009830A (en) |
| CN (1) | CN1061600A (en) |
| AU (1) | AU642056B2 (en) |
| CA (1) | CA2055946A1 (en) |
| CS (1) | CS353891A3 (en) |
| DK (1) | DK189291A (en) |
| FI (1) | FI915509A7 (en) |
| HU (1) | HU206884B (en) |
| IL (1) | IL100059A0 (en) |
| NO (1) | NO914563L (en) |
| PL (1) | PL292497A1 (en) |
| YU (1) | YU182991A (en) |
| ZA (1) | ZA918998B (en) |
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|---|---|---|---|---|
| SG91852A1 (en) | 1998-12-21 | 2002-10-15 | Toyo Boseki | Hindered amine compound, resin composition, polyurethane fiber and production method and use thereof |
| JP2023509160A (en) | 2020-01-03 | 2023-03-07 | ミアー ホールディングス エルエルシー | CONTAINER, CONTAINER MANUFACTURING METHOD AND RELATED SYSTEM |
| USD1084774S1 (en) | 2023-03-01 | 2025-07-22 | Miir Holdings, Llc | Cup |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU190377B (en) * | 1982-03-12 | 1986-08-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing theophyllinyl-alkyl-oxadiazoles |
| EP0171005B1 (en) * | 1984-07-27 | 1989-11-23 | BOEHRINGER BIOCHEMIA ROBIN S.p.A. | Xanthinylmethylthiazolidines, process for their preparation and pharmaceutical compositions containing them |
| HU197574B (en) * | 1986-10-09 | 1989-04-28 | Chinoin Gyogyszer Es Vegyeszet | Process for production of derivatives of 3,7-dihydro-3-methil-7-//1,2,4-oxadiasole/-3-il/alkylenil/-1h-purin-2,6-dion and medical compositions containing these substances |
| IT1197516B (en) * | 1986-12-24 | 1988-11-30 | Abc Ist Biolog Chem Spa | THEOFILLINMETYLANIC AND THEOFILLINMETYLDITIAN DERIVATIVES PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM |
| HU198933B (en) * | 1987-11-02 | 1989-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing new xanthine derivatives and pharmaceutical compositions comprising same as active ingredient |
-
1990
- 1990-11-22 HU HU907236A patent/HU206884B/en not_active IP Right Cessation
-
1991
- 1991-11-13 ZA ZA918998A patent/ZA918998B/en unknown
- 1991-11-14 IL IL100059A patent/IL100059A0/en unknown
- 1991-11-20 DK DK189291A patent/DK189291A/en not_active Application Discontinuation
- 1991-11-20 AU AU88036/91A patent/AU642056B2/en not_active Ceased
- 1991-11-21 CA CA002055946A patent/CA2055946A1/en not_active Abandoned
- 1991-11-21 NO NO91914563A patent/NO914563L/en unknown
- 1991-11-21 YU YU182991A patent/YU182991A/en unknown
- 1991-11-22 CS CS913538A patent/CS353891A3/en unknown
- 1991-11-22 KR KR1019910020978A patent/KR920009830A/en not_active Ceased
- 1991-11-22 CN CN91110928A patent/CN1061600A/en active Pending
- 1991-11-22 EP EP91119958A patent/EP0488079A1/en not_active Withdrawn
- 1991-11-22 JP JP3334191A patent/JPH05262770A/en active Pending
- 1991-11-22 PL PL29249791A patent/PL292497A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| PL292497A1 (en) | 1992-10-19 |
| NO914563D0 (en) | 1991-11-21 |
| ZA918998B (en) | 1992-11-25 |
| IL100059A0 (en) | 1992-08-18 |
| HU206884B (en) | 1993-01-28 |
| KR920009830A (en) | 1992-06-25 |
| AU8803691A (en) | 1992-05-28 |
| DK189291D0 (en) | 1991-11-20 |
| FI915509A0 (en) | 1991-11-22 |
| AU642056B2 (en) | 1993-10-07 |
| EP0488079A1 (en) | 1992-06-03 |
| FI915509A7 (en) | 1992-05-23 |
| CS353891A3 (en) | 1992-06-17 |
| JPH05262770A (en) | 1993-10-12 |
| NO914563L (en) | 1992-05-25 |
| DK189291A (en) | 1992-05-23 |
| CN1061600A (en) | 1992-06-03 |
| HU907236D0 (en) | 1991-05-28 |
| YU182991A (en) | 1994-01-20 |
| HUT59925A (en) | 1992-07-28 |
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