WO1993021204A1 - Procede de preparation de cholesta-5,7-diene-3 beta,25-diol, et d'analogues de celui-ci - Google Patents

Procede de preparation de cholesta-5,7-diene-3 beta,25-diol, et d'analogues de celui-ci Download PDF

Info

Publication number
WO1993021204A1
WO1993021204A1 PCT/US1993/003556 US9303556W WO9321204A1 WO 1993021204 A1 WO1993021204 A1 WO 1993021204A1 US 9303556 W US9303556 W US 9303556W WO 9321204 A1 WO9321204 A1 WO 9321204A1
Authority
WO
WIPO (PCT)
Prior art keywords
structural formula
lower alkyl
compound
carbon atoms
diene
Prior art date
Application number
PCT/US1993/003556
Other languages
English (en)
Inventor
Masato Tanabe
John G. Johansson
Dennis Yasuda
Original Assignee
Sri International
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sri International filed Critical Sri International
Publication of WO1993021204A1 publication Critical patent/WO1993021204A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only

Definitions

  • This invention relates generally to synthetic methods involving steroids, and more particularly relates to a novel method for preparing cholesta-5,7-diene-3B,25-diol and analogs thereof.
  • the invention additionally relates to novel steroids useful as intermediates in the aforementioned process.
  • the present invention derives from the development of a biotechnological fermentation process that produces a yeast sterol mixture enriched in cholesta-5,7,24-triene-3B-ol and accompanied by other di-olefinic yeast sterol metabolites.
  • the aforementioned trienol having the chemical structure (I)
  • the present invention derives from the aforementioned process, and involves the rnodificafion of the Diels-AIder adducts at the ⁇ r ⁇ double bond prior to adduct cleavage.
  • the present process is a simple, straightforward synthesis which is especially useful in the preparation of cholesta-5,7-diene ⁇ 3B,25-dioI, a pro-vitamin D3 metabolite which may be converted by sunlight or otherphotochemical methods to yield 25-hydroxy vitarni ⁇ D3.
  • the invention also enables the preparation of analogs of cholesta-5,7-diene-3B,25-diols which contain structural modifications at the C-l, C-2, C-3 and or C-ll positions.
  • the compounds which may be prepared using the techniques of the present invention are valuable as synthetic intermediates in the preparation of vitamin D analogs. They also constitute, in a general sense, high value-added chemical products and may be used in a variety of contexts, e.g., in topical pharmaceutical formulations for the treatment of skin diseases or the like, in oral vitamin compositions, and as livestock feed additives.
  • Khim..9(1):118-122 (1983) disclose a cyclopropylcarbinyl rearrangement for preparing 25-hydroxychloresterol and 25- hy droxyprovitamin D3.
  • the synthesis involves an intermediate which is a Diels-AIder adduct of a
  • a synthetic method which involves (a) reacting a Diels-AIder adduct having the structural formula
  • the R's are both N or both C-Q wherein the Q's are H or together form a third bond;
  • X and Y are electron-withdrawing groups and independently are -COOH, -CHO, -NO2,
  • R 2 is H, lower alkyl or monocyclic aryl of 5 to 7 carbon atoms and containing up to 5 ring substituents, wherein the ring substituents are -(CO2) n -NH2, -(CH 2 )-COOH, -NO2, halogen or lower alkyl, wherein n is an integer in the range of 0 to 6 inclusive;
  • R3 is H or R'CO- wherein R' is lower alkyl or monocyclic aryl of 5 to 7 carbon atoms; and
  • R , R5 and R" are independently H, hydroxyl or lower alkyl.
  • R's, X, Y, R ⁇ , R ⁇ , R ⁇ and R > are as defined above.
  • novel compounds are provided having the structural formula
  • R ⁇ , R and R-* are as defined above.
  • a sterol includes mixtures of sterols
  • reference to “a steroid” includes mixtures of two or more steroids, and the like.
  • Alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • Preferred “alkyl” groups herein contain 1 to 12 carbon atoms.
  • “Lower alkyl” refers to an alkyl group of 1 to 6, more preferably 1 to 4, carbon atoms.
  • Alkylene refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (-CH2-), ethylene (-
  • “Lower alkylene” refers to an alkylene group of 1 to 6, more preferably 1 to 4, carbon atoms.
  • Alkenylene refers to a difunctional branched or unbranched hydrocarbon chain containing from 2 to 24 carbon atoms and at least one double bond.
  • Lower alkenylene refers to an alkenylene group of 2 to 6, more preferably 2 to 5, carbon atoms.
  • Alkynyl refers to a branched or unbranched acetylenically unsaturated hydrocarbon group of 2 to 24 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, octynyl, decynyl, tetradecenyl, hexadecynyl, and the like.
  • “Lower alkynyl” refers to an alkynyl group of 2 to 6, more preferably 2 to 4, carbon atoms.
  • “Lower acyl” refers to an acyl group wherein R' is lower alkyl as defined above.
  • Aryl refers to a phenyl or 1- or 2-naphthyl group.
  • “Monocyclic aryl” refers to a phenyl group.
  • these groups are substituted with up to five ring substituents selected from the group consisting of -(CH2) n -NI_2, -(CH 2 ) n -COOH, -NO2, halogen and lower alkyl, where n is an integer in the range of 0 to 6 inclusive.
  • Arylene refers to a difunctional aromatic moiety; "monocyclic arylene” refers to a phenylene group. These groups may be substituted with up to four ring substituents selected from the group consisting of -(CH2) n -NH2, -(CH2) n -COOH, -NO2, halogen and lower alkyl, where n is an integer in the range of 0 to 6 inclusive.
  • Halo or “halogen” refers to fluoro, chloro, bromo or iodo, usually regarding halo substitution for a hydrogen atom in an organic compound. Of the halos, chloro and fluoro are generally preferred with fluoro generally being the more preferred.
  • Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted phenyl means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl wherein there is substitution.
  • This system is intended to conform the numbering of the cyclopentanophenanthrene nucleus to the convention used by the IUPAC or Chemical Abstracts Service.
  • the term "steroid” as used herein is intended to mean a chemical compound having the aforementioned cyclopentanophenanthrene nucleus.
  • ⁇ and ⁇ indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn.
  • ⁇ denoted by a broken line
  • ⁇ indicates that the group at the position in question is below the general plane of the molecule as drawn
  • ⁇ denoted by a bold line
  • bonds are not explicitly indicated to be “ ⁇ ” or “ ⁇ ”, it should be assumed that the structural formula encompasses both types of compounds, with the stereochemical configuration of the naturally occurring steroid molecule preferred.
  • the five- or s ⁇ x-membered rings of the steroid molecule are often designated A, B, C and D as shown.
  • sterol as used herein is intended to mean a steroid molecule having the backbone structure illustrated above, and containing at least one hydroxyl group, typically a single hydroxyl group at the 3-position.
  • purified compound intends a composition which contains at least about 80 wt.% of that compound, preferably at least about 90 wt.%, and most preferably at least about 99 wt.%.
  • R wherein the R's, X, Y, R , R ⁇ and R ⁇ are as defined above.
  • the R ⁇ moiety, if other than H, is thus a hydroxyl-protecting group; typical R ⁇ moieties are H, CH3CO-, and Cg ⁇ CO-. If R , R-> and R" are other than H and OH, they will generally be methyl or ethyl, more typically methyl.
  • the substituents X and Y are electron-withdrawing groups which are as defined earlier herein. Examples of particular dienophiles within the aforementioned group include the following:
  • dienophiles are available commercially from a number of sources, e.g., from the Aldrich Chemical Company, Milwaukee, WI. As will be appreciated by those skilled in the art, such dienophiles may also be readily synthesized using conventional techniques (see, e.g., S.W. Moje and P. Beak, J. Org. Chem. 39f20.:2951 (1974), and K. Rufenacht, Helv. Chim. Acta 51:518 (1968)).
  • a dienophiie precursor is used which may be converted to a dienophiie with a suitable oxidizing agent.
  • the dienophiie precursor has the structural formula X-NH- NH-Y wherein X and Y are as defined above.
  • Exemplary dienophiie precursors are wherein X and Y are linked together to form a -(CO)-Z-(CO)- bridge, with Z as defined above.
  • Z is monocyclic arylene of 5 to 7 carbon atoms substituted with up to 2 substituents selected from the group consisting of -(Cf_2) n -NI_2 and -(CH2) n -COOH, wherein n is an integer in the range of 0 to 6 inclusive.
  • Dienophiie precursors within the aforementioned group may be available commercially or may be readily synthesized using starting materials and techniques known to those skilled in the art of synthetic organic chemistry. Examples of particular dienophiie precursors useful herein (again, such compounds are available commercially, or may be readily synthesized) include the following:
  • Any oxidizing agent capable of oxidizing the dienophiie precursor to an active dienophiie may be used, with the exception of oxidizing agents which could interfere with the formation of the Diels-Alder adduct or which could interact detrimentally in some other way with any of the sterols in the sterol mixture.
  • exemplary oxidizing agents include potassium peroxymonosulfate, lead tetraacetate, iodosobenzene diacetate, N-bromosuccinimide and t-butyl hypochlorite.
  • both types of reactions are carried out in an inert atmosphere, in a non-reactive, preferably polar organic solvent effective to dissolve the reactants.
  • the oxidizing agent be added gradually to a solution of the sterol and the dienophiie in the selected solvent, and that the procedure be carried out at a relatively low temperature, i.e., 10°C or lower (0°C to 5 * C, as may be obtained by an iceXwater bath, is optimal). At least about 15 minutes, preferably at least 1 hour, should be allowed for the reaction to occur.
  • the adduct is removed from the reaction mixture, preferably chromatographically.
  • a silica gel column which will preferentially bind the adduct is particularly preferred.
  • the adduct is then purified using conventional methods, e.g., using recrystallization, precipitation or chromatographic techniques, prior to use in the present synthetic method.
  • the chemical and physical properties of the Diels-Alder adduct can be varied by manipulating the substituents present on the dienophiie as well as by varying R ⁇ .
