IL99782A - 2-halo-9-(hetero) aryl-ergolines their production and pharmaceutical compositions containing them - Google Patents
2-halo-9-(hetero) aryl-ergolines their production and pharmaceutical compositions containing themInfo
- Publication number
- IL99782A IL99782A IL9978291A IL9978291A IL99782A IL 99782 A IL99782 A IL 99782A IL 9978291 A IL9978291 A IL 9978291A IL 9978291 A IL9978291 A IL 9978291A IL 99782 A IL99782 A IL 99782A
- Authority
- IL
- Israel
- Prior art keywords
- phenyl
- compound
- acid addition
- formula
- free base
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Electromagnets (AREA)
- Fixed Capacitors And Capacitor Manufacturing Machines (AREA)
- Soft Magnetic Materials (AREA)
Abstract
Ergoline derivatives of the formula I <IMAGE> in which R1, R2 and R3 are as defined in the description, their preparation and use as therapeutics.
Description
99782/2 "tmN η^Όηη mnpn -p om ΏΏΤ ,ΐ",ι7 ΊΚ-ι ,'ΊΝ( υπ)-9-ιι7η-2 ηπ^ιη 2-Halo-9-(hetero)aryl-ergoline, their production and pharmaceutical compositions containing them SANDOZ AG., C: 84547/9 99782/2 )mx Π^ΌΏΠ rnnpn ^-p oni χηηη ,l7i3iN-,7 N(npn)-9-i' n-2 ππ^π 2-Halo-9-(hetero)aryl-ergoline, their production and pharmaceutical compositions containing them SANDOZ AG., C: 84547/9 99782/2 - 1 - The present invention relates to new ergoline derivatives.
More particularly the invention provides compounds of formula I, wherein Ri is hydrogen or (C1_4)alkyl, R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C1_4 )alkyl, (Ci_4) alkoxy or trifluoromethyl and R3 is chlorine, bromine or iodine, in free base or acid addition salt form.
Compounds similar to those of formula (I), but being un-substituted at the 2-position and having dopaminergic (dopamine agonistic) activity are known from DE 3900947-A1. It has now surprisingly been found that the 2-halogenated compounds of the present invention exhibit dopamine antagonistic activity. - 2 - 100-7692 In accordance with usual practice in the literature, the above representation of formula I embraces the isomers with the configuration as indicated, as well as their antipodes. The invention covers both antipodes as well as their mixtures, e.g. their racemic mixtures.
Any alkyl or alkoxy preferably has one or two carbon atoms and especially one.
Ri is preferably alkyl, particularly methyl.
R2 is preferably phenyl, particularly unsubstituted phenyl.
R3 is preferably chlorine.
The preferred compound is the (+)-[5R(5P,9a,10a)]-2-chloro-6-methyl-9-phenyl-ergoline in free base or acid addition salt form.
The invention also provides a process for the production of a compound of formula I or an acid addition salt thereof, which includes the step of halogenating a compound of formula II, wherein Ri and R2 are as defined above and recovering the resultant compound of formula I in free base or acid addition salt form. - 3 - 100-7692 The halogenation of the compounds of formula II may take place i accordance with methods well known from the chemistry of ergot alkaloids.
Working up of the reaction mixtures obtained according to the above process, and purification of the compounds of formula I thus obtained, may be effected in accordance with known methods.
The racemates may be separated into the individual optically active components, using known methods, e.g. formation of acid addition salts with optically active acids, and fractiona- ed crystallisation of the diastereoisomeric acid addition salts. Optically pure compounds of formula I may also be obtained from optically pure starting materials.
Acid addition salts can be produced from the free base forms in known manner, and vice versa.
The starting compounds of formula II may be produced in accordance with the following reaction scheme, using known methods, e.g. as described in the following example 1: - 4 - 100-7692 - 5 - 100-7692 Insofar as the production of the starting products is not described, these are known or they may be produced by known processes or in analogous manner to known processes.
