CA1099214A - Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use - Google Patents
Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical useInfo
- Publication number
- CA1099214A CA1099214A CA279,610A CA279610A CA1099214A CA 1099214 A CA1099214 A CA 1099214A CA 279610 A CA279610 A CA 279610A CA 1099214 A CA1099214 A CA 1099214A
- Authority
- CA
- Canada
- Prior art keywords
- verbenone
- myrtenal
- compounds
- pinocarveol
- tion
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
-
- 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
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C45/82—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Balsamics such as verbenone, myrtenal and pino-carveol can be prepared from an oxidized mixture of ter-penes by subjecting such a mixture coming from the oxida-tion of pinenes to a strong oxidizing treatment followed by the separation of the carbonyl compounds and the vacuum fract-ional distillation of the resultant mixture so as to recover the expected compounds in a state of very high purity. The balsamic compounds in question are useful in the treatment of bronchopneumonial diseases and each of such compounds has specific indications of its own according to the individual pathalogical pattern concerned.
Balsamics such as verbenone, myrtenal and pino-carveol can be prepared from an oxidized mixture of ter-penes by subjecting such a mixture coming from the oxida-tion of pinenes to a strong oxidizing treatment followed by the separation of the carbonyl compounds and the vacuum fract-ional distillation of the resultant mixture so as to recover the expected compounds in a state of very high purity. The balsamic compounds in question are useful in the treatment of bronchopneumonial diseases and each of such compounds has specific indications of its own according to the individual pathalogical pattern concerned.
Description
CASE Y ~I P
~his invention relates to the prepara-tio:n o-~ verbe-none~
myrtenal and pinocarveol starting from oxidized terpene mixtures~
and their use in the therapeutics of bronchopneumonial d.i.seases.
The preparation of verbenone and myrtenal starting from alpha-pinene by oxidizing self-catalysis in the presence of salts of chromiumg cobalt, and o-thers has been repeatedly described with yield of from 15% to 20%o One of the reasons for -the low reaction yields is the formation of side-products of the homolytic reaction (radicalic reaction) such as verbenols and myrtenolsg these latter being alcohols which cannot be further oxidized to the ketones in the specific reaction medi~mO
In the Swiss Pa-tent Specification N 542 163 of the same applican-ts hereof~ a method is described for the preparation of ter-pene frac~ions which are useful in -the treatment of bronchopneumo-nial diseases~ said method being based on the oxidation o mixtures which predominantly contain alpha-pinene~ More particularly, with the method according to the above mentioned Swiss patent9 two terpene fractions are ob-tainedg~which~ dis-till.grespectivelyg in the temperature ranges of from 40C to 600C and of from 650C to 103C.
It has now been found9 and this is the subject-matter of the present inventiong that such ox1dation mixtures can be subjected to an additional treatment whichg in the case of the preparation of verbenone and myrtenalg is a fur-ther oxidation -treatment to be carried out with chromium trioxide in sulfl1ric acidg whereas~ in the case of pinocarveOl , it consists in opening the oxyrane ring of the alpha-pinene epoxide and subseqllent -transposition of the resultant compound~
It has been found, in Çac-tg that in the case of verbenone in and myrtenal~ the oxidizing treatment with chromium trioxide in sulfuric acid of the oxidation mlx-tures of the Swiss patent afore-mentioned, the oxidative method goes on with a totc~l disappearance of '~
9~
the alcohols and a formation of ea~bonyl. compounds (ketolles and aldehydes)0 Upon treatment with chromiLLm -trlo~i.de in sulfuric acld an :isolati.on of -the as-obtained ketone bo~'L,es is accomplish~
ed 'by a bis~Llfite complex and -ractional distillation.
In the case of pinocarveolthe opening of the oxyrane ring is preferab].y carried out with alu.mi.n~ isopropoxide~ whereafter the removal of the carbonyl compounds and the fractional. distilla-tion are proceedecl with in o:rcler -to isolate pinocarveolO
As regards the therapeuti.cal u.se of the compounds obtained with the me-thod according to the present inven-tion7 the thera-peutical use of the terpene fractions di.sclosed .in the Swiss patent 542 163 is already known9 ancl more particularly the use of the fra,tion which clisti~s in -the 65C-103C range (t~ be indicated hereinafter as the "frac-tion 2"~o The balsamic ancl analept.ic actlons of such fraction 2 are already known9 the therapeutical use of such rac-tion be.ing just due to such actionsO
- In addi.tion -to the uncertainty from a scienti.fic standpoint as to the exact identification o th.e acti-ve principles which are responsible for the therepeutical aetivity of pharmaceu-tical compo-sitions based on such fraction 29 the drawback is apparent9 from an industrial viewpoint~ of working on a mixture of compounds having a eomposition whieh is ehangeable9 even within a certain rangeO In addition~ the fact is worth noting that the pharmaceutical composi-tion containing the fraction 2 has a general. indication as a 'balsa-mic~ along with a few side acti~i.ti.es9 without any possibility being afforded of-exal.ting bhe one of these acti.vities p~eferably over the others3 or of imp-roving the general activi.ty~
It has now heen found~ and -th:iæ :is anot.ller as~)ects of the present .inventlon9 tha-t -the te:rpene compoLmds in question po~ssessg in additi.on to a~ome alrea~y known actionæ~ su.ch as th.e 'balsamic and the analeptlc ac-tion.s~ also apprec~.i.a'b:l.e bronchodilati.ng~ antl-z~ ~
phlOgisticg artiexudat.ive and a:ntiaggregative~ ac-tionsO
The demonstration of -the pharmacological ac-tivity of ver-benoneg pi~ocarveol a~d myr-ter~al is based o-~. the fol,lowing para -meters :
1. Acute toxicity Act.ion o~ t:h.e bronehial. muscles Ac-tion on the in-flamrnatory process 4 0 Action on haemolysis Ac-tion on th.e thrombocyte aggregation Ant.ibacterial action~
ln all these -teOEts5 -the acti~ity of' the diferent compounds has been compared,wi-th that of the -raction 2 as def'ined above and with that of therc~peutical preparatïons based on terpene alcohols~
more particularly sobrer~la The individual compounds the subject of the present invention will ~e now consi.dered :
A - Verbenone 1~ Acute Toxicit~ O ~
TABLE 1 reports the LD$o (and the -fiducial limits 95~ as determined accord.ing to the Lltchfield and W:ilcoxon method (JO Pharma-col. Expo TherO~ 96~ 999 1949)g by admin~ster~7ng verbenone both intraperitoneally (i~po ) and orally (p~O) to groups of 10 mice and 6 rabbits per dose~
T A B L E
COMPOUND Animals Sex Administra- LD Gleason classi-tion route mi~igrams fication ~" W o Mice mal.e iopo 361 (337~-385~ Poor fema:L _ ~,,_~ ~"_ ~,_ __~
VERBENONE Mice male pOo~ 1410 (l.'L6$~1706) 51:i.gh.t 3 female 1,530 (1124-1912) ~ O
Rabbit~ ma~Le i~po 3l~ (250-384) Poor female 232 (l97-274) Rabbi-ts rnale pOOD 790 ~608-1027) Poor female 65.5 (57~-/533 On the basls O:e -these data -the verbenone appears a well tolera-ted eompound~ since its toxlcity is of the slight or poor magnitude aecording to the Gleason classi.-fieation~ as related to the anim.al spee.i.es and the administration route~
~his invention relates to the prepara-tio:n o-~ verbe-none~
myrtenal and pinocarveol starting from oxidized terpene mixtures~
and their use in the therapeutics of bronchopneumonial d.i.seases.
The preparation of verbenone and myrtenal starting from alpha-pinene by oxidizing self-catalysis in the presence of salts of chromiumg cobalt, and o-thers has been repeatedly described with yield of from 15% to 20%o One of the reasons for -the low reaction yields is the formation of side-products of the homolytic reaction (radicalic reaction) such as verbenols and myrtenolsg these latter being alcohols which cannot be further oxidized to the ketones in the specific reaction medi~mO
In the Swiss Pa-tent Specification N 542 163 of the same applican-ts hereof~ a method is described for the preparation of ter-pene frac~ions which are useful in -the treatment of bronchopneumo-nial diseases~ said method being based on the oxidation o mixtures which predominantly contain alpha-pinene~ More particularly, with the method according to the above mentioned Swiss patent9 two terpene fractions are ob-tainedg~which~ dis-till.grespectivelyg in the temperature ranges of from 40C to 600C and of from 650C to 103C.
It has now been found9 and this is the subject-matter of the present inventiong that such ox1dation mixtures can be subjected to an additional treatment whichg in the case of the preparation of verbenone and myrtenalg is a fur-ther oxidation -treatment to be carried out with chromium trioxide in sulfl1ric acidg whereas~ in the case of pinocarveOl , it consists in opening the oxyrane ring of the alpha-pinene epoxide and subseqllent -transposition of the resultant compound~
It has been found, in Çac-tg that in the case of verbenone in and myrtenal~ the oxidizing treatment with chromium trioxide in sulfuric acid of the oxidation mlx-tures of the Swiss patent afore-mentioned, the oxidative method goes on with a totc~l disappearance of '~
9~
the alcohols and a formation of ea~bonyl. compounds (ketolles and aldehydes)0 Upon treatment with chromiLLm -trlo~i.de in sulfuric acld an :isolati.on of -the as-obtained ketone bo~'L,es is accomplish~
ed 'by a bis~Llfite complex and -ractional distillation.
In the case of pinocarveolthe opening of the oxyrane ring is preferab].y carried out with alu.mi.n~ isopropoxide~ whereafter the removal of the carbonyl compounds and the fractional. distilla-tion are proceedecl with in o:rcler -to isolate pinocarveolO
As regards the therapeuti.cal u.se of the compounds obtained with the me-thod according to the present inven-tion7 the thera-peutical use of the terpene fractions di.sclosed .in the Swiss patent 542 163 is already known9 ancl more particularly the use of the fra,tion which clisti~s in -the 65C-103C range (t~ be indicated hereinafter as the "frac-tion 2"~o The balsamic ancl analept.ic actlons of such fraction 2 are already known9 the therapeutical use of such rac-tion be.ing just due to such actionsO
- In addi.tion -to the uncertainty from a scienti.fic standpoint as to the exact identification o th.e acti-ve principles which are responsible for the therepeutical aetivity of pharmaceu-tical compo-sitions based on such fraction 29 the drawback is apparent9 from an industrial viewpoint~ of working on a mixture of compounds having a eomposition whieh is ehangeable9 even within a certain rangeO In addition~ the fact is worth noting that the pharmaceutical composi-tion containing the fraction 2 has a general. indication as a 'balsa-mic~ along with a few side acti~i.ti.es9 without any possibility being afforded of-exal.ting bhe one of these acti.vities p~eferably over the others3 or of imp-roving the general activi.ty~
It has now heen found~ and -th:iæ :is anot.ller as~)ects of the present .inventlon9 tha-t -the te:rpene compoLmds in question po~ssessg in additi.on to a~ome alrea~y known actionæ~ su.ch as th.e 'balsamic and the analeptlc ac-tion.s~ also apprec~.i.a'b:l.e bronchodilati.ng~ antl-z~ ~
phlOgisticg artiexudat.ive and a:ntiaggregative~ ac-tionsO
The demonstration of -the pharmacological ac-tivity of ver-benoneg pi~ocarveol a~d myr-ter~al is based o-~. the fol,lowing para -meters :
1. Acute toxicity Act.ion o~ t:h.e bronehial. muscles Ac-tion on the in-flamrnatory process 4 0 Action on haemolysis Ac-tion on th.e thrombocyte aggregation Ant.ibacterial action~
ln all these -teOEts5 -the acti~ity of' the diferent compounds has been compared,wi-th that of the -raction 2 as def'ined above and with that of therc~peutical preparatïons based on terpene alcohols~
more particularly sobrer~la The individual compounds the subject of the present invention will ~e now consi.dered :
A - Verbenone 1~ Acute Toxicit~ O ~
TABLE 1 reports the LD$o (and the -fiducial limits 95~ as determined accord.ing to the Lltchfield and W:ilcoxon method (JO Pharma-col. Expo TherO~ 96~ 999 1949)g by admin~ster~7ng verbenone both intraperitoneally (i~po ) and orally (p~O) to groups of 10 mice and 6 rabbits per dose~
T A B L E
COMPOUND Animals Sex Administra- LD Gleason classi-tion route mi~igrams fication ~" W o Mice mal.e iopo 361 (337~-385~ Poor fema:L _ ~,,_~ ~"_ ~,_ __~
VERBENONE Mice male pOo~ 1410 (l.'L6$~1706) 51:i.gh.t 3 female 1,530 (1124-1912) ~ O
Rabbit~ ma~Le i~po 3l~ (250-384) Poor female 232 (l97-274) Rabbi-ts rnale pOOD 790 ~608-1027) Poor female 65.5 (57~-/533 On the basls O:e -these data -the verbenone appears a well tolera-ted eompound~ since its toxlcity is of the slight or poor magnitude aecording to the Gleason classi.-fieation~ as related to the anim.al spee.i.es and the administration route~
2~ Bronchoclilat,i~LfL~
The verbenone has exhibitedg both in vitro and l vivo a pronounced bronchodilating ac-tîvity9 by vir-tue of which it distin-guishes in a statistically significallt way both o~er the other medi-einaL subs-tances present in the fraction 2 o:E the SWi3S patent 542 163 ancL over the referenoe terpene3 .ioso sobrerol~
a - in vit_ On the Guinea pig traehea~ isola-ted aceordlng to the techni.que by Costantine (J~Pharm.O PharmaeolO9 l7~ 384~ 1965)g the verbenone hrings about the relaxation oE the smooth tracheal muscles a-t the eoneentration of 125 to ~000 mierograms per milli.li-ter with an 20 intensity whieh is sig~ificantly higher than that of the terpenes of the fraetion 2 and also than th.at of sobrerol (TABLE 2)~ In add.itiong at coneentrations in t.he range of from lV 3M to 5010 it inhibits the histamine i.nduced eontractions o~ the isolated Guinea-pig trachea (Histamine 10 M~ see TABLE 3 3 o T A B L E
PereeIItages of re.Laxat.ion (a~erage -; standard de~iat.ion of 4 preparations3 of the .isolated Guinea-p.i.g traehea as brought about by eoncentrat:ions of L25-.500 and 2~0~0 mierogrrarrls per m:illiliterO
~Og~2~
COMPOUND :P~eparation3125 lug/ m3500 jLg /ml 27000 ~g/~ml VERBENONE aveO 26025 61~25 71037 stdOdev~2~39 2039 1015 F`RACTlON 2 ave~ 1305 33~75 52025 4 stcl"devO 1070 11,4C) 2~.95 SOBREROL aveO1087 5062 20~75 stdDdevO 1019 2013 1,49 _A B L E
Verbenone percentages of inhib.ition of the histaminic spasm due to rela~a-tion o-E the smooth tracheal muscles ~average ~
standard deviation of 4 preparations~ :
CONCENTRATION 10-3~ 501~ 3M
.Av.erage 2902 9608 Standard devia-tion 501 1696 . _ bo in vivo The verbenone injected intravenously in anes~thesi~ed dogs at dosages of -from oO6 milligrams per kilogram body wei.ght to 408 mgs /kg/how~ produces a pronounced recluction of the lung resistances as determinecl accorc~ng to the techniql~e by Diamond ~ArchO Int~
PharmacodynO~ 168g 239~ 19673 ~see TABLE 4). In addition7 verbe-none perfused intravenously in rabbits at the dose unit of 2~5 mls per kilogram bowo per minllte~ inhibit,s lih~ histamine induced experlmental bronc,hospam (~:Lstamine lOO mLcrog:rams per k.ilo~
gram bJw~ intravenously) to a de~ree ~:hi.ch is sta-t.is-ticall.y hi~he.r ~g2~
than that of the terpenes o~ t~le fract.ion 2 ancl also -t:han -tha-t o~ sobrerol (TABLE 5)~0 T A ~ L E ~
VERBENONE ~- Percentage red~ct:ions of the l.urlg Resist,ance by intravenous admini,stratlon to dogs (Average l Standard devi,ati.on o:r 4 an.imals ,) Do3age mgs /kg bow~ o~6 1~ 2~4 408 Ave.rage7~175 lOr85 220225 3006 Standard deviatlon60786 7~;7 180636 130507 l o T ~ B L E _5 Percentages of inhibîti.on of the h:istamine-lnduced broncho-spasm by intravenous perf-usion i.n rabbi-ts (ave,rage of 4 animals ' stand.ard deviation)O
Per~usion times COMPOUND 15 30 . 6 0 minutes m:inutes minutes ~____ _ _ _ VERBENONE average 36 ~ 2.54& 0 27 7 3 ~ 3 stdOdev~, lo65 9000 7017 . ~
FRACTION 2 average 16~,30 24.~20 38~92 s-tdOdevo 3~62 4039 3~67 ., , . _ , _ . _ ~ n . . . _ ., v . . . ~
SOBRERO:L a-verage 2ql5 L ol5 3~97 ~ stdqdevO 403C) 603~ 8tl73 3o An~i~inflammator;y ~ctivity ~ -In albine rats of the COBS (Charles R.i.ver) stoek~ verbenone as administered intraperito:nea,l.1y at the dosage o~' 30 mi.ll.igrams per k;logram bow J ~ in'hibits t'he experimen-tal oedem~ in th.e paw as ~ ~, ~39~
induced by carrageenin (Winter~ C~AO et al~ ProcO SocO Exp~
Biol. MedOg 111~ 544g 1962~)both in normal rats and in su~rarenal-ectomized rats to a degree which iS9 Erom the sta-tistical stand-point, significantly improved over those O-e the rac-tion 2 and of sobrerol (TABLE 6)o When adminis-tered intraperi-toneally in rats at the dosages o 36 and 120 milligrams per kilogram b.w~ verbenone displays an intense antiexudative activity in the experime:ntalJ t~rpentine -~-~
i~duced pleuritis (Hurley~ JO VO et alOg J~ PathOg 91~ 57531966) to a degree which can be compared to that of aspirin (TABLE 7)0 T A B ~ E_ _6 Anti~inflamma-tory activity on the carrageenin-induced oedema in ratsO ~
CO~POUND Dosage milligrams/kg bow~ % inhibition of plantar intraperitoneally oedema~ as after 4 hrs~
from adm.inistration (ave~+ S-tdOdevOon 6 ani.mals ..... .~ ... __._ _ _ . . . __. ~ ___ FR~CTION 2 3 21 ., .... ... _ . . ~ .. ...... .