  • basic properties can be imparted to the Diels-Alder adduct by the use of a dienophiie containing a basic substituent, e.g., - I_2, -(C__2) n -N__2, or the like.
  • the adduct is then a basic molecule and separable from the reaction mixture using acid extraction.
  • acidic properties can be imparted to the Diels-Alder adduct by the use of a dienophiie containing an acid substituent, e.g., -COOH,
  • the adduct will then be an acidic molecule and separable from the reaction mixture using basic extraction.
  • R3 may be converted to a functionality which imparts desirable crystallization and/or precipitation parameters.
  • a hydroxyl group present at C-3 may be readily converted to a benzoate species, which in turn will make the adduct more crystalline and more readily separable from the reaction mixture.
  • the present invention involves reaction of the Diels-Alder adduct with an oxidizing agent effective to convert the ⁇ 2 double bond to a 24,25-oxido moiety, followed by treatment with a reducing agent selected to effect adduct cleavage, opening of the 24,25-epoxide, and conversion of the C-3 moiety to a hydroxyl group.
  • the first reaction, oxidation may be represented by the following scheme:
  • the reaction is preferably carried out on the adduct as isolated and purified as described in the preceding paragraph.
  • Virtually any oxidizing agent may be used here, providing that the agent is effective to convert the 24,25-double bond to an epoxide functionality and does not cause any side reactions to occur in the remainder of the molecule.
  • Suitable oxidizing agents include, for example, peracetic acid, __2 ⁇ /base, perphthahc acid, N-bromosuccinimide (e.g., in an acetone/water r ⁇ ixture), and m-chloroperoxybenzo ⁇ c acid.
  • the reaction is carried out by gradually adding the oxidizing agent to a solution of the Diels-Alder adduct in a selected solvent, preferably a nonpolar organic solvent, at a relatively low temperature, i.e., 10 ⁇ C or lower (0 ⁇ C to 5°C, as may be obtained by an ice/water bath, is optimal). At least about 15 minutes, preferably 30 minutes or more, is allowed for the reaction to occur.
  • the 24,25-oxido derivative may be isolated by evaporating the solvent from the reaction mixture.
  • the 24,25-oxido isolated in the preceding step is then treated with a reducing agent selected such that three separate molecular transformations will occur approximately simultaneously: (1) cleavage of the Diels-Alder adduct to regenerate the 5,7-diene moiety; (2) conversion of the 24,25- epoxide moiety to yield a 25-hydroxy functionality; and (3) if R ⁇ is other than hydrogen in the Diels-Alder adduct, conversion of the C-3 moiety to a hydroxyl group.
  • This reaction may be represented as follows:
  • Suitable reducing agents include, for example, lithium aluminum hydride (“LAH”), diisobutyl aluminum hydride (“DiBAL”), Red-Al® (a solution of sodium bis(2-methoxy-ethoxy) aluminum hydride in toluene, available from the Aldrich Chemical Company, Inc., Milwaukee WI.) or the like. Lithium aluminum hydride is particularly preferred.
  • the reaction proceeds initially at a low temperature, i.e., 10 * C or lower (again, as may be obtained by an ice/water bath), followed by, after at least about 30 minutes, warming to at least about 50° C for at least several minutes. Excess reducing agent and any salts or derivatives thereof are then removed, e.g., by filtration through celite or the like. Evaporation of the reaction mixture will then give rise to the 5,7-diene- containing, 25-hydroxy steroid.
  • LAH lithium aluminum hydride
  • DIBAL diisobutyl aluminum hydride
  • R's, X, Y, R 3 , R 4 , R 5 and R 6 are defined above.
  • Preferred compounds within this class include the following:
  • the crude product was dissolved in a mixture of ethyl acetate and 20% hexane, and filtered through silica gel (125 g). After all the non-reacted sterols had been washed off the column, the adduct was eluted with 50% ethyl acetate in hexane. The yield of pure adduct was
  • Example 5 The procedure of Examples 1 through 4 may be repeated, except that 4-phen l-l,2,4- triazoIine-3,5-dione (e.g., as may be obtained from Aldrich Chemical Co.) is substituted for phthalhydrazid in the procedure of Example 1 and no lead tetraacetate is used.
  • 4-phen l-l,2,4- triazoIine-3,5-dione e.g., as may be obtained from Aldrich Chemical Co.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention se rapporte à un procédé de synthèse de cholesta-5,7-diène-3β,25-diol, et d'analogues de celui-ci. Un additif diénique d'un stéroïde contenant un 5,7-diène et une double liaison Δ24 est mis en réaction avec un agent oxydant pour produire une fraction 24,25-oxydo, après quoi un traitement est effectué au moyen d'un agent de réduction pouvant sequestrer l'additif et convertir la fraction 24,25-oxydo en un groupe 25-hydroxy. De nouveaux composés, qui sont des additifs diéniques de stéroïdes contenant du 5,7-diène, et qui contiennent un groupe 24,25-oxydo, son également décrits.
PCT/US1993/003556 1992-04-15 1993-04-14 Procede de preparation de cholesta-5,7-diene-3 beta,25-diol, et d'analogues de celui-ci WO1993021204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86932892A 1992-04-15 1992-04-15
US07/869,328 1992-04-15

Publications (1)

Publication Number Publication Date
WO1993021204A1 true WO1993021204A1 (fr) 1993-10-28

Family

ID=25353349

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/003556 WO1993021204A1 (fr) 1992-04-15 1993-04-14 Procede de preparation de cholesta-5,7-diene-3 beta,25-diol, et d'analogues de celui-ci

Country Status (1)

Country Link
WO (1) WO1993021204A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093192A1 (fr) 2015-11-30 2017-06-08 Dsm Ip Assets B.V. Cristallisation du 25-hydroxy-7-déhydrocholestérol
CN109627279A (zh) * 2019-02-01 2019-04-16 浙江花园营养科技有限公司 一种活性维生素d3中间体的制备方法
CN111892637A (zh) * 2020-07-16 2020-11-06 山东海能生物工程有限公司 一种7-脱氢-25-羟基胆固醇的制备方法
CN113004367A (zh) * 2019-12-19 2021-06-22 帝斯曼知识产权资产管理有限公司 新的狄尔斯-阿尔德加合物和衍生物

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF GENERAL CHEMISTRY USSR vol. 46, no. 7, July 1976, NEW YORK US pages 1598 - 1600 M. K. SHAKHOVA ET AL 'Structure of the Product of the Jones Chromium Trioxide Oxidation of the 1,4-Phthalazinedione-7-Dehydrocholesterol Adduct' *
JOURNAL OF GENERAL CHEMISTRY USSR vol. 58, no. 1, January 1988, NEW YORK US pages 191 - 198 A. I. SHUL`MAN ET AL 'Synthesis of Hydroxylated Group D Provitamin Derivatives' *
JOURNAL OF ORGANIC CHEMISTRY. vol. 39, no. 14, 12 July 1974, EASTON US pages 2018 - 2023 J. P. MOREAU ET AL 'Synthesis of 5-alpha-Cholesta-7,24-dien-3-beta-ol and Cholesta-5,7,24-trien-3-beta-ol' cited in the application *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, no. 22, 1973, LETCHWORTH GB pages 2731 - 2733 D. R. CRUMP ET AL '22(S)-Hydroxyvitamin D4' cited in the application *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, no. 7, 1976, LETCHWORTH GB pages 731 - 735 S. C. EYLEY ET AL 'Synthesis of 25-Hydroxyprovitamin D3 and 25,26-Dihydroxyprovitamin D3' cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093192A1 (fr) 2015-11-30 2017-06-08 Dsm Ip Assets B.V. Cristallisation du 25-hydroxy-7-déhydrocholestérol
US10316055B2 (en) 2015-11-30 2019-06-11 Dsm Ip Assets B.V. Crystallization of 25-hydroxy-7-dehydrocholesterol
CN109627279A (zh) * 2019-02-01 2019-04-16 浙江花园营养科技有限公司 一种活性维生素d3中间体的制备方法
CN113004367A (zh) * 2019-12-19 2021-06-22 帝斯曼知识产权资产管理有限公司 新的狄尔斯-阿尔德加合物和衍生物
CN111892637A (zh) * 2020-07-16 2020-11-06 山东海能生物工程有限公司 一种7-脱氢-25-羟基胆固醇的制备方法

Similar Documents

Publication Publication Date Title
DE2463203C2 (fr)
EP1274718B1 (fr) Procede de preparation de 7.alpha.-hydroxy 3-aminosubstitues sterols au moyen de produits intermediaires dotes d'un groupe 7.alpha.-hydroxy non protege
AU2001253427A1 (en) A process for the preparation of 7.alpha.-hydroxy 3-aminosubstituted sterols using intermediates with an unprotected 7.alpha.-hydroxy group
HU191131B (en) Process for preparing 13-alpha-alkyl-gonanes and pharmaceutical compositions containing such compounds
AU746559B2 (en) Stereoselective synthesis of 24-hydroxylated compounds useful for the preparation of aminosterols, vitamin D analogs, and other compounds
EA015478B1 (ru) ПРОМЫШЛЕННЫЙ СПОСОБ СИНТЕЗА 17-АЦЕТОКСИ-11β-[4-(ДИМЕТИЛАМИНО)ФЕНИЛ]-21-МЕТОКСИ-19-НОРПРЕГН-4,9-ДИЕН-3,20-ДИОНА И КЛЮЧЕВЫЕ ПРОМЕЖУТОЧНЫЕ СОЕДИНЕНИЯ ДАННОГО СПОСОБА
EP0023856B1 (fr) Dérivés 17-((hydroxyméthyl)(formamido) méthylène) stéroides, leur préparation, leur application à l'introduction de la chaîne latérale hydroxyacétyle
FI87791B (fi) Foerfarande foer framstaellning av 17 -(cyklopropyloxi)androst-5-en-3 -ol och naerstaoende foereningar, som aer anvaendbara som c17-20 lyas inhibitorer
KR20030028456A (ko) 불포화 지방산 촉매를 사용하여 스테롤 5,7-디엔의디일즈-앨더 부가물을 제조하는 방법
WO1993021204A1 (fr) Procede de preparation de cholesta-5,7-diene-3 beta,25-diol, et d'analogues de celui-ci
DE69005709T2 (de) Adduktaldehyd und seine Anwendung in der Herstellung von Vitamin-D-Derivaten.
US5391777A (en) Isolation of steroids containing a 5,7-diene functionality from a sterol mixture
EP0015122A1 (fr) Dérivés du 25-hydroxy-24-oxo cholestane et leur préparation
JPS58124800A (ja) Δ↑５‖↑７−ステロイドの製造方法
JP3228488B2 (ja) ２０−エピステロイド誘導体およびその製造方法
KR20100063370A (ko) 로큐로니움 브로마이드의 제조방법
HU187843B (en) Process for producing 17-alpha-hydroxy-17-beta-bracket-hydroxy-acetyl-bracket closed-steroides
GB2075982A (en) 1-3-dihydroxy-27-nor-cholesta-5-en and 5,7-dien-25-one
US7868194B2 (en) Process for the preparation of 21-hydroxy steroids with control of the epimeric distribution at the C-21 position
JP2953665B2 (ja) ステロイド誘導体の製造方法
Göndös et al. Synthesis and oxidation of pregna‐3, 5‐dien‐20‐ols and‐20‐one and selective reduction of pregna‐3, 5‐dien‐20‐one
EP1389623B1 (fr) Synthése stéréoselective de composés hydroxyles-24 utiles dans la préparation d'aminostéroles, d'analogues et vitamine d et d'autres composés
JP2714392B2 (ja) ステロイド誘導体の製造法
TWI570131B (zh) 製備１７－經取代類固醇之方法
WO2002101014A2 (fr) Procede permettant la production de steroides estra-4,9(10)-diene

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP KR

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA