• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1527161 Steroid 3-enol esters LEO AB 18 Feb 1977 [19 Feb 1976] 06512/76 Heading C2U The invention comprises compounds of formula wherein St is a steroid #<SP>2</SP>-3-yl or #<SP>3</SP>-3-yl radical comprising up to 40 carbon atoms (inclusive of substituents) and a total of 1-4 double bonds in the gonane nucleus; and R is wherein R<SP>1</SP> is C 2-4 #- or γ-haloalkyl (the halogen being Cl or Br); R<SP>2</SP> is H, C 1-4 alkyl, C 1-4 alkoxy or halo; A is a C 1-4 n-alkylene or C 2-4 n-alkenylene radical optionally bearing (a) 1 or 2 C 1-4 alkyl groups, and/or (b) an amino or C 1-4 alkanoylamino group on the carbon atom adjacent to the CO; X is O or S; and k and m are each 0 or 1, k being 1 when m is 1. Preparation of I is by enol esterification of the parent storoid 3-ones. Modifications and alternative preparations are also described but not exemplified. Anti-tumour compositions for oral, parenteral, topical, rectal and vaginal administration comprise a compound I and a carrier.
    公开号:SU828970A3
    申请号:SU772451700
    申请日:1977-02-14
    公开日:1981-05-07
    发明作者:Якоб Фекс Ханс；Вальдемар Хансен Бертил；Аксель Холмберг Кристер；Бертил Хегберг Кнут；Кенивес Имре
    申请人:Актиеболагет Лео (Фирма)；
    IPC主号:
    专利说明:

    Values of, or bgo, the cancer-containing, untreated, derivative are reacted with steroid B,, C10to: ry l1 means the keto form of the compound St-OH, in the presence of an anhydride, such as transfluoru, xus, anhydride, or a catalyst — a strong organic or neorga: VIVECO acids, such as arylsulphonic or superhloric acid, with the keto and hydroxyl groups in steroid B being protected, if necessary, followed by the release of the protector, and then peleviuyu products are isolated by known α-methods. Example 1. A mixture consisting of 4 {4-N, IsI-6ac (2-chloroethyl) -amine-phenyl yl butane anhydride (82.6 g), 17-aceto: xypreg-4-en-3, 20 -dione (18.6 g) and 4-toluenexy sulfonic acid (3.8 g), heated at 100 ° C under nitrogen atmosphere IB for 3 hours, and then a mixture of pyridine (200 ml) and ice (60 g ). After 3 h, add a 5 M "HCI solution (1000x1) to the cooling solution and extract the solution with a mixture (1: 1) ethyl acetate-ether (3x500 ml). The organic phase is washed with 0.5 M aqueous K2CO3 solution and water, dried and evaporated. An oil is obtained, which is subjected to an xp OLM atomic form on a silica gel column using toluene: ethyl acetate (2: 1) as a solvent for the eluoride. The eluate fraction (R / 0.5) gives 17 -acetoxy-3-, X-6 "c (2-chloroethyl) -amino-phenyl} -butanoyloxy-Pregna-3,5-diene-20-one (1), tm 151 -152 ° C after recrystallization from mix ef.ir - hexane. Similarly, from the corresponding starting materials of the genus 1, the following compounds are obtained: 4; 4 - X, N - Bis (2-chloroethyl) - amino phenyl} - bta: oyloxy | - pregna-3,5-dien 20-one. 17 ( 3-Aieto, xi-3- {4-lN, N-6 "c (2-chloroethyl) amylo-phenylaceto-ks1 1 -androsta-3