Haemol~ytic activit~ in vitro O -Verbenone protects in vitro the red blood cells o e rats -rom the haemolysis as induced by capillary-active-agents (Tween 80) with an effective concentration 50% (EC 50) of 63905 micrograms per kg bowo (fiducial limits 95~ : 51800-760011)~
Antia~r~ative activity~ in vitro ~ - ~
Verbenoneg at conc~3ntrations of from 160 to 1.280 m.icrograms/
milli3.iter inhibits the thrombocyte aggregation Erom ADP in vi-trog evaluated according to the me-thod by Born and Cross (J~ Physi.ol~ 7 Londong 168~ 178~ 1963) to a degree which is higher t:han that Oe the terpenes of -the Fraction 2 and of sobrerol (TABLE 8)o T A B L E _ 7 Activity of Verbe:none on the Turpentine-Induced Pleuri-tis in Rats O -Intraperitoneal Exudate~ + StdODevO Inhlbition Signifi-administration mls 3 ~0 cativity Controls 1097 0024 (solvent) Aspirin 1030 0013 34 % ~ 0~01 (100 mgs/kg) Verbenone 1023 0024 3706% ~ OoOl (36 mgs /kg) Verbenone 0097 0022 50~1% .~OoOl (120 mgs ~'kg~
T A B L E __8 Thrombocyte aggregation inhibition percen-tage (average of repeated -tests)O-FINAL CONCENTRATIONS % INHIBITION
.
CONTROL o -: VERB~NONE 1280 ~1g/ml 100 '` " 640 " 44 " 320 " 6 " 160 ll 0 ____~
CONTROL
SOBREROL4000 " 32 " 200~ " 2~
" 1500 " 12 Il 1000 ~' 4 CONTROL O
FRACTION 2 1280 " 70 " 1016 " :l8 " 806 " 14 " 640 " O
9~
z~
6 D Antibacterial activit~
Yerbenone possesses a poor antibacterial activity on the Gram-positive and Gram-nega-tî.ve germs~ w.i-th a MIC (Mirnimum Irlhibitlng concen-tratioll ) of 800 micrograms/ml on _~eus and Escherichla coli (TABLE 9) and is as active as Fraction 2 ancl more active than sobrerolO
Minimum Inhibiting Concentrations (MIC) in micrograms per milliter . -Mieroorganism Staphylococcus Escherichia coli Compound aureus F`R~CTION 2 ~00 800 SOBREROL ~
Summing up~ the compo-und has proven -to possess a pro:nounced bronchodilating action~ by virtue of whic:h it distinguishes in a s-ta-tistically significant manner both over the other m.edicaments pre~
sen-t in ~raction 2 of Swiss Patent 542 163 and -the re-ference ter-pene (sobrerol)O
On aecount of these partieular properties~ ~e~benone is efect ive as the active ingredien-t oE a pharmaceutical preparation which is especially adapted for the trleatmen-t of bronchopneumonial diseases which are accompanied by an obstructiorl of -the respira-tory ehannels due -to in-flammation and i.nfectious causati.ve agentsO The dosage envisaged for therapeu.t:i-cal appliea-tions is irom 10 -to 100 milligrams dailyO
B - MYRTENAL
lo Acute to icit~ O ~
The I.D5n as determined accordi:ng -to the methocl by I.i-tchfield and Wilcoxo~J PharmacolD Expo TherO~ 969 99~ 1949) by aclm:inistering 10"
23.~
the myr-tenal întravenously -to groups of 10 mice was 170 milli-grams per kilogram bow~
2~ Bronchodilato~ etivit~
___ Myrtenal has shswng both l vitro and i.n vi-vo a fair broncho-di.l.ating activity~
a - in v _ro On the isolated Guinea pig trachea according to t:he tech-ni~lue by Costantine (J~ ParmO Pharmacol~ 17~ 384, 1965 )3 myrtenal determines the relaxation of the -tracheal smooth muscles a-t t:he concen-tration of 125~200 micrograms/ml. with an in-tensi-ty which is s-tatistically higher than -that of -the F:raction 2 and that o-f sobrerol (TABLE lO)o T A B L E lO
Percentage of relaxation (average ~ standard deviat:ion of 4 prepara-tions) o-f -the isolated Guinea~pig trachea as determined by concentrations of 125~500 and 2~000 micrograms/milliliterO
Compound Preparations 125 500 2~000 Nmicrogr/ml microgr/mlm.i.crogr/ml MYRTENAL 4 aveO 7~.S 4'?o5 ~2~5 stdOdeva 500 1500 2007 aveO13~5 33075 52025 stdOdev~1~70 1.49 2095 aveO 1087 So62 201~75 SOBR~ROL 4 stdOdeY~ 1019 2~13 1~49 b _- iD VlVO
~ yrtenal perfused intravenou.sly in rabbits at the dosage o-f.
205 millil~t~rs per kg bow~ per m:inute inhibi.ts -the exper-Lmental hi.stamirle~indu.ced bronchospasm (hi.stam.ine 100 m:ic:rograms/kg b.w.
The verbenone has exhibitedg both in vitro and l vivo a pronounced bronchodilating ac-tîvity9 by vir-tue of which it distin-guishes in a statistically significallt way both o~er the other medi-einaL subs-tances present in the fraction 2 o:E the SWi3S patent 542 163 ancL over the referenoe terpene3 .ioso sobrerol~
a - in vit_ On the Guinea pig traehea~ isola-ted aceordlng to the techni.que by Costantine (J~Pharm.O PharmaeolO9 l7~ 384~ 1965)g the verbenone hrings about the relaxation oE the smooth tracheal muscles a-t the eoneentration of 125 to ~000 mierograms per milli.li-ter with an 20 intensity whieh is sig~ificantly higher than that of the terpenes of the fraetion 2 and also than th.at of sobrerol (TABLE 2)~ In add.itiong at coneentrations in t.he range of from lV 3M to 5010 it inhibits the histamine i.nduced eontractions o~ the isolated Guinea-pig trachea (Histamine 10 M~ see TABLE 3 3 o T A B L E
PereeIItages of re.Laxat.ion (a~erage -; standard de~iat.ion of 4 preparations3 of the .isolated Guinea-p.i.g traehea as brought about by eoncentrat:ions of L25-.500 and 2~0~0 mierogrrarrls per m:illiliterO
~Og~2~
COMPOUND :P~eparation3125 lug/ m3500 jLg /ml 27000 ~g/~ml VERBENONE aveO 26025 61~25 71037 stdOdev~2~39 2039 1015 F`RACTlON 2 ave~ 1305 33~75 52025 4 stcl"devO 1070 11,4C) 2~.95 SOBREROL aveO1087 5062 20~75 stdDdevO 1019 2013 1,49 _A B L E
Verbenone percentages of inhib.ition of the histaminic spasm due to rela~a-tion o-E the smooth tracheal muscles ~average ~
standard deviation of 4 preparations~ :
CONCENTRATION 10-3~ 501~ 3M
.Av.erage 2902 9608 Standard devia-tion 501 1696 . _ bo in vivo The verbenone injected intravenously in anes~thesi~ed dogs at dosages of -from oO6 milligrams per kilogram body wei.ght to 408 mgs /kg/how~ produces a pronounced recluction of the lung resistances as determinecl accorc~ng to the techniql~e by Diamond ~ArchO Int~
PharmacodynO~ 168g 239~ 19673 ~see TABLE 4). In addition7 verbe-none perfused intravenously in rabbits at the dose unit of 2~5 mls per kilogram bowo per minllte~ inhibit,s lih~ histamine induced experlmental bronc,hospam (~:Lstamine lOO mLcrog:rams per k.ilo~
gram bJw~ intravenously) to a de~ree ~:hi.ch is sta-t.is-ticall.y hi~he.r ~g2~
than that of the terpenes o~ t~le fract.ion 2 ancl also -t:han -tha-t o~ sobrerol (TABLE 5)~0 T A ~ L E ~
VERBENONE ~- Percentage red~ct:ions of the l.urlg Resist,ance by intravenous admini,stratlon to dogs (Average l Standard devi,ati.on o:r 4 an.imals ,) Do3age mgs /kg bow~ o~6 1~ 2~4 408 Ave.rage7~175 lOr85 220225 3006 Standard deviatlon60786 7~;7 180636 130507 l o T ~ B L E _5 Percentages of inhibîti.on of the h:istamine-lnduced broncho-spasm by intravenous perf-usion i.n rabbi-ts (ave,rage of 4 animals ' stand.ard deviation)O
Per~usion times COMPOUND 15 30 . 6 0 minutes m:inutes minutes ~____ _ _ _ VERBENONE average 36 ~ 2.54& 0 27 7 3 ~ 3 stdOdev~, lo65 9000 7017 . ~
FRACTION 2 average 16~,30 24.~20 38~92 s-tdOdevo 3~62 4039 3~67 ., , . _ , _ . _ ~ n . . . _ ., v . . . ~
SOBRERO:L a-verage 2ql5 L ol5 3~97 ~ stdqdevO 403C) 603~ 8tl73 3o An~i~inflammator;y ~ctivity ~ -In albine rats of the COBS (Charles R.i.ver) stoek~ verbenone as administered intraperito:nea,l.1y at the dosage o~' 30 mi.ll.igrams per k;logram bow J ~ in'hibits t'he experimen-tal oedem~ in th.e paw as ~ ~, ~39~
induced by carrageenin (Winter~ C~AO et al~ ProcO SocO Exp~
Biol. MedOg 111~ 544g 1962~)both in normal rats and in su~rarenal-ectomized rats to a degree which iS9 Erom the sta-tistical stand-point, significantly improved over those O-e the rac-tion 2 and of sobrerol (TABLE 6)o When adminis-tered intraperi-toneally in rats at the dosages o 36 and 120 milligrams per kilogram b.w~ verbenone displays an intense antiexudative activity in the experime:ntalJ t~rpentine -~-~
i~duced pleuritis (Hurley~ JO VO et alOg J~ PathOg 91~ 57531966) to a degree which can be compared to that of aspirin (TABLE 7)0 T A B ~ E_ _6 Anti~inflamma-tory activity on the carrageenin-induced oedema in ratsO ~
CO~POUND Dosage milligrams/kg bow~ % inhibition of plantar intraperitoneally oedema~ as after 4 hrs~
from adm.inistration (ave~+ S-tdOdevOon 6 ani.mals ..... .~ ... __._ _ _ . . . __. ~ ___ FR~CTION 2 3 21 ., .... ... _ . . ~ .. ...... .
Haemol~ytic activit~ in vitro O -Verbenone protects in vitro the red blood cells o e rats -rom the haemolysis as induced by capillary-active-agents (Tween 80) with an effective concentration 50% (EC 50) of 63905 micrograms per kg bowo (fiducial limits 95~ : 51800-760011)~
Antia~r~ative activity~ in vitro ~ - ~
Verbenoneg at conc~3ntrations of from 160 to 1.280 m.icrograms/
milli3.iter inhibits the thrombocyte aggregation Erom ADP in vi-trog evaluated according to the me-thod by Born and Cross (J~ Physi.ol~ 7 Londong 168~ 178~ 1963) to a degree which is higher t:han that Oe the terpenes of -the Fraction 2 and of sobrerol (TABLE 8)o T A B L E _ 7 Activity of Verbe:none on the Turpentine-Induced Pleuri-tis in Rats O -Intraperitoneal Exudate~ + StdODevO Inhlbition Signifi-administration mls 3 ~0 cativity Controls 1097 0024 (solvent) Aspirin 1030 0013 34 % ~ 0~01 (100 mgs/kg) Verbenone 1023 0024 3706% ~ OoOl (36 mgs /kg) Verbenone 0097 0022 50~1% .~OoOl (120 mgs ~'kg~
T A B L E __8 Thrombocyte aggregation inhibition percen-tage (average of repeated -tests)O-FINAL CONCENTRATIONS % INHIBITION
.
CONTROL o -: VERB~NONE 1280 ~1g/ml 100 '` " 640 " 44 " 320 " 6 " 160 ll 0 ____~
CONTROL
SOBREROL4000 " 32 " 200~ " 2~
" 1500 " 12 Il 1000 ~' 4 CONTROL O
FRACTION 2 1280 " 70 " 1016 " :l8 " 806 " 14 " 640 " O
9~
z~
6 D Antibacterial activit~
Yerbenone possesses a poor antibacterial activity on the Gram-positive and Gram-nega-tî.ve germs~ w.i-th a MIC (Mirnimum Irlhibitlng concen-tratioll ) of 800 micrograms/ml on _~eus and Escherichla coli (TABLE 9) and is as active as Fraction 2 ancl more active than sobrerolO
Minimum Inhibiting Concentrations (MIC) in micrograms per milliter . -Mieroorganism Staphylococcus Escherichia coli Compound aureus F`R~CTION 2 ~00 800 SOBREROL ~
Summing up~ the compo-und has proven -to possess a pro:nounced bronchodilating action~ by virtue of whic:h it distinguishes in a s-ta-tistically significant manner both over the other m.edicaments pre~
sen-t in ~raction 2 of Swiss Patent 542 163 and -the re-ference ter-pene (sobrerol)O
On aecount of these partieular properties~ ~e~benone is efect ive as the active ingredien-t oE a pharmaceutical preparation which is especially adapted for the trleatmen-t of bronchopneumonial diseases which are accompanied by an obstructiorl of -the respira-tory ehannels due -to in-flammation and i.nfectious causati.ve agentsO The dosage envisaged for therapeu.t:i-cal appliea-tions is irom 10 -to 100 milligrams dailyO
B - MYRTENAL
lo Acute to icit~ O ~
The I.D5n as determined accordi:ng -to the methocl by I.i-tchfield and Wilcoxo~J PharmacolD Expo TherO~ 969 99~ 1949) by aclm:inistering 10"
23.~
the myr-tenal întravenously -to groups of 10 mice was 170 milli-grams per kilogram bow~
2~ Bronchodilato~ etivit~
___ Myrtenal has shswng both l vitro and i.n vi-vo a fair broncho-di.l.ating activity~
a - in v _ro On the isolated Guinea pig trachea according to t:he tech-ni~lue by Costantine (J~ ParmO Pharmacol~ 17~ 384, 1965 )3 myrtenal determines the relaxation of the -tracheal smooth muscles a-t t:he concen-tration of 125~200 micrograms/ml. with an in-tensi-ty which is s-tatistically higher than -that of -the F:raction 2 and that o-f sobrerol (TABLE lO)o T A B L E lO
Percentage of relaxation (average ~ standard deviat:ion of 4 prepara-tions) o-f -the isolated Guinea~pig trachea as determined by concentrations of 125~500 and 2~000 micrograms/milliliterO
Compound Preparations 125 500 2~000 Nmicrogr/ml microgr/mlm.i.crogr/ml MYRTENAL 4 aveO 7~.S 4'?o5 ~2~5 stdOdeva 500 1500 2007 aveO13~5 33075 52025 stdOdev~1~70 1.49 2095 aveO 1087 So62 201~75 SOBR~ROL 4 stdOdeY~ 1019 2~13 1~49 b _- iD VlVO
~ yrtenal perfused intravenou.sly in rabbits at the dosage o-f.
205 millil~t~rs per kg bow~ per m:inute inhibi.ts -the exper-Lmental hi.stamirle~indu.ced bronchospasm (hi.stam.ine 100 m:ic:rograms/kg b.w.
3 intra-veno-usly~ in a manner wh.i.ch is statis-tically ~ ,rher than tha-l;
of sobrerol and slightly lower -than -that of Fraction 2 (TABLE 11)o T A B L ~ 11 Percentages of inhibition of the ~i.stamine induced broncho-spasm by intravenous perfusion in rabbi-ts (average on 4 ani.mals + standard deviation)O
Perfusion times 15 mins, 30 mins~ 69 minsO
Compound ,, . ~
MYRTENAL ave~ 25~4 2004 28,8 stdf~devo lOr4 1602 13~5 10 FRACTION 2 aveO 16030 24~0 38~92 std,devO 3062 403~ 3067 SOBREROI, ave~ 2~15 1~l5 3~97 s-td~devO ~0~O ~o39 8~73 3 Anti-inflammat~ ac-tivity O -In albino rats of the CO~S ~Char1.es River) s-tock9 myrtenal as administered intraperitoneally at the closage o-f 30 milligrams per kg bowo inhibits the experimental paw oedema from injec-tion of carrageenin (Win-ter9 A~CO et alOg Proc~SocOExpO BiolOMedO 111~
544g 1962) to a degree which is more intense than that of Frac-tion 2 and also than that of sobrerol (TABLE 12) 0 T A B L E_ 12 Anti-inflammatory activity on the carrageenin oedema in rats~
Compound Dosage % inh:ibiti.or. on the plantar mg /kg bowo oe.dema aft~r 4 hou:rs as from intraperito~ administration (average on 6 neal~.y animals + stdo deviat,ion) FRACTION 2 30 ~1 SOBRE,ROL 30 11 92~
Antihaemolytic acti~ n -vitro r Myrtenal at concentrations o~ from 80 to 5~0 micrograms/ml.
protects the red. blood cells of rats from the :h~e~olys.~s as i.n-duced by capillary active agents (Twee:n 80) wi.th a.n Effecti~e Co.n-centration 50% eq~al -to 157009 microgr~ms/ml (fiducial limits 95% -- 11 2o3 ~ 18~o9)~
Antiae~re~atlve activi-ty . ~
Myrtcnal at concentration~ from 160 t,o 1~280 m.icrograms/ml inhibi.ts i vitro the thrombvcyte aggregation -from ADPg e~alua-ted according to the method by Born and Cross (J. Physiol~g Lond.ong 168~ 1789 1963)9 to ~ degree which i3 h:igher than those of F'raction 2 and sobrerol~
T A B L ~
Thrombocyte aggregation o % inhibi~,lon (average o-f repeated tests) FINAL CONCENTRl~TIONS % INHIBITION
CONTROL
MYRTENAL 1280 jug/ml 75 ~' 6~o ll 20 " 320 1~ 12 CONTROL O
SOBREROL 4000 ll 32 2000 ~ 2 ~' 15 oo 11 1 2 Il looo 4 .. -CONTROL o FRACTION 2 1280 " 7 1016 ll 1 2~9L
FR~CTION 2 806 ' ~g /ml 14 " 640 " O
~_ Myrtenal possesses a pronounced antibac-terial activity on Gram-positive germs~ less,intense on Gram-negative ones with a Mi.nimum Inhibiting Concentration (MIC) of 200 micrograms/ml on Sta~hylococcus aureus~ and of 800 micrograms/ml. on Escherichi.a coli and is more active both than Fraction 2 and ,sobrerol.
(TABLE 14)o T A B L E~
M:inimum Inh:ibiting Concen-trations (MIC) in micrograms/milli-liter O
Microorganism ~ ylococcus Escherichia Compound aureus coli .. _ . ",_ _ .
Myrtenal 200 800 Fraction 2 800 800 Sobrerol ~ v~
. -- ~
This compoundg myrtenal~ has shown~ by way of conclufiiong that it possesses a marked antibacterial action by virtue of which it 20 distinguishes in a statistically significant way from both the terper~mixtures of Fraction 2 of Swiss patent and the other medi-cinal substances o-f referenceg Myrtenal has an anti in.Elammatory action of poor magnitudea it displays an antihaemolytic activity andg fi.nally~ it has also a bronchodilating type acti,on and an anti-aggrega-tive action as well~ , On account of' these particu1ar features there~ofj myrtenal is indica-ted as an active ingre~.i.ent of' medicinal compositions which are particular'ly sui-table for the therapy of 'bronchopne~lmonial diseases when an importarlt bacte:rlal. component is presen-t~ or wheng 1~
at any rate., an anti.bio-tic~-based therapy is requiredO In con-nection with such i.ndications~ -the a~linistrat.i.on of a daily dosage of' from 10 -to 100 milligrams of myrtenal ls suggestedO
C - PINOCARVEOL
Acute toxici~
~_ ~
The ~D50 as determined according to the method by Litchfield and Wilcoxon (J'O PharmO Exp~ Ther. 96, 98g 1949) by adminîstering p.inocarveQl intravenously to groups of 10 rats per dosa~e was equa.l -to 140 millig:rams per k:ilogramO
20 Bronshodilating act vity Pinocarveol. has exhibited~ both in_vi-tro and in vivo~ a fair bronchodilating actlon~
a ~ in vitro On the G~inea-pig trachea isolated according to the technique by Costantlne (J~Pharm. Pharmacol.0~17~ 384~ 1965)~ pinocarveol determines the relaxation of the smooth tracheal muscles at the concentrat.ion of 125-~oOOO micrograms/ml wi.th an intensity which is statistlcally hîghe.r than that of sobrerol and which can be compared to that of Fraction 20 b - in vivo Pinocarveol perfwsed in-travenously i.n ra'bbits at the dosage of 205 milligrams per kilogram and per m:inute ~ the experimen-tal bronchospasm induced by histamine (100 micrograms per kilogramg intravenously) in a manner which is statistical-l.y hi~her than those of FRACTION 2 and of sobrerolO
3. Anti- ~
In albi.no rats of the COBS (Charles R.i~er) stockg pi.nocarveol adminis-tered intravenously at the dosage of 30 milligrams per kg inhibits the experLmental paw oedema from injection of carra 3o geenin (Winter9 CoA~ et a~ Proc. Soc~:ExpOB,Lol~ Med~ l'L'L, 544~
1962) to a degree whîch is more intense than those of Fraction 2 and of sobrero.LO
Z~
ctivi..t~ ~vitro~-Pinocarveol at concentrations of from 20 -to 200 micro-grams/ml protects the red blood cells of rats from the haemolysis cau.sed by cap.il.Lary-ac-tive agen-ts (Tween 80) wi-th an Effective Con~
centra-tion 50% (EC 50) of 132~29 micrograms/rnl (F'iducial limits 95% - 111~5~153~0~)o s,~g~.ive ac-t:Lvity ~ -Pinocarveol at concentrations of' from 160 to 10280 micro~grams/ml inhibit.s9 l _ .itroJ the thrombocyte aggrega-tion due to 10. ADP~ evaluated according to the method by Born and Cross (J~ Physiol..
London~ 168a 1783 1963) to a degree which exceeds t:hat of the ter-penes of the Frac-tion 2 and that of sobrerol~
Anti-bacterial activlty O -Pinocarveol i..s endowed with a poor an-tibacterial ac:tivity both on Gram~posit~ve and Gram-negative germs with a MIC (Minimum Inhibiting Concentration) of 800 micrograms/ml on Staphyloooccus aureus and Escher-ichia coli and is thus more active than sobrerol and as active as Fraction 20 Summing up, th.e compound pinocarveol has proven to possess a pronounced anti inflammatory aCtiOn by virtue of whi.ch it distin-guishes in a statistically signifLcant manner from the other medici-nal subs-tances such as the mixture of Fraction 2 of the Swiss Patent aforementioned and the reference terpene(sobrerol~)~
P:inocarveol possesses a poor bronchodilating action and is also endowed with a pronounced antihaemolytic activity9 by virtue of wh.ich it is possible -to attribute to such compound a stabilizing action at -the cel.lular membrane level~
Pinocarveol displays a poor antibacterial action and also exhibits a consp:icuous anti.aggregative ac-ti,onO
On account of its particular properkiesa pinocarveol can. be the active ingredien-t of a medicament wh:i.ch i.s particularly su:it~
able for the treatment of bronchopneumonial diseases wh.ich are ac-16~
%~
companied by a strong :inflamma-tory pa-ttern of -the respiratory channelsO
The dosages to be recvmmended for this therapeutic appli-cation are from 10 to 100 mi.ll.igrams dailyO
The pha~maceutical compositions according to the present inventi.on can be presented in the form of preparations f`or oral a~ninistrati.on9 normal or delayed~actiong such as soft capsules~
or injectable ampoules, suppoæitories~ sprays in various solution forms~ ointments and balms with the usu.al media~ fillers and so on as conventionally used in the pharmaceutical. art~ both as individual components and iIl association with medicaments indicated in the diseases referred to above9 that is~ antibiotics, antibacterial subs-tancesa chen~therapeu-tic substancesg sulfonamide drugsg anti-inflan~Ia-tory d:rugs, cortisone preparations and analgesicsO
The following examples are intended to illustrate without limi-tation the preparation of the compounds according to the present in~entionO
EX~MPLE
____ a - Alcohol oxidation lUO grams of the terpene mixture of Fraction 2 of the Swiss Patent 542 163~20~30% oÇ whi.ch comprise~ compound.s havlng a car-bonyl moiety (predominantly verbenone and myrtenal)whereas 50-60~
comprises compounds having an alcoholic moiety (mainly verbenol and myrtenol) are dissolved in 2~000 mls of dry acetoneO
Separately~ the oxidizing sol-ution is prepared by admixing cautiously 37~41 grams of CrO3 wi-th 32~2 mls of concO II2S04 in -the quantity of water which is sufficient to make up a final volume exactly equal to 140 mlsO
The chromic acid is then added slowly and dropwise to the ace-tone solution with stirring~ coo:Llng on an ice bath so as to main-tain the temperature constantly below 30~Co On completi.on of the addition~ filtra-tion is carr;i~d out on a Celite (Trade Mark) a:nd 2~
the filtrate is taken up by evaporating off acetone under reduced pressure at 40C~ The residue i.s then dilu.ted with wat,cr9 neutra-lized :i.Il cold condl.tions wi-th 10% :NaOH a:nd extracted wi-th CHC-L3 until. exhausting the mo-ther liquors. The combinecl organic extrac-ts are dried. over anhydrous Na2S04 and evaporated to dryness undcr re~
~uced pressure at 40Co By so doing~ there are obtained about 100 grams o-f a raw prod~ct which i3 composed.~ for so-60% by compounds having a carbonyl moiety (prevailingly verbenone and myrtenal)~
b_ - Se~ ~ m th~ raw materlal as obtained F:rom the oxidatio~l run 0 An app:ropriate vessel is charged with lOO grams of a raw mixture as obtained from the stag~, a of this methodg dissolved in 500 mls of ether and a soluti.on Eormed by 120 grams of NaHS03 and 72 grams of NaHC03 in 2~000 mls of waterO T:he mixture is vigorously shaken during abou.t 20 hours at room tempera-ture9 and -the~ -transferred -to a separatory -fun-.nel and the organic phase is discarded. The aqueous phase is washed twi.~e with 500 mls of ether each time~ whereafter the aqueous bisulfite soluti.on is taken up and subjected to stea~
dîsti.llation~ Thc processing of the distil.late gives 50--55 grams o a mixture whlch is virtually composed by pure verbenone and myrtenalO
c - Obtention o~ pure verbenone a:nd myrtenal O -50 grams of the product coming from the previo-us s-tage are subjected to fractionation in a vacuo at 20 millimeters of mercury~
using a reflu~ column ~illed with nickel shavings9 T:he distillation is carr.ied out slowly (5 -to 8 m:Ls ~ hou.r~ by maintaining a refl.ux ratio of about 40 to 1 the whole run throughoutO The -fract:ion which disti~ at 90C-9.~C is composed by myr-tenal (19 gratns) arld has the -eollowing physico~chemical speci-~i.ca-t:ions :
n2o -- 1050 d a oO98 D
z~g~
Inf:rared Analysi~ : bands at 1684 cm y C=O (conju~ated) 1623 cm. ' y C C (conjura-ted~
14~1 cm y C~H
UltraViolet Analysis ~ (E-tOH) = 246 nm ( ~ about 8~00) The semicarba~one mel.ts at 210~C-215C~
The fraction whlch d.ist~ls sub~equently at 110C~113~C at 20 ml.lli-meters of mercury is composed by ~rerbenone (28~5 g:rams~ and has th.e following physico-chemlcal specl-fications :
~0 10 n = 1~49 d - 0~97 Inrared band~ at 1670 cm 1 ~ C=O (co.njugated) 1615 cm C=C (¢onjugated) 1650-1.435-13~0 IJltraviolet ~ (EtQ~ - 2SO nm ~ = 79300 Semicarbazone : mO poi.nt 1~8C~190C
EX~MPLE 2 rsi.on of al ~ ~ ~
60 grams of the terpene mix-ture of Fraction 2 Oe the Swiss Patent N S42 163~10-i5~ of which compri.ses alpha-pinene epoxide~
where~s.2,0-30% con~ists of compounds havin~ a car'honyl moiety9 and 50~
60% consi3~ ~e compounds having an alcoholic mo.iety (verbeno1.~pino~
carveol and. myrtenol)9 are dissolved in 60 mls o anhydrous tolueneO
To the solu~ion is added an excess of aluminum isopropoxide (about 2-3 grams) and the mixture is boiled during 10 minutesO The mix-ture is carefl1lly cooled and slowly aoidifled by cautiously adding dilu-ted sulfuric acidg while still keeping a-t a tempera-ture of 0C or belowO The phases are separatedJ the liquors are ex:hausted with toluene~ the organi.c solutions oosnbined~ wassled w~.th water and dried o~er anhydrous Na2SO~O Filtration i$ carri.ed out and evapo:ra-tion at 60~C under reduced pressu:re is e.e*ected untiJ.. a solid re-sidue is obta.ined~ There are obta.ined about 60 grams of a raw 1~30 ;4 product which is exempt f~om epoxide and is enriched with com-pounds having an alcoholic function (pinocarveol~ verbenol and myrte:nol ) O
ration of the car'bonyl com~ounds ~, The residue which has been obtained from the pre~ious stage is takerl up with 300 mls of diethyl. ether and the resultant solu-'tiOIl is subjected to vigorous stirring wi-th a mixture ormed by 60 g~ams of NatlS039 36 grams of NaHC03 and 1~000 mls o~ water~
such treatment heing carried out during 20 hours at room -temperature~
The mixture is -transferred into a 3eparatory funnel and the phases are separated. l'he aqueous phase contains myrtenal and verbenone .in the form of soluble bisu,l.fi-te adducts~ from which they can be reco~e~ed in the form of pure products by working accorcli.ng to what has been .indicated -or the previous stages~ The organic phase~
which contains the alcoho~Lic compoundsg is washed to neu-trality with water~ dried over Na2S049 filtered and evaporated to dryness under recluced pressure ~ There are obtained 40-50 grams of a residue which is predominantly composed by pinocarveol~ verbenol and myr-tenol.
c - 0btention_of pu ~ O ~
The r~sidue coming rom the prev.ious stage is subjected to a seri.es of fractional dist.illation under VaCUIlm~ at 20 millimeters of mercury, using a reflux column filled with nickel shavings~ The distillatiorl is carried out slowly (5~6 mls / hour) by maintaining a reflux ratio o-f about 40 1. during the entire runO The fraction whlch di.s-tî~s at 100C-106C under 20 milli.meters of mercury and w.hich is strvngly enriched with pinocarveolJ is collected and sub jected -to redistillation ~mder the same condi-tionsO There are obtain-ed t5-18 grams approxO of 95%-98~ pure pinocarveol which has the following physico c'hemica'L ,,pecificati~ns : b~point .103-104C under nD = 104988 ; d20 = oO98 20 nlm tlg Infrared analysis : characteristic bancls of terminal double hond at 6Ooo micirons and at 11O20 micronsO
20.,
of sobrerol and slightly lower -than -that of Fraction 2 (TABLE 11)o T A B L ~ 11 Percentages of inhibition of the ~i.stamine induced broncho-spasm by intravenous perfusion in rabbi-ts (average on 4 ani.mals + standard deviation)O
Perfusion times 15 mins, 30 mins~ 69 minsO
Compound ,, . ~
MYRTENAL ave~ 25~4 2004 28,8 stdf~devo lOr4 1602 13~5 10 FRACTION 2 aveO 16030 24~0 38~92 std,devO 3062 403~ 3067 SOBREROI, ave~ 2~15 1~l5 3~97 s-td~devO ~0~O ~o39 8~73 3 Anti-inflammat~ ac-tivity O -In albino rats of the CO~S ~Char1.es River) s-tock9 myrtenal as administered intraperitoneally at the closage o-f 30 milligrams per kg bowo inhibits the experimental paw oedema from injec-tion of carrageenin (Win-ter9 A~CO et alOg Proc~SocOExpO BiolOMedO 111~
544g 1962) to a degree which is more intense than that of Frac-tion 2 and also than that of sobrerol (TABLE 12) 0 T A B L E_ 12 Anti-inflammatory activity on the carrageenin oedema in rats~
Compound Dosage % inh:ibiti.or. on the plantar mg /kg bowo oe.dema aft~r 4 hou:rs as from intraperito~ administration (average on 6 neal~.y animals + stdo deviat,ion) FRACTION 2 30 ~1 SOBRE,ROL 30 11 92~
Antihaemolytic acti~ n -vitro r Myrtenal at concentrations o~ from 80 to 5~0 micrograms/ml.
protects the red. blood cells of rats from the :h~e~olys.~s as i.n-duced by capillary active agents (Twee:n 80) wi.th a.n Effecti~e Co.n-centration 50% eq~al -to 157009 microgr~ms/ml (fiducial limits 95% -- 11 2o3 ~ 18~o9)~
Antiae~re~atlve activi-ty . ~
Myrtcnal at concentration~ from 160 t,o 1~280 m.icrograms/ml inhibi.ts i vitro the thrombvcyte aggregation -from ADPg e~alua-ted according to the method by Born and Cross (J. Physiol~g Lond.ong 168~ 1789 1963)9 to ~ degree which i3 h:igher than those of F'raction 2 and sobrerol~
T A B L ~
Thrombocyte aggregation o % inhibi~,lon (average o-f repeated tests) FINAL CONCENTRl~TIONS % INHIBITION
CONTROL
MYRTENAL 1280 jug/ml 75 ~' 6~o ll 20 " 320 1~ 12 CONTROL O
SOBREROL 4000 ll 32 2000 ~ 2 ~' 15 oo 11 1 2 Il looo 4 .. -CONTROL o FRACTION 2 1280 " 7 1016 ll 1 2~9L
FR~CTION 2 806 ' ~g /ml 14 " 640 " O
~_ Myrtenal possesses a pronounced antibac-terial activity on Gram-positive germs~ less,intense on Gram-negative ones with a Mi.nimum Inhibiting Concentration (MIC) of 200 micrograms/ml on Sta~hylococcus aureus~ and of 800 micrograms/ml. on Escherichi.a coli and is more active both than Fraction 2 and ,sobrerol.
(TABLE 14)o T A B L E~
M:inimum Inh:ibiting Concen-trations (MIC) in micrograms/milli-liter O
Microorganism ~ ylococcus Escherichia Compound aureus coli .. _ . ",_ _ .
Myrtenal 200 800 Fraction 2 800 800 Sobrerol ~ v~
. -- ~
This compoundg myrtenal~ has shown~ by way of conclufiiong that it possesses a marked antibacterial action by virtue of which it 20 distinguishes in a statistically significant way from both the terper~mixtures of Fraction 2 of Swiss patent and the other medi-cinal substances o-f referenceg Myrtenal has an anti in.Elammatory action of poor magnitudea it displays an antihaemolytic activity andg fi.nally~ it has also a bronchodilating type acti,on and an anti-aggrega-tive action as well~ , On account of' these particu1ar features there~ofj myrtenal is indica-ted as an active ingre~.i.ent of' medicinal compositions which are particular'ly sui-table for the therapy of 'bronchopne~lmonial diseases when an importarlt bacte:rlal. component is presen-t~ or wheng 1~
at any rate., an anti.bio-tic~-based therapy is requiredO In con-nection with such i.ndications~ -the a~linistrat.i.on of a daily dosage of' from 10 -to 100 milligrams of myrtenal ls suggestedO
C - PINOCARVEOL
Acute toxici~
~_ ~
The ~D50 as determined according to the method by Litchfield and Wilcoxon (J'O PharmO Exp~ Ther. 96, 98g 1949) by adminîstering p.inocarveQl intravenously to groups of 10 rats per dosa~e was equa.l -to 140 millig:rams per k:ilogramO
20 Bronshodilating act vity Pinocarveol. has exhibited~ both in_vi-tro and in vivo~ a fair bronchodilating actlon~
a ~ in vitro On the G~inea-pig trachea isolated according to the technique by Costantlne (J~Pharm. Pharmacol.0~17~ 384~ 1965)~ pinocarveol determines the relaxation of the smooth tracheal muscles at the concentrat.ion of 125-~oOOO micrograms/ml wi.th an intensity which is statistlcally hîghe.r than that of sobrerol and which can be compared to that of Fraction 20 b - in vivo Pinocarveol perfwsed in-travenously i.n ra'bbits at the dosage of 205 milligrams per kilogram and per m:inute ~ the experimen-tal bronchospasm induced by histamine (100 micrograms per kilogramg intravenously) in a manner which is statistical-l.y hi~her than those of FRACTION 2 and of sobrerolO
3. Anti- ~
In albi.no rats of the COBS (Charles R.i~er) stockg pi.nocarveol adminis-tered intravenously at the dosage of 30 milligrams per kg inhibits the experLmental paw oedema from injection of carra 3o geenin (Winter9 CoA~ et a~ Proc. Soc~:ExpOB,Lol~ Med~ l'L'L, 544~
1962) to a degree whîch is more intense than those of Fraction 2 and of sobrero.LO
Z~
ctivi..t~ ~vitro~-Pinocarveol at concentrations of from 20 -to 200 micro-grams/ml protects the red blood cells of rats from the haemolysis cau.sed by cap.il.Lary-ac-tive agen-ts (Tween 80) wi-th an Effective Con~
centra-tion 50% (EC 50) of 132~29 micrograms/rnl (F'iducial limits 95% - 111~5~153~0~)o s,~g~.ive ac-t:Lvity ~ -Pinocarveol at concentrations of' from 160 to 10280 micro~grams/ml inhibit.s9 l _ .itroJ the thrombocyte aggrega-tion due to 10. ADP~ evaluated according to the method by Born and Cross (J~ Physiol..
London~ 168a 1783 1963) to a degree which exceeds t:hat of the ter-penes of the Frac-tion 2 and that of sobrerol~
Anti-bacterial activlty O -Pinocarveol i..s endowed with a poor an-tibacterial ac:tivity both on Gram~posit~ve and Gram-negative germs with a MIC (Minimum Inhibiting Concentration) of 800 micrograms/ml on Staphyloooccus aureus and Escher-ichia coli and is thus more active than sobrerol and as active as Fraction 20 Summing up, th.e compound pinocarveol has proven to possess a pronounced anti inflammatory aCtiOn by virtue of whi.ch it distin-guishes in a statistically signifLcant manner from the other medici-nal subs-tances such as the mixture of Fraction 2 of the Swiss Patent aforementioned and the reference terpene(sobrerol~)~
P:inocarveol possesses a poor bronchodilating action and is also endowed with a pronounced antihaemolytic activity9 by virtue of wh.ich it is possible -to attribute to such compound a stabilizing action at -the cel.lular membrane level~
Pinocarveol displays a poor antibacterial action and also exhibits a consp:icuous anti.aggregative ac-ti,onO
On account of its particular properkiesa pinocarveol can. be the active ingredien-t of a medicament wh:i.ch i.s particularly su:it~
able for the treatment of bronchopneumonial diseases wh.ich are ac-16~
%~
companied by a strong :inflamma-tory pa-ttern of -the respiratory channelsO
The dosages to be recvmmended for this therapeutic appli-cation are from 10 to 100 mi.ll.igrams dailyO
The pha~maceutical compositions according to the present inventi.on can be presented in the form of preparations f`or oral a~ninistrati.on9 normal or delayed~actiong such as soft capsules~
or injectable ampoules, suppoæitories~ sprays in various solution forms~ ointments and balms with the usu.al media~ fillers and so on as conventionally used in the pharmaceutical. art~ both as individual components and iIl association with medicaments indicated in the diseases referred to above9 that is~ antibiotics, antibacterial subs-tancesa chen~therapeu-tic substancesg sulfonamide drugsg anti-inflan~Ia-tory d:rugs, cortisone preparations and analgesicsO
The following examples are intended to illustrate without limi-tation the preparation of the compounds according to the present in~entionO
EX~MPLE
____ a - Alcohol oxidation lUO grams of the terpene mixture of Fraction 2 of the Swiss Patent 542 163~20~30% oÇ whi.ch comprise~ compound.s havlng a car-bonyl moiety (predominantly verbenone and myrtenal)whereas 50-60~
comprises compounds having an alcoholic moiety (mainly verbenol and myrtenol) are dissolved in 2~000 mls of dry acetoneO
Separately~ the oxidizing sol-ution is prepared by admixing cautiously 37~41 grams of CrO3 wi-th 32~2 mls of concO II2S04 in -the quantity of water which is sufficient to make up a final volume exactly equal to 140 mlsO
The chromic acid is then added slowly and dropwise to the ace-tone solution with stirring~ coo:Llng on an ice bath so as to main-tain the temperature constantly below 30~Co On completi.on of the addition~ filtra-tion is carr;i~d out on a Celite (Trade Mark) a:nd 2~
the filtrate is taken up by evaporating off acetone under reduced pressure at 40C~ The residue i.s then dilu.ted with wat,cr9 neutra-lized :i.Il cold condl.tions wi-th 10% :NaOH a:nd extracted wi-th CHC-L3 until. exhausting the mo-ther liquors. The combinecl organic extrac-ts are dried. over anhydrous Na2S04 and evaporated to dryness undcr re~
~uced pressure at 40Co By so doing~ there are obtained about 100 grams o-f a raw prod~ct which i3 composed.~ for so-60% by compounds having a carbonyl moiety (prevailingly verbenone and myrtenal)~
b_ - Se~ ~ m th~ raw materlal as obtained F:rom the oxidatio~l run 0 An app:ropriate vessel is charged with lOO grams of a raw mixture as obtained from the stag~, a of this methodg dissolved in 500 mls of ether and a soluti.on Eormed by 120 grams of NaHS03 and 72 grams of NaHC03 in 2~000 mls of waterO T:he mixture is vigorously shaken during abou.t 20 hours at room tempera-ture9 and -the~ -transferred -to a separatory -fun-.nel and the organic phase is discarded. The aqueous phase is washed twi.~e with 500 mls of ether each time~ whereafter the aqueous bisulfite soluti.on is taken up and subjected to stea~
dîsti.llation~ Thc processing of the distil.late gives 50--55 grams o a mixture whlch is virtually composed by pure verbenone and myrtenalO
c - Obtention o~ pure verbenone a:nd myrtenal O -50 grams of the product coming from the previo-us s-tage are subjected to fractionation in a vacuo at 20 millimeters of mercury~
using a reflu~ column ~illed with nickel shavings9 T:he distillation is carr.ied out slowly (5 -to 8 m:Ls ~ hou.r~ by maintaining a refl.ux ratio of about 40 to 1 the whole run throughoutO The -fract:ion which disti~ at 90C-9.~C is composed by myr-tenal (19 gratns) arld has the -eollowing physico~chemical speci-~i.ca-t:ions :
n2o -- 1050 d a oO98 D
z~g~
Inf:rared Analysi~ : bands at 1684 cm y C=O (conju~ated) 1623 cm. ' y C C (conjura-ted~
14~1 cm y C~H
UltraViolet Analysis ~ (E-tOH) = 246 nm ( ~ about 8~00) The semicarba~one mel.ts at 210~C-215C~
The fraction whlch d.ist~ls sub~equently at 110C~113~C at 20 ml.lli-meters of mercury is composed by ~rerbenone (28~5 g:rams~ and has th.e following physico-chemlcal specl-fications :
~0 10 n = 1~49 d - 0~97 Inrared band~ at 1670 cm 1 ~ C=O (co.njugated) 1615 cm C=C (¢onjugated) 1650-1.435-13~0 IJltraviolet ~ (EtQ~ - 2SO nm ~ = 79300 Semicarbazone : mO poi.nt 1~8C~190C
EX~MPLE 2 rsi.on of al ~ ~ ~
60 grams of the terpene mix-ture of Fraction 2 Oe the Swiss Patent N S42 163~10-i5~ of which compri.ses alpha-pinene epoxide~
where~s.2,0-30% con~ists of compounds havin~ a car'honyl moiety9 and 50~
60% consi3~ ~e compounds having an alcoholic mo.iety (verbeno1.~pino~
carveol and. myrtenol)9 are dissolved in 60 mls o anhydrous tolueneO
To the solu~ion is added an excess of aluminum isopropoxide (about 2-3 grams) and the mixture is boiled during 10 minutesO The mix-ture is carefl1lly cooled and slowly aoidifled by cautiously adding dilu-ted sulfuric acidg while still keeping a-t a tempera-ture of 0C or belowO The phases are separatedJ the liquors are ex:hausted with toluene~ the organi.c solutions oosnbined~ wassled w~.th water and dried o~er anhydrous Na2SO~O Filtration i$ carri.ed out and evapo:ra-tion at 60~C under reduced pressu:re is e.e*ected untiJ.. a solid re-sidue is obta.ined~ There are obta.ined about 60 grams of a raw 1~30 ;4 product which is exempt f~om epoxide and is enriched with com-pounds having an alcoholic function (pinocarveol~ verbenol and myrte:nol ) O
ration of the car'bonyl com~ounds ~, The residue which has been obtained from the pre~ious stage is takerl up with 300 mls of diethyl. ether and the resultant solu-'tiOIl is subjected to vigorous stirring wi-th a mixture ormed by 60 g~ams of NatlS039 36 grams of NaHC03 and 1~000 mls o~ water~
such treatment heing carried out during 20 hours at room -temperature~
The mixture is -transferred into a 3eparatory funnel and the phases are separated. l'he aqueous phase contains myrtenal and verbenone .in the form of soluble bisu,l.fi-te adducts~ from which they can be reco~e~ed in the form of pure products by working accorcli.ng to what has been .indicated -or the previous stages~ The organic phase~
which contains the alcoho~Lic compoundsg is washed to neu-trality with water~ dried over Na2S049 filtered and evaporated to dryness under recluced pressure ~ There are obtained 40-50 grams of a residue which is predominantly composed by pinocarveol~ verbenol and myr-tenol.
c - 0btention_of pu ~ O ~
The r~sidue coming rom the prev.ious stage is subjected to a seri.es of fractional dist.illation under VaCUIlm~ at 20 millimeters of mercury, using a reflux column filled with nickel shavings~ The distillatiorl is carried out slowly (5~6 mls / hour) by maintaining a reflux ratio o-f about 40 1. during the entire runO The fraction whlch di.s-tî~s at 100C-106C under 20 milli.meters of mercury and w.hich is strvngly enriched with pinocarveolJ is collected and sub jected -to redistillation ~mder the same condi-tionsO There are obtain-ed t5-18 grams approxO of 95%-98~ pure pinocarveol which has the following physico c'hemica'L ,,pecificati~ns : b~point .103-104C under nD = 104988 ; d20 = oO98 20 nlm tlg Infrared analysis : characteristic bancls of terminal double hond at 6Ooo micirons and at 11O20 micronsO
20.,
Claims (2)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for the treatment of diseases of the respiratory system which are accompanied by obstruction of the respiratory channels of a spactic, inflammatory and infectious nature, which contains as a unit dosage , 10 to 100 milligrams of one compound selected from verbenone, myrtenal and pinocarveol and a pharmaceutical excipient therefor.
2. A pharmaceutical composition according to claim 1, characterized in that said compound is myrtenal, associated with an antibiotic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA369,574A CA1129885A (en) | 1976-06-03 | 1981-01-28 | Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH704276A CH625197A5 (en) | 1976-06-03 | 1976-06-03 | Process for preparing verbenone, myrtenal and pinocarveol |
| CH7042/76 | 1976-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1099214A true CA1099214A (en) | 1981-04-14 |
Family
ID=4319020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,610A Expired CA1099214A (en) | 1976-06-03 | 1977-06-01 | Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS52151156A (en) |
| AR (1) | AR214200A1 (en) |
| AT (1) | AT351520B (en) |
| AU (1) | AU519521B2 (en) |
| BE (1) | BE855297A (en) |
| CA (1) | CA1099214A (en) |
| CH (1) | CH625197A5 (en) |
| CS (1) | CS251755B2 (en) |
| DD (1) | DD130475A1 (en) |
| DE (2) | DE2725247A1 (en) |
| DK (1) | DK244277A (en) |
| ES (1) | ES459425A1 (en) |
| FI (1) | FI771765A (en) |
| FR (2) | FR2416878A1 (en) |
| GB (2) | GB1585832A (en) |
| HU (1) | HU178205B (en) |
| IT (1) | IT1074511B (en) |
| NL (1) | NL7705934A (en) |
| NO (1) | NO771926L (en) |
| OA (1) | OA05678A (en) |
| PL (1) | PL116550B1 (en) |
| PT (1) | PT66619B (en) |
| SE (2) | SE424723B (en) |
| SU (1) | SU816396A3 (en) |
| ZA (1) | ZA773345B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04239414A (en) * | 1991-01-24 | 1992-08-27 | Sekisui Chem Co Ltd | Device and method for banding with adhesive tape |
| IT1251615B (en) * | 1991-10-04 | 1995-05-17 | Golgi Sa | ANTIELASTASIC ACTIVITY MEDICATION. |
| IT1312537B1 (en) * | 1999-04-16 | 2002-04-22 | Euphar Group Srl | DERIVATIVES OF (-) - VERBENONE. |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1103814A (en) * | 1953-04-30 | 1955-11-07 | Glidden Co | Improvements relating to the treatment of mixtures and autoxidation products of the terpene |
| US2911442A (en) * | 1953-04-30 | 1959-11-03 | Glidden Co | Production of oxygenated terpenes from alpha-pinene |
| FR1377525A (en) * | 1963-09-25 | 1964-11-06 | Centre Nat Rech Scient | Process for preparing terpene ketones |
| FR1572146A (en) * | 1967-05-10 | 1969-06-27 | ||
| US3673066A (en) * | 1969-02-14 | 1972-06-27 | Lab De L Ozothine | Process for the accelerated obtaining of terpenic oxides using ultraviolet light |
| CH523962A (en) * | 1969-08-18 | 1972-06-15 | Int Flavors & Fragrances Inc | Use of indane derivatives as odorous principles |
| CH542163A (en) * | 1971-06-14 | 1973-09-30 | Buskine Sa | Process for the production of a terpene mixture |
| FR2267296A1 (en) * | 1974-04-12 | 1975-11-07 | Anvar | Myrtenol synthesis - by isomerisation of beta-pinene epoxide |
-
1976
- 1976-06-03 CH CH704276A patent/CH625197A5/en not_active IP Right Cessation
-
1977
- 1977-05-25 GB GB1504/80A patent/GB1585832A/en not_active Expired
- 1977-05-25 GB GB22089/77A patent/GB1585831A/en not_active Expired
- 1977-05-31 NL NL7705934A patent/NL7705934A/en not_active Application Discontinuation
- 1977-05-31 PT PT66619A patent/PT66619B/en unknown
- 1977-05-31 CS CS773586A patent/CS251755B2/en unknown
- 1977-06-01 NO NO771926A patent/NO771926L/en unknown
- 1977-06-01 AU AU25732/77A patent/AU519521B2/en not_active Expired
- 1977-06-01 SE SE7706385A patent/SE424723B/en unknown
- 1977-06-01 BE BE178116A patent/BE855297A/en unknown
- 1977-06-01 CA CA279,610A patent/CA1099214A/en not_active Expired
- 1977-06-02 PL PL1977198600A patent/PL116550B1/en unknown
- 1977-06-02 SU SU772494040A patent/SU816396A3/en active
- 1977-06-02 ES ES459425A patent/ES459425A1/en not_active Expired
- 1977-06-02 DK DK244277A patent/DK244277A/en not_active Application Discontinuation
- 1977-06-02 JP JP6404177A patent/JPS52151156A/en active Pending
- 1977-06-02 HU HU77CO341A patent/HU178205B/en unknown
- 1977-06-02 FI FI771765A patent/FI771765A/fi not_active Application Discontinuation
- 1977-06-03 DD DD7700199291A patent/DD130475A1/en unknown
- 1977-06-03 DE DE19772725247 patent/DE2725247A1/en active Granted
- 1977-06-03 AT AT394077A patent/AT351520B/en not_active IP Right Cessation
- 1977-06-03 IT IT24385/77A patent/IT1074511B/en active Protection Beyond IP Right Term
- 1977-06-03 OA OA56187A patent/OA05678A/en unknown
- 1977-06-03 DE DE2760410A patent/DE2760410C2/de not_active Expired - Fee Related
- 1977-06-03 FR FR7717088A patent/FR2416878A1/en not_active Withdrawn
- 1977-06-03 ZA ZA00773345A patent/ZA773345B/en unknown
- 1977-06-08 AR AR267933A patent/AR214200A1/en active
-
1981
- 1981-05-06 FR FR8108999A patent/FR2479804A1/en not_active Withdrawn
- 1981-09-25 SE SE8105687A patent/SE8105687L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2479804A1 (en) | 1981-10-09 |
| PL116550B1 (en) | 1981-06-30 |
| DK244277A (en) | 1977-12-04 |
| PT66619A (en) | 1977-06-01 |
| AR214200A1 (en) | 1979-05-15 |
| NO771926L (en) | 1977-12-06 |
| GB1585832A (en) | 1981-03-11 |
| DD130475A1 (en) | 1978-04-05 |
| CH625197A5 (en) | 1981-09-15 |
| SE8105687L (en) | 1981-09-25 |
| DE2760410C2 (en) | 1990-08-16 |
| SE7706385L (en) | 1977-12-04 |
| AT351520B (en) | 1979-07-25 |
| GB1585831A (en) | 1981-03-11 |
| SU816396A3 (en) | 1981-03-23 |
| DE2725247C2 (en) | 1987-02-12 |
| ZA773345B (en) | 1978-04-26 |
| BE855297A (en) | 1977-10-03 |
| ATA394077A (en) | 1979-01-15 |
| CS251755B2 (en) | 1987-08-13 |
| AU2573277A (en) | 1978-12-07 |
| JPS52151156A (en) | 1977-12-15 |
| DE2725247A1 (en) | 1977-12-22 |
| AU519521B2 (en) | 1981-12-10 |
| PL198600A1 (en) | 1978-06-19 |
| IT1074511B (en) | 1985-04-20 |
| NL7705934A (en) | 1977-12-06 |
| PT66619B (en) | 1978-10-27 |
| FI771765A (en) | 1977-12-04 |
| ES459425A1 (en) | 1978-04-01 |
| SE424723B (en) | 1982-08-09 |
| HU178205B (en) | 1982-03-28 |
| OA05678A (en) | 1981-05-31 |
| FR2416878A1 (en) | 1979-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Butler | The metabolic conversion of 5, 5-diphenyl hydantoin to 5-(p-hydroxyphenyl)-5-phenyl hydantoin | |
| Papageorgiou | Naturally occurring isohexenylnaphthazarin pigments: a new class of drugs | |
| US4346103A (en) | Treatment for arthritis and substances for use in such treatment | |
| Doering et al. | Synthesis of substituted tropolones | |
| Johnson | The formation of cyclic ketones by intramolecular acylation | |
| Laidman et al. | Substance SC (ubichromenol): a naturally-occurring cyclic isomeride of ubiquinone-50 | |
| CA1099214A (en) | Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use | |
| US4225589A (en) | Daunorubicin derivatives | |
| Kawazu et al. | Piscicidal Constituents of Calophyllum Inophyllum (Commemoration Issue Dedicated to Professor Minoru Ohno On the Occasion of his Retirement) | |
| US3969369A (en) | Bruceantin | |
| EP1745000A2 (en) | Novel anthraquinones and process for the preparation and method of use thereof | |
| Bridge et al. | 317. Experiments on the synthesis of rotenone and its derivatives. Part XIII | |
| US4190675A (en) | Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use | |
| Dodds et al. | Synthetic oestrogenic compounds related to stilbene and diphenylethane. Ill | |
| Bridge et al. | 57. Experiments on the synthesis of rotenone and its derivatives. Part XII. The 2: 2-dimethyl-â—� 3-chromen residue of toxicarol | |
| US3652666A (en) | 2-(3-benzyl-2-methoxy-phenyl) alkanoic acids | |
| Rao | 176. Morellin, a constituent of the seeds of Garcinia morella | |
| Wagner et al. | Synthesis of the New 5-Phosphomethyl-6-chromanyl Acetate of Vitamin K1 (20) by a Novel Cyclization Reaction | |
| Field et al. | Organic Disulfides and Related Substances. XI. Bisalkylidene,-alkylene, and-arylene Disulfides Containing 2-Aminoethyl Moieties1 | |
| King et al. | 1008. Tanshinones. Part I. The synthesis of an isomer of tanshinone-I | |
| US2594314A (en) | Process for preparing an antipernicious anemia concentrate | |
| Penfold et al. | 316. 1-Δ 3-Carene-5: 6-epoxide, a constituent of the oil from Zieria Smithii | |
| US3682963A (en) | Dimethylbenzodithian-2-oxide | |
| McGookin et al. | 150. Rottlerin. Part I | |
| CA1129885A (en) | Method for the preparation of verbenone, myrtenal and pinocarveol and their therapeutical use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |