GB1582688A - 7,10-dimethyl-5,9-imino-4,5,8,9-tetrahydro-cycloocta(b)-thiophenes - Google Patents
7,10-dimethyl-5,9-imino-4,5,8,9-tetrahydro-cycloocta(b)-thiophenes Download PDFInfo
- Publication number
- GB1582688A GB1582688A GB13838/78A GB1383878A GB1582688A GB 1582688 A GB1582688 A GB 1582688A GB 13838/78 A GB13838/78 A GB 13838/78A GB 1383878 A GB1383878 A GB 1383878A GB 1582688 A GB1582688 A GB 1582688A
- Authority
- GB
- United Kingdom
- Prior art keywords
- imino
- tetrahydro
- dimethyl
- cyclooct
- thiophene
- 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.)
- Expired
Links
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- HLNJFEXZDGURGZ-UHFFFAOYSA-M 1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1 HLNJFEXZDGURGZ-UHFFFAOYSA-M 0.000 claims description 4
- QHDYEBDDCPGWCC-UHFFFAOYSA-M [Br-].[Mg+]C=1C=CSC=1 Chemical compound [Br-].[Mg+]C=1C=CSC=1 QHDYEBDDCPGWCC-UHFFFAOYSA-M 0.000 claims description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 6
- 229960004193 dextropropoxyphene Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000577218 Phenes Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229960002523 mercuric chloride Drugs 0.000 description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 2
- 229940075930 picrate Drugs 0.000 description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LNUYBCUFHJCJFD-UHFFFAOYSA-M 1,3,4-trimethylpyridin-1-ium;iodide Chemical compound [I-].CC1=CC=[N+](C)C=C1C LNUYBCUFHJCJFD-UHFFFAOYSA-M 0.000 description 1
- YOBTXORLVXZWSR-UHFFFAOYSA-M 1,4-dimethylpyridin-1-ium;iodide Chemical compound [I-].CC1=CC=[N+](C)C=C1 YOBTXORLVXZWSR-UHFFFAOYSA-M 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- -1 5,9 - IMINO 4,5,8,9 - TETRAHYDRO - CYCLOOCT[b]THIOPHENE Chemical compound 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
(54) 7,10-DIMETHYL-5,9-IMINO-4,5,8,9-TETRAHYDRO- CYCLOOCTA [b] -THIOPHENES
(71-) We, LABORATORIOS MADE, S.A., a Spanish Company established at Avda Burgos 5cm850, Madrid, Spain, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to analgesics and provides, as new compounds, the 7,10dimethyl - 5,9 - imino - 4,5,8,9 - tetrahydro - cyclooct[b]thiophenes of formula I below, in which R is hydrogen or alkyl, preferably of 1 to 4 carbon atoms, for example methyl, and their pharmacologically acceptable acid addition salts, for example their picrates. These compounds are analgesics.
According to a feature of the invention the compounds of formula I are prepared by reacting 3 - thienylmagnesium bromide with an N - methylpyridinium iodide of the formula II below to give an unstable dihydropyridine intermediate which is converted without isolation into the desired compound of formula I, in accordance with the following reaction scheme:
In the first step of this process, 3 - thienylmagnesium bromide is preferably obtained in conditions of high dilution and in inert atmosphere and is then made to react at reflux temperature with an N - methylpyridinium iodide in anhydrous ether.
The unstable dihydropyridine intermediate obtained is treated without purification in acid medium. After alkalization of the resulting solution and extraction with an organic solvent the 7,10 - dimethyl - 5,9 - imino - 4,5,8,9 - tetrahydro - cyclooct[b]thiophene of formula (I) is obtained. It may be purified and characterised as its picrate.
The following Examples illustrate the invention.
EXAMPLE 1.
7,10-Dimethyl-5,9-imino-4,5,8,9-tetrahydrocyclooct [b] thiophene (I.R= H) To obtain 3 - thienylmagnesium bromide, use has been made of a "modified
cyclic reactor" containing a continuous flow column provided with a separation funnel, coolant and reaction flask. The reactor column is packed with 70 g of magnesium shavings alternated with thin layers of mercuric chloride and is revered with a
saturated solution of mercuric chloride in anhydrous ether. Following 12 hours standing, 250 ml of anhydrous ether are introduced in a flask and refluxed for two hours. Tile flask is replaced by another equipped for mechanical stirring in which 10 g of 1,4dimethylpyridinium iodide are introduced in 150 cc of anhydrous ether. 8 g of 3thienyl bromide are placed in the separation funnel in 75 ml of anhydrous ether. A few ml of the halide solution are added to the magnesium column, and when it is observed that the reaction has begun the flask is heated to reflux temperature, the addition continuing slowly for two hours. A nitrogen atmosphere is maintained in the system during the entire process. When the addition has concluded, reflux is continued for one hour and 30 minutes. The ether solution is then poured onto 250 ml of a saturated aqueous solution of ammonium chloride and ice, the mixture is alkalised with concentrated ammonium hydroxide and extracted with ether. The ether solution is extracted with 10% hydrochloric acid. The resulting aqueous layer is heated at reflux temperature for one hour, and is then alkalised with concentrated ammonium hydroxide and extracted with ether. The resulting ether solution is dried over sodium sulphate, and evaporated. 35 g of an oil are obtained (37.7% yield) from which the pirate is made. A sample thereof recrystallised from absolute ethanol has a melting point of 165--170"C.
Analysis for CisHisN4SO(I,R=H).
Calculated: C, 49.76; H, 4.14; N, 12.90; S, 7.37%
Found: C, 49.59; H, 4.31; N, 12.78; S, 7.66%
EXAMPLE 2.
6,7,1 0-Trimethyl-5,9-imino-4,5,8,9-tetrahydrocyclooct [b ] thiophene (I,R = CH,) This compound is made by the procedure of Example 1 starting from 1,3,4trimethylpyridinium iodide. An analytic sample of the corresponding picrate is recrystallised from ethanol and has a melting point of 20S3 C.
Analysis for Cl9H20N4SO7(I,R=CHs) Calculated: C, 50.91; H, 4.46; N, 12.50; S, 7.15%
Found: C, 50.74; H, 4.69; N, 12.40; S, 7.37%
PHARMACOLIGICAL PROPERTIES OF 7,10 - DIMETHYL -. 5,9 - IMINO
4,5,8,9 - TETRAHYDRO - CYCLOOCT[b]THIOPHENE (I,R=H)
This compound has analgesic activity. Its toxicity and activity have been compared with that of dextropropoxyphene.
A -- ACUTE TOXICITY
Acute toxicity studies have been made in albino Swiss I.C.R. mice, of both sexes, having a weight of 30 * 2 g, kept without food for 24 hours prior to the experiment.
Temperature and relative humidity of the atmopshere were kept constant. The products were administered intraperitoneally, the number of deaths having been noted 48 hours after treatment. The lethal dose (LD,0) was calculated by the Litchfield-Wilcoxon test. The following are the results obtained.
.TABLE I
Product Lid50 (mg/kg)
I, R=H 159.4
Dextropropoxyphene 140 B - ANALGESIC ACTIVITY
1. Thermal analgesia
The thermal analgesic effect has been studied in albino Swiss I.C.R. mice. The 55 C hot-plate technique has been used with batches of 10 mice. The products under study were administered intraperitoneally. After 30 minutes the mice were placed on the hot-plate and note was made of the time it took them to jump, in seconds. Batches of control animals were injected only with distilled water. The results are shown in
Table II.
TABLE II
Significance of differences Jumping time in Dextropropoxy- Treatment Dose sec. x iS.E.M.(1) Control phene Control - 64 # 7.911 - - I, R=H 50 mg/kg 114.2 4 14.168 p < O.01 p < 0.01 Dextropro poxyphene 50 mg/kg 164 + 7.319 p < 0.00005 - The product of the invention shows analgesic activity, but is less potent than dextropropoxyphene.
2. Chemical analgesia
The analgesic effect has been studied in white Swiss I.C.R. mice, with the acetic acid writhing technique, using batches of 10 mice. The products under study were administered intraperitoneally, and after 30 minute 0.25 ml of 1% acetic acid was injected intraperitoneally. A batch of control animals received only the acetic acid.
The number of writhes in each mouse were noted 20 minutes after the acetic acid was administered. The results are shown in Table III.
TABLE III
Significance of differences No. No. of writhes Dextropropoxy Treatment Dose x # S.E.M. Control phene Control - 130 i 7.764 - I, R=H 25 mg/kg 85.3 j13.915 p < O.02 N.S.
Dextropro poxyphene | 25 mg/kg 68.4 + 5.258 p < 0.00005 The product of the invention shows substantially the same analgesic activity as dextropropoxyphene.
The invention therefore includes within its scope pharmaceutical compositions comprising a compound of the formula I or a pharmacologically acceptable acid addition salt thereof in association with a compatible pharmaceutically acceptable carrier, for example in the form of a tablet, pill, capsule, syrup, elexir, or sterile injectable solution or suspension.
Claims (8)
1. 7,10 - Dimethyl - 5,9 - imino - 4,5,8,9 - tetrahydro - cyclooct[b]thiophenes of the formula:
in which R is hydrogen or alkyl and their pharmacologically acceptable acid addition salts.
2. 7,10 - Dimethyl - 5,9 - imino - 4,5,8,9 - tetrahydro - cyclooct[b]thiophene and its pharmacologically acceptable acid addition salts.
3. 6,7,10 - Trimethyl - 5,9 - imino - 4,5,8,9 - tetrahydro - cyclooct[b]thiophene and its pharmaceutically acceptable acid addition salts.
4. A process for the preparation of a 7,10 - dimethyl - 5,9 - imino - 4,8,9,10tetrahydro - cyclooct [b] thiophene as claimed in claim 1 which comprises reacting 3thienylmagnesium bromide with an N - methylpyridinium iodide of the formula:
in which R is as defined in claim 1, to give an unstable dihydropyridine intermediate which is converted without isolation into the desired 7,10 - dimethyl - 5,9 - imino4,8,9,10 - tetrahydro - cyclooct[b]thiophene by-treatment with an acid.
5. Process according to claim 4 in which the 3 - thienylmagnesium bromide is reacted with the N-methylpyridinium iodide in anhydrous ether under an inert atmosphere at reflux temperature.
6. Process according to claim 4 substantially as described in Example 1.
7. A compound as claimed in claim 1 when prepared by the process of any of claims 4 to 6.
8. A pharmaceutical composition comprising a compound as claimed in claim 1, 2, 3 or 7 in association with a compatible pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES457780A ES457780A1 (en) | 1977-04-14 | 1977-04-14 | 7,10-dimethyl-5,9-imino-4,5,8,9-tetrahydro-cycloocta(b)-thiophenes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1582688A true GB1582688A (en) | 1981-01-14 |
Family
ID=8473545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB13838/78A Expired GB1582688A (en) | 1977-04-14 | 1978-04-07 | 7,10-dimethyl-5,9-imino-4,5,8,9-tetrahydro-cycloocta(b)-thiophenes |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS53137996A (en) |
| DE (1) | DE2814645C3 (en) |
| ES (1) | ES457780A1 (en) |
| FR (1) | FR2387233A1 (en) |
| GB (1) | GB1582688A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9416141B2 (en) | 2012-09-28 | 2016-08-16 | University Of Washington Through Its Center For Commercialization | Compounds and methods for preventing, treating and/or protecting against sensory hair cell death |
| US9493482B2 (en) | 2015-02-06 | 2016-11-15 | University Of Washington | Compounds and methods for preventing or treating sensory hair cell death |
-
1977
- 1977-04-14 ES ES457780A patent/ES457780A1/en not_active Expired
-
1978
- 1978-04-05 DE DE2814645A patent/DE2814645C3/en not_active Expired
- 1978-04-05 FR FR7810068A patent/FR2387233A1/en not_active Withdrawn
- 1978-04-07 GB GB13838/78A patent/GB1582688A/en not_active Expired
- 1978-04-12 JP JP4225478A patent/JPS53137996A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9416141B2 (en) | 2012-09-28 | 2016-08-16 | University Of Washington Through Its Center For Commercialization | Compounds and methods for preventing, treating and/or protecting against sensory hair cell death |
| US9902738B2 (en) | 2012-09-28 | 2018-02-27 | University Of Washington Through Its Center For Commercialization | Compounds and methods for preventing, treating and/or protecting against sensory hair cell death |
| US9493482B2 (en) | 2015-02-06 | 2016-11-15 | University Of Washington | Compounds and methods for preventing or treating sensory hair cell death |
| US10399994B2 (en) | 2015-02-06 | 2019-09-03 | University Of Washington | Compounds and methods for preventing or treating sensory hair cell death |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2814645B2 (en) | 1979-11-29 |
| JPS53137996A (en) | 1978-12-01 |
| FR2387233A1 (en) | 1978-11-10 |
| DE2814645C3 (en) | 1980-07-31 |
| DE2814645A1 (en) | 1978-10-19 |
| ES457780A1 (en) | 1978-08-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |