Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/24—Condensed ring systems having three or more rings
  • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/14—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/24—Condensed ring systems having three or more rings
  • C07H15/244—Anthraquinone radicals, e.g. sennosides

Definitions

• This invention concerns synthetic methods in the preparation of desired organic compounds. More particularly, the invention concerns general methods which can be used specifically for the preparation of intermediates in the synthesis of C-glycosidic adriamycin and araetantrone analogs which will have useful anti-tumor activity.
• Adriamycin is a commercial name for doxorubicin. which is a polycyclic naphthacene-based glycoside of the deoxyamino sugar, daunosamine.
• a class of similar compounds, which are also glycosides of daunosamine, but which contain polycyclic systems related to anthracene, is represented by ametantrone and mitoxantrone. This class also has powerful anti-tumor activity.
• the present invention provides a general means for obtaining essential intermediates in the production of the desired C-glycosides. It is also of general use in obtaining pentadienyl and acetaldehyde derivatives of 2-deoxypyranose sugars.
• This invention enables the production of C.1 (2,4-pentadienyl)glycosides of a 2-deoxypyranose, and, in particular, these derivatives of daunosamine.
• the method is useful for preparing the acetaldehyde derivatives as well.
• the resulting pentadienyl derivatives are useful as intermediates because they can then be linked to appropriate polycyclic systems using a Diels- ⁇ lder reaction and converted to desired C-glycosidic adriamycin analogs using standard means known in the art.
• the acetaldehyde derivatives are useful as substrates for Wittig type reactions to obtain related pentadienyl derivatives.
• the methods of the invention provide the first enabling disclosure directed to these C-glycosides.
• the invention relates to a method for preparing C.1-(2,4-pentadiene) derivatives of 2-deoxypyranose sugars. This method is applicable to the preparation of such derivatives of daunosamine. It comprises treating the 2-deoxypyranose, which has a leaving group at C.1, with a 1-trimethylsilyl-2,4-pentadiene in the presence of a Lewis acid.
• the invention relates to a method for the preparation of C.1 acetaldehyde derivatives of
• 2-deoxypyranoses in particular, of daunosamine. using an analogous process to obtain the C.1 allyl derivatives, and then subjecting these to ozonolysis.
• the invention relates to the intermediates so prepared and to the target compounds to which these intermediates are converted.
• the invention relates to compounds of the formula:
• X is O or NH
• R is COCH 3 , COCH 2 OH, CHOHCH 3 , CHOHCH 2 OH, H, 1-3C alkyl, 1-2C terminal hydroxyalkyl or the 2-7C alkyl or aryl organic acid esters or 1-6C alkyl ethers thereof; or 13-ketimine (such as hydrazones and oximes) derivatives of COCH 3 or COCH 2 OH; at least one of R 2 and R 3 is H, and the other is OH or OCH 3 ; and
• a and B are each independently H or alkyl
• the compounds of formula (1) are useful as anti-tumor agents.
• Another aspect of the invention relates to compounds of the formula:
• R, R 2 , R 3 , A and B are as above-defined, and W is H or OH.
• These compounds of formula (2) are also useful anti-tumor agents.
• the invention relates to compounds of the formula:
• P is a protecting group, such as acetyl, trichloroacetyl, or, optimally trifluoroacetyl;
• R 4 is H or a protecting group, such as acyl
• Q is H, alkyl (1-3C), OMe, OEt, -OCH 2 CH 2 OMe, -O-tetrahydropyranyl, Br, or COOMe.
• the compounds of formula (3) result from modifying a polycyclic ring system which results from the Diels-Alder condensation of the appropriate pentadienyl glycosides with the appropriate anthracene tetrone analogs.
• This polycyclic ring system is contained in the compounds of formula (4):
• the invention relates to the compounds of formula (4) wherein Q, P, Y and R 4 are as above-defined; and wherein the dotted line at Z indicates either a ⁇ bond or an epoxide ring.
• the invention relates to compounds of formula (5) which are intermediates analogous to those of formula (4) but which result from Diels-Alder condensation with a naphthalene analog.
• the compound of formula (5) have the structure:
• OEt, -OCH 2 CH 2 OMe, or -O-tetrahydropyranyl, and the compound of formula (7) are obtainable as the direct substitution products in the pentadienylation or allylation method of the invention.
• Compound (8) is the ozonolysis product of compound (7).
• Compounds of formula (6) wherein Q is as above, and also wherein Q is ethyl, propyl, isopropyl, Br, or COOMe, are obtainable by a Wittig reaction using the compound of formula (8).
• alkyl is defined as a straight or branched chain hydrocarbon substituent having the designated number of carbon atoms; alkoxy is
• Aryl refers to a substituent containing a benzene ring which is linked to the substituted compound referred to either directly, or through a lower alkyl (1-4C) chain. Aryl substituents are, therefore, exemplified by phenyl, phenylethyl, 2-phenyl-2- methylpropyl, and the like. Aroyl is wherein Ar is aryl as above defined.
• a 2-deoxy hexopyranose (or other substrate) which is “activated”, for example, in the 1-position is “activated” by the presence of a good leaving group in that position.
• the daunosamine sugars may conveniently be activated in the 1-position by esterifying the -OH with an aroyl group, especially p-nitrobenzoyl.
• the compounds claimed herein contain a number of chiral centers. Where the depiction of such chiral centers is ambiguous, it is understood that either configuration comes within the denoted species of the formula.
• the ordinary conventions of projection formulas are used where configuration is specified. If it is desired to separate the compounds into forms which are represented by only one configuration, this is possible using standard techniques for the separation of organic chemicals, such as recrystallization, chromatography, thin layer chromatography, and the like. All of the compounds of the invention contain daunosamine or a protected form, stereoisomer, or derivative of daunosamine.
• compounds of the invention contain configurations at the daunosamine chiral centers which are already fixed, and all of the permutations of the remaining chiral centers will generate compounds which are diastereomers with respect to each other, permitting standard separation techniques to be used.
• the hydroxyl and methylene bridge on ring A occupy chiral carbons.
• the compounds of the invention include all of the stereoisomers, although those which are isosteres of the adriamycin series are preferred.
• Those compounds which are direct products of Diels-Alder addition (formulas (4) and (5)) under most conditions contain the methylene link from ring A to daunosamine and the two cis hydrogens at the A/B ring fusion on opposite sides of the ring.
• the substitution which leads to the formation of the pentadienyl glycosides or allyl glycosides is stereoselective in accord with results predicted by the anomeric effect, enhanced in some cases by participation of an O-acyl or O-aroyl group at C-4.
• the desired stereoisormer may be separated using standard separation techniques.
• At the heart of the invention is an effective, and, optimally, stereoselective method for forming the C.1 glycosides of 2-deoxy-hexopyranoses.
• the method comprises treating the substrate 2-deoxy-hexopyranose with 1-trimethylsilyl-2,4-pentadiene or 1-trimethylsilyl-2-propene to obtain the corresponding C.1-(2,4-pentadienyl) or C.1 allyl glycoside respectively. Either of these glycosides may be converted to the corresponding pyranosyl acetaldehyde by ozonolysis.
• the products of the reactions which represent the methods of the invention are particularly important when the pyranose substrate is daunosamine (i.e., 2,3,6-trideoxy-3-amino-L-lyxohexopyranose).
• the pentadienyl products are capable of reacting with suitable dieneophiles included in polycyclic naphthalene or anthracene based systems to obtain C glycosides of anthracene or naphthacene polycyclic systems, respectively. These products are readily convertible to adriamycin or ametantrone/mitoxantrone analogs with anti-tumor activity.
• allyl glycoside products are primarily useful by virtue of their ability to be converted to the corresponding acetaldehyde derivatives which can then be used as substrates for Wittig type reactions to obtain pentadienyl glycosides that bear a greater variety of Q substituents than are obtainable directly using a trimethylsilyl pentadiene.
• the methods of the invention offer both a general method for forming C. 1 allyl or pentadienyl substituted 2-deoxy-hexopyranoses, and a method specifically for obtaining intermediates in the synthesis of compounds with anti-tumor activity.
• the routes made possible to obtain these compounds are set forth in schematic form in reaction scheme 1.
• R in the compounds of formula (1) or (2) thus produced must be H or methyl, or embodiments of R obtainable by addition to an A-ring carbonyl, as further described below. Additional embodiments of R may be obtained, however, by use of the Wittig reaction with the daunosaminyl acetaldehyde of formula (8) (right hand route).
• the resulting C-glycosidic analogs of the adriamycin group are then used in a manner similar to that disclosed with respect to the adriamycin group per se, as, for example, set forth in U.S. patent 4.464,529 issued 7 August 1984 to the same assignee, and incorporated herein by reference.
• the C-glycosidic ametantrones/mitoxantrones are used as described by Wallace, R. E., et al, Cancer Res (1979) 39:1570; (1980) 40: 1427 incorporated herein by reference.
• a 2-deoxyhexopyranose sugar substrate "activated"-- i.e., containing a suitable leaving group, at position 1 is treated with either allyl trimethylsilane, 2.4-pentadienyl trimethylsilane or the corresponding 2-methoxy-, 2-ethoxy-, 2-methyl-, 2-(2-methoxy)ethoxy- or 2-tetrahydropyranoxy- derivatives of 2,4-pentadienyl trimethylsilane in the presence of a Lewis acid.
• the trimethylsilane starting materials are available by synthesis using known methods. Any available allyl or pentadienyl trimethylsilane compound can be used and the foregoing are listed as among those previously synthesized.
• the substrate sugar is a 2-deoxyhexopyranose having a suitable leaving group at position 1.
• suitable leaving groups include aroyl substituents such as benzoyl, toluoyl, or p-nitrobenzoyl or may be fluoro.
• the p-nitrobenzoyl leaving group is extremely successful, and the reaction is optimally stereoselective when this leaving group is used.
• Alternative leaving groups may result in loss of stereoselectivity. Accordingly, the p-nitrobenzoyl leaving group is highly preferred and it is, indeed, pointless to utilize others as the p-nitrobenzoyl derivative is quite easily made, and is entirely satisfactory.
• the ⁇ p-nitrobenzoyl (pNB) derivative of daunosamine yields almost exclusively the ⁇ glycosylated product.
• the remaining substituents on the pyranose ring may influence the stereoselectivity; in particular an acyl or aroyl group in the 4 position of daunosamine aids in the formation of the ⁇ derivative.
• the substrate sugar may be any 2-deoxyhexopyranose and may have additional deoxy positions, as well as amino substitutions. That is. positions 3, 4, and 6 may each be, independently, OH as in the basic pyranose structure, deoxy, or deoxyamino, wherein the hydroxy and amino groups may occupy either of the two possible chiral configurations.
• amino groups are present, they must be protected by suitable protecting groups such as acyl or aroyl.
• suitable protecting groups such as acyl or aroyl.
• a particularly useful protecting group is trifluoroacetyl. This group is entirely successful, easily attached, easily removed when desired, and quite effective. While alternate protecting groups could, in principle, be used, as was the case with the pNB derivative of the C.1 hydxoxyl, there is no particular point in seeking alternatives in the face of this success.
• Hydroxyl groups are desirably, but not necessarily protected as well. Suitable protecting groups include benzoyl, pNB, and other acyl or aroyl esters. pNB appears particularly satisfactory for this purpose.
• a particularly preferred substrate because of the utility of the products, is a protected daunosamine, e.g. , 1,4-di-O-p-nitrobenzoyl-2,3,6-trideoxy-3-trifluoroacetamido- ⁇ -L-lyxo-hexopyranose.
• a protected daunosamine e.g. , 1,4-di-O-p-nitrobenzoyl-2,3,6-trideoxy-3-trifluoroacetamido- ⁇ -L-lyxo-hexopyranose.
• the reaction is conducted in the presence of a Lewis acid such as TiCl 4 or Me 3 SiOSO 2 CF 3 , and most preferably in the presence of boron trifluoride etherate.
• a Lewis acid such as TiCl 4 or Me 3 SiOSO 2 CF 3
• the reaction is carried out by preparing a mixture of the pyranose and silane reagents in the presence of a moderately polar aprotic organic solvent such as, for example, acetonitrile, ether, or tetrahydrofuran, preferably acetonitrile.
• the Lewis acid for example, boron trifluoride in ether solution is added slowly to the mixture, preferably dropwise.
• the reaction is allowed to increase in temperature to approximately room temperature and stirred for sufficient time to allow the reaction to go substantially to completion, usually around 2-4 hr.
• the product is isolated from the reaction mixture using ordinary means, such as extraction into an inert organic solvent from aqueous base, followed by evaporation
• reaction conditions are quite mild and straightforward, and depending on the stereochemistry of the ring, and the nature of the leaving group, a high yield of the desired ⁇ product (i.e., the ⁇ glycoside) is obtained.
• the resulting C.1-(2,4-pentadienyl)-glycosides can be converted, by Diels-Alder reaction with suitable polycyclic systems, to intermediates in the formation of adriamycin analogs or the corresponding ametantrones.
• the carbohydrate substrate for the Diels-Alder reaction is an N-protected 2,3,6-trideoxy-3-amino- ⁇ -L-lyxohexopyranoside having the C.1 pentadienyl substitution.
• the amino group may be protected by any suitable acylating agent such as and preferably, for example, trifluoroacetyl. This amino group may then, subsequently, be converted to alternative N-derivatives as will be described below.
• the 4-hydroxy group of the daunosamine may be in the free hydroxyl form, or may be esterified by reaction with suitable carboxylic acid derivatives to give the acyl or aroyl or substituted aroyl ester. The ester group may later be removed by standard hydrolysis procedures.
• the dienophile used for the Diels-Alder reaction in preparing the useful intermediates to the adriamycin or ametantrone analogs is generally a polycyclic dione or tetrone, and the product is a naphthacene or anthracene derivative.
• a useful dieneophile is 5,8-dihydroxy-1,4-naphthaquinone.
• useful dieneophile substrates are compounds of the formula:
• the Diels-Alder reaction shown in scheme 3 is performed in the presence of an inert aprotic solvent such as, for example, toluene.
• the reaction is carried out under an inert atmosphere such as nitrogen, at a temperature range of about 60°C-100°C, preferably about 80°C-85°C for approximately several hours.
• the product is isolated using routine procedures.
• the 4-hydroxyl is shown as unprotected; however in a preferred embodiment a pNB group would be used for this purpose.
• the linking methylene in the product is on the opposite side of the ring from the hydrogens of the A/B ring bridge (this resulting from the endo reaction); thus the representations in Reaction Scheme 3 are of diastereomeric pairs which may be separated using standard chromatographic techniques.
• the first steps of the conversion to the target compounds result in enolization of the carbonyl moieties of ring B to a hydroquinone.
• This is a one-step reaction if Z is a ⁇ bond, but a three-step reaction if Z represents an epoxide.
• Z represents an epoxide
• the compound of formula (4) is first reduced to the corresponding alkene in a two step reaction using, first sodium dithionite to aromatize the C ring, followed by treating with lead tetraacetate to give the desired alkene.
• This alkene is, of course, the direct product of the Diels-Alder reaction when Z is a ⁇ bond.
• the alkene is then treated with acid in the presence of a polar solvent and in an inert atmosphere at approximately room temperature for sufficient time to permit the desired enolization to take place. This time is usually 2-6 hr, roughly around 4 hr.
• the desired product of formula (3) is accompanied by a side product of formula (11) as shown in reaction scheme 4.
• the compound of formula (11) may also have useful anti-tumor activity when modified by removal of protecting groups as described in ⁇ B.6 below.
• the protecting group for the amino which is, ideally, trifluoroacetyl is still present.
• the hydroxyl at position 4 will, under most conditions also retain the protecting group which was present through the previous reactions, although the 4-position is shown here with a free OH.
• a and B may also be effected as described in ⁇ B.6. Similarly, removal of protecting groups from the side products of formula (11) results in analogous compounds with anti-tumor activity.
• a ring ⁇ bond will be conducted in a manner dependent on the nature of Q. If Q is H in formula (3) this will be done with a regioselective agent such as a bulky alkyl borane, preferably 9-BBN under conditions suitable for this reagent (see, for example, Brown, H. C, et al, J Am Chem Soc (1977) 99:3427).
• a regioselective agent such as a bulky alkyl borane, preferably 9-BBN under conditions suitable for this reagent (see, for example, Brown, H. C, et al, J Am Chem Soc (1977) 99:3427).
• the addition results in a compound which differs from a compound of formula (1) wherein R is H only in requiring the removal of protecting groups, and optional modification of the sugar substituents, as described in ⁇ B.6.
• the appropriate hydration product is used to obtain an intermediate with a carbonyl group in the A ring.
• Q is H
• the hydration product is oxidized using a relatively mild oxidizing agent, such as dimethyl sulfoxide/dicyclohexylcarbodiimide or pyridinium chlorochromate under neutral conditions to obtain the corresponding ketone.
• Q is a leaving group such as Br or OMe, no oxidation is necessary.
• An acetylide is then added to the ketone as shown in reaction scheme 5, and the product converted to the desired embodiments of R.
• the ketone is treated with a sodium or lithium acetylide, or the corresponding magnesium bromide acetylide and hydrated in the presence of mercuric oxide to obtain the addition product shown in reaction scheme 5 as formula (10).
• Modifications of the acyl group to obtain the various alternate embodiments of R in formula (1) employ conversions known in the art.
• the compound of formula (10) may, itself, be deprotected and modified as desired according to the procedures set forth in ⁇ B.6 to obtain embodiments of the formula (1) wherein R is COCH 3 , such as, for example, 3-acetyl-1,2,3,4-tetrahydro-5,12-dihydroxy-1-[(2,3,6-trideoxy-3-amino- ⁇ -L-lyxo-hexopyranosyl)methyl] naphthacene-6,11-dione.
• the acyl may also be reduced to the corresponding alcohol, thus providing an intermediate for conversion by deprotection and modification procedures to compounds of formula (1) wherein R is CHOHCH 3 , such as 3-(l-hydroxyethyl)-1,2,3,4-tetrahydro-5,12-dihydroxy-1-[(2,3,6-trideoxy-3-araino- ⁇ -L-lyxohexopyranosyl)methyl]naphthacene-6,11-dione. This may optionally be followed by derivatization to the ester or ether. Reaction with bromine at the ⁇ carbon of the acyl substituent permits formation of embodiments wherein R contains a terminal hydroxy or ester or ether derivative thereof.
• R is COCH 2 OH, such as 3-(2-hydroxyacetyl)-1,2,3,4-tetrahydro-5,12-dihydroxy-1-[(2,3,6-trideoxy-3-araino- ⁇ -L-lyxo-hexopyranosyl) methyl]naphthacene-6,11-dione.
• the intermediates bearing the -COCH 2 OH substituent may be used to obtain various additional embodiments of R.
• the carbonyl is reduced to the alcohol, by treating with an appropriate metal hydride, to obtain compounds suitable for deprotection and modification to the various compounds of formula (1) wherein R is CHOHCH 2 OH, such as 3-(1,2-dihydroxyethyl)-1,2,3,4-tetrahydro-5,12-dihydroxy-1-[(2,3,6-trideoxy-3-amino- ⁇ -L-lyxo-hexopyranosyl) methyl]naphthacene-6,11-dione.
• the carbonyl may be reduced to the methylene, leaving intact the terminal hydroxy, thus permitting conversion to compounds of formula (1) wherein R is CH 2 CH 2 OH, and their corresponding esters and ethers.
• Exemplary of such compounds is 3-(2-hydroxyethyl)-1,2,3,4-tetrahydro-5,12-dihydroxy-1-[(2,3,6-trideoxy-3-amino- ⁇ -L-lyxo-hexopyranosyl)methyl]naphthacene-6,11-dione.
• the compounds of the invention of formula (2) which are ametantrone analogs may be prepared from the intermediate obtained by Diels-Alder reaction without preliminary modification of the polycyclic system. The final step will be aromatization of the A ring as shown in reaction scheme 7.
• the boron trifluoride was added dropwise to a mixture of the pyranose and silane in 100 ml of acetonitrile, protected from moisture in an ice bath.
• the eluate (ethyl acetate) contained 380 mg (82%) of foam, which was crystallized from 30 ml of hexane to give 359 mg (77%) of (E)-1-(2,3,6-trideoxy-3-trifluoroacetaraido- ⁇ -L-lyxo-hexopyranosyl)-2,4-pentadiene, mp 111-112oC. Analysis was consistent with C 13 H 18 F 3 NO 3 and the NMR (300 MHz) matched that expected for the desired product.
• the pentadienyl pyranose from Example 4 was first benzoylated at the 4 position. Benzoyl chloride was added to a solution of 150 mg (0.511 mmoles) pyranose in 25 ml of dry pyridine. with magnetic stirring, in an ice bath and protected from moisture. The mixture was brought to room temperature, heated to 45°C for 4 hr and then stirred at room temperature for 18 hr. The solution was poured into 100 ml ice water and extracted with 2 x 50 ml CHCl 3 .
• the CHCl 3 was washed with 50 ml 1 N HCl, 50 ml saturated NaHCO 3 and 50 ml H 2 O. The CHCl 3 was then dried over MgSO 4 , filtered and evaporated to dryness to yield 210 mg (103%) of a syrup. This residue was chromatographed on a 20 x 20 cm x 2 mm thick silica gel plate with 25% EtOAc/hexane and gave R f ⁇ 0.45. The eluted (EtOAc) product was 182 mg which remained a gum on "recrystallization" with Et 2 O/hexane or MeOH/H 2 O. The IR showed no OH and good benzoyl carbonyl peaks and the NMR was consistent with the expected product.
• the Diels-Alder product from the condensation of the epoxyanthracene system was converted to a compound of formula (3) in a three step process that includes a two step conversion of the epoxide to the corresponding alkene ( ⁇ s A and B), followed by aromatization of the B ring.
• NMR showed a mixture of desired product and compound made by internal Diels-Alder reaction with positions 4a and 9a of the tetrone.
• desired product is unstable to silica gel, it was subjected to aromatization as set forth below without further purification.
• Example 8 ⁇ B.
• TFA was removed from the product of Example 9, ⁇ B to give 1-[(2,3,6-trideoxy-3-amino- ⁇ -L-lyxohexopyranosyl)methyl]-9,10-anthraquinone as follows: 50 mg (0.112 mmoles) of 1-[(2,3,6-trideoxy-3-trifluoro acetamido- ⁇ -L-lyxo-hexopyranosyl)methyl]-9,10-anthraquinons were mixed with 1 ml N butyl amine in 15 ml MeOH.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=24705589

Family Applications (1)

Country Status (3)

Families Citing this family (1)

• 1985
  • 1985-10-07 EP EP19850905166 patent/EP0202245A1/de not_active Withdrawn
  • 1985-10-07 WO PCT/US1985/001917 patent/WO1986003201A1/en unknown
  • 1985-10-29 CA CA 494083 patent/CA1330792C/en not_active Expired - Fee Related

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events