The new compounds in free base or pharmaceutically acceptable acid addition salt form, hereinafter referred to as compounds according to the invention, exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
The compounds according to the invention have in particular dopamine-antagonistic activity in vivo on the central nervous system, which is demonstrated in the following animal models: Using cerebral dialysis [method of A. Imperato and G. Di Chiara, European Journal of Pharmacology, 156 (1988) 385 - 393] on freely moving rats, a significant increase in dopamine release is established at doses of ca. 1 to 5 mg/kg i.p.
On the mouse, at doses of ca. 2 mg/kg s.c. or p.o., there was observed a significant inhibition of rearing induced by subcutaneous administration of 0.5 mg/kg apomorphine.
On the rat, at doses of ca. 1 to 10 mg/kg p.o. or s.c. or ca. 0.1 to 1 mg/kg i.p., the compounds according to the invention inhibit the locomotor activity increase which was induced by administering 10 mg/kg p.o. of the Di-agonist (-)-(6aR, 12bR)-4,6, 6a, 7 ,8, 12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine. In this test, the substance to be tested is applied one hour before the Di-agonist, and the locomotor activity is measured under red light using photoelectric cells.
The compounds according to the invention can therefore be used as dopamine-antagonists, e.g. in the treatment of schizophrenia. - 6 - 100-7692 An indicated daily dosage is in the range from about 10 to 200 mg, especially about 40 to 160 mg, of a compound according to the invention, together with solid or liquid carriers or diluents.
In accordance with the foregoing, the present invention also provides a compound according to the invention, for use as a pharmaceutical, e.g. for the treatment of schizophrenia.
The present invention furthermore provides a pharmaceutical composition comprising a compound according to the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner.
In the following examples, all temperatures are uncorrected and are in degrees Centigrade. - 7 - 100-7692 EXAMPLE 1; (+)-[5R(5p,9ct, 10α) ]-2-chloro-6-methyl-9-phenyl- ergoline a) (-)-(2aS)-l-benzoyl-4-methylamino-l,2,2a,3-tetrahydro-benz- [c,d]indole 12 g of raethylamine are introduced at 0 - 5° into a solution of 20 g (73 mmol) of (+)-l-benzoyl-l,2,2a,3,4,5-hexahydro-4- ketobenz[c,d] indole and 2 g of montmorillonite (K10) catalyst in 200 ml of tetrahydrofuran. After stirring for 5 hours at 0°, the solution is filtered, the solvent is concentrated by evaporation and recrystallized from methylene chloride/ether. The title compound thus obtained melts at 163° (decomp.). [α]ϋ20 = -154° (c = 1 in methylene chloride). b) (-)-[3S(9a)]-l-benzoyl-2,3-dihydro-5,10-dldehydro-7-oxo- 6-methy1-9-pheny1-ergoline 12.5 g (75 mmol) of cinnamic acid chloride, dissolved in 60 ml of methylene chloride, are added in drops at -20° to a solution of 20.9 g (72 mmol) of the compound obtained under a) and 11 ml (130 mmol) of pyridine in 400 ml of methylene chloride. After stirring for 3½ hours, the reaction solution is washed with water, 2 N hydrochloric acid and saturated KHCO3. After drying over magnesium sulphate, the yellow-brown oil is crystallized with acetone/pentane. M.p.: 248 - 250°. D20 = -149.3° (c = 1 in methylene chloride). c) (+)-[3S(9a) ]-l-benzyl-2,3-dihydro-5, 10-didehydro-6-methyl-9- phenyl-ergoline Aluminium hydride is produced by adding 10.1 g (100 mmol) of sulphuric acid in drops at -30° to a suspension of 7.8 g (200 mmol) of lithium aluminium hydride in 175 ml of tetra- - 8 - 100-7692 hydrofuran. 17 g (41 mmol) of the compound obtained under b) are added in drops to this suspension at 15 - 20° over the course of 30 minutes. After stirring for 2 hours, 25 ml of saturated Na2S04 solution and 10 ml of cone. NaOH are added in drops in succession at 0°. After filtration and evaporation of the solvent, the residue is crystallized from ether/pentane, m.p.: 144 - 146°. [a]D20 = 111.5° (c = 1 in methylene chloride). d) (-)-[3S(5β,9a, 10β)]-l-benzyl-2,3-dihydro-6-methyl-9-pheny1- ergoline 3.4 g of NaCNBH3 are added at 0° to a solution of 14 g (35.6 mmol) of the compound obtained under c) and 50 mg of brom-cresol green in 450 ml of tetrahydrofuran/methanol (2:1). The pH is maintained at 5 by adding 14 ml of 4.3 N hydrochloric acid in ethanol. After 2½ hours, the solution is concentrated by evaporation, rendered alkaline with saturated 2CO3 and extracted with methylene chloride. After drying and evaporating, yellow crystals with a m.p. of 89 - 92° are obtained. [a]D20 = -39.9° (c = 1 in methylene chloride). e) (-)-[3S(5β,9a, lOct)]-l-benzyl-2,3-dihydro-6-methy1-9-pheny1- ergoline A solution of 12 g (32 mmol) of the compound obtained under d), 8.5 g (32 mmol) of 18-Crown-6 and 3.6 g (32 mmol) of potassium-t.-butylate in 250 ml of abs. dimethyl sulphoxide is stirred for 18 hours at room temperature. After dilution with 500 ml of ice water, extraction takes place 3 x with ethyl acetate and the organic phases are washed 1 x with water, dried over magnesium sulphate and concentrated by - 9 - 100-7692 evaporation. The dark, brown oil is recrystallized from acetone/pentane. M.p.: 125 - 127°. [a]D20 = -107.4° (c = 1 in methylene chloride). f) (-)-[3S(5 , 9a, 10a) ]-2, 3-dihydro-6-methyl-9-phenyl-ergoline A solution of 6.0 g (15 mmol) of the compound obtained under e), 30 ml of 1 N hydrochloric acid and 500 mg of Pd catalyst (10%) in 100 ml of methanol is hydrogenated at room temperature. After filtration of the catalyst, the solution is mixed with 100 ml of 2 N sodium hydroxide and extracted with methylene chloride. After drying over magnesium sulphate, the organic phases are concentrated by evaporation. The crystalline residue melts at 158 - 160°. [a]D20 = -86.6° (c = 1 in methylene chloride). g) (+)-[5R(9a, 10a) ]-6-methyl-9-phenyl-ergoline A solution of 4.5 g (14.8 mmol) of the compound obtained under f), 5.2 g (44.3 mmol) of indole and 2.8 g of benzene- selenic acid anhydride in 90 ml of tetrahydrofuran is stirred for 4 hours at room temperature. After concentration by evaporation, the residue is recrystallized from acetone/- ether. M.p. > 290°. [a]D20 = 31.0° (c = 0.5 in pyridine). h) (+)-[5R(5β,9a,10a)]-2-chloro-6-methyl-9-phen l-ergoline 1.76 ml of BF3.etherate are added at -10° to a suspension consisting of 2 g of (+)-[5R(5g,9a,10a)]-6-methyl-9-phenyl- ergoline in 30 ml of acetonitrile. 0.54 ml of sulphuryl chloride are added in drops at 0° to the homogeneous solution over the course of 5 minutes. After stirring for 30 minutes, working up is effected by adding 5 ml of 4 N sodium carbonate - 10 - 100-7692 solution, extracting with ethyl acetate, drying over sodium sulphate, concentrating by evaporation and recrystallizing from methanol/acetone. M.p.: from 230° decomposition. [a]D20 = 30.8° (c = 0.5 in pyridine).
The following enantiomer is obtained analogously to example 1: The following racemic forms are obtained analogously to example 1, but starting with (+)-l-benzoyl-l,2,2a,3,4,5-hexa-hydro-4-ketobenz[c,d] indole: Example R2 R3 M.p. (base) 3 CH3 phenyl CI 262 - 264° 4 CH3 p-F-phenyl CI 251 - 254° 5 CH3 p-CF3 -phenyl CI 252 - 256° (decomp.) 6 CH3 phenyl Br 246 - 248° 7 CH3 phenyl 223° (decomp.)
Claims (1)
1. A compound of formula I H wherein Rj. is hydrogen or (Ci_4)alkyl, R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (Ci_4)alkyl, (Ci_4) alkoxy or trifluoromethyl and R3 is chlorine, bromine or iodine, in free base or acid addition salt form. A compound of claim 1 wherein Rx , R2 and R3 are respectively CH3 , p-Cl-phenyl and CI; CH3 , phenyl and CI; CH3, p-F-phenyl and Cl; CH3, p-CF3-phenyl and Cl; CH3 , phenyl and Br; or CH3 , phenyl and > in free base or acid addition salt form. A compound of claim 1 which is the (+)-[5R(5 ,9a, 10a) ]- 2-chloro-6-methyl-9-phenyl-ergoline in free base or acid addition salt form. - 12 - 100-7692 A compound according to any one of claims 1 to 3, for use as a pharmaceutical. A compound according to any one of claims 1 to 3, for use as a dopamine antagonist. A compound according to any one of claims 1 to 3, for use in the treatment of schizophrenia. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 in pharmaceutically acceptable form, in association with a pharmaceutical carrier or diluent. A process for the production of a compound of claim 1, which includes the step of halogenating a compound of formula II H wherein Rj. and R2 are as defined in claim 1, and recovering the resultant compound of formula I in free base or acid addition salt form. A compound of formula I in free base or acid addition salt form, as defined in claim 1, whenever produced by the process of claim 8.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4033496A DE4033496A1 (en) | 1990-10-20 | 1990-10-20 | NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND USE |
Publications (2)
Publication Number | Publication Date |
---|---|
IL99782A0 IL99782A0 (en) | 1992-08-18 |
IL99782A true IL99782A (en) | 1995-05-26 |
Family
ID=6416775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL9978291A IL99782A (en) | 1990-10-20 | 1991-10-18 | 2-halo-9-(hetero) aryl-ergolines their production and pharmaceutical compositions containing them |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP0483063B1 (en) |
JP (1) | JPH04257583A (en) |
KR (1) | KR920008038A (en) |
AT (1) | ATE111099T1 (en) |
AU (1) | AU638874B2 (en) |
CA (1) | CA2053712A1 (en) |
CZ (1) | CZ279954B6 (en) |
DE (2) | DE4033496A1 (en) |
DK (1) | DK0483063T3 (en) |
ES (1) | ES2059097T3 (en) |
FI (1) | FI914942A (en) |
HU (1) | HU210805B (en) |
IE (1) | IE913663A1 (en) |
IL (1) | IL99782A (en) |
MX (1) | MX9101659A (en) |
MY (1) | MY131110A (en) |
NZ (1) | NZ240280A (en) |
PT (1) | PT99286A (en) |
RO (1) | RO106992B1 (en) |
ZA (1) | ZA918346B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102245625A (en) | 2008-10-17 | 2011-11-16 | 威斯康星旧生研究基金会 | Method of making biologically active alpha-beta peptides |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1517973A (en) * | 1974-07-19 | 1978-07-19 | Sandoz Ltd | 6-methyl-8alpha-n,n-dimethylsulphamoylaminoergoline i |
AR223177A1 (en) * | 1978-05-23 | 1981-07-31 | Lilly Industries Ltd | PROCEDURE FOR PREPARING INDOLO-ISOQUINOLINE DERIVATIVES |
HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
GB8702364D0 (en) * | 1987-02-03 | 1987-03-11 | Erba Farmitalia | Ergolinyl heterocycles |
HUT51275A (en) * | 1988-01-26 | 1990-04-28 | Sandoz Ag | Process for producing ergolin derivatives and pharmaceutical compositions containing them |
CA2049053A1 (en) * | 1990-01-25 | 1991-07-26 | Sergio Mantegani | Process for preparing ergoline derivatives |
-
1990
- 1990-10-20 DE DE4033496A patent/DE4033496A1/en not_active Withdrawn
-
1991
- 1991-10-10 HU HU913212A patent/HU210805B/en not_active IP Right Cessation
- 1991-10-16 MY MYPI91001908A patent/MY131110A/en unknown
- 1991-10-17 EP EP91810800A patent/EP0483063B1/en not_active Expired - Lifetime
- 1991-10-17 ES ES91810800T patent/ES2059097T3/en not_active Expired - Lifetime
- 1991-10-17 DE DE59102829T patent/DE59102829D1/en not_active Expired - Fee Related
- 1991-10-17 CZ CS913153A patent/CZ279954B6/en unknown
- 1991-10-17 DK DK91810800.2T patent/DK0483063T3/en active
- 1991-10-17 AT AT91810800T patent/ATE111099T1/en not_active IP Right Cessation
- 1991-10-18 PT PT99286A patent/PT99286A/en not_active Application Discontinuation
- 1991-10-18 FI FI914942A patent/FI914942A/en not_active Application Discontinuation
- 1991-10-18 MX MX9101659A patent/MX9101659A/en unknown
- 1991-10-18 IE IE366391A patent/IE913663A1/en unknown
- 1991-10-18 NZ NZ240280A patent/NZ240280A/en unknown
- 1991-10-18 AU AU86006/91A patent/AU638874B2/en not_active Ceased
- 1991-10-18 CA CA002053712A patent/CA2053712A1/en not_active Abandoned
- 1991-10-18 ZA ZA918346A patent/ZA918346B/en unknown
- 1991-10-18 JP JP3270854A patent/JPH04257583A/en active Pending
- 1991-10-18 IL IL9978291A patent/IL99782A/en not_active IP Right Cessation
- 1991-10-19 KR KR1019910018481A patent/KR920008038A/en not_active Application Discontinuation
-
1992
- 1992-02-13 RO RO9200149A patent/RO106992B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
MX9101659A (en) | 1994-01-31 |
ATE111099T1 (en) | 1994-09-15 |
PT99286A (en) | 1992-08-31 |
DK0483063T3 (en) | 1994-11-14 |
CZ279954B6 (en) | 1995-09-13 |
IE913663A1 (en) | 1992-04-22 |
DE59102829D1 (en) | 1994-10-13 |
ES2059097T3 (en) | 1994-11-01 |
EP0483063B1 (en) | 1994-09-07 |
KR920008038A (en) | 1992-05-27 |
ZA918346B (en) | 1993-04-19 |
HU210805B (en) | 1995-07-28 |
HUT60495A (en) | 1992-09-28 |
CA2053712A1 (en) | 1992-04-21 |
MY131110A (en) | 2007-07-31 |
NZ240280A (en) | 1993-09-27 |
IL99782A0 (en) | 1992-08-18 |
EP0483063A1 (en) | 1992-04-29 |
CS315391A3 (en) | 1992-05-13 |
FI914942A (en) | 1992-04-21 |
AU638874B2 (en) | 1993-07-08 |
RO106992B1 (en) | 1993-08-30 |
FI914942A0 (en) | 1991-10-18 |
JPH04257583A (en) | 1992-09-11 |
AU8600691A (en) | 1992-04-30 |
DE4033496A1 (en) | 1992-04-23 |
HU913212D0 (en) | 1992-01-28 |
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Legal Events
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RH | Patent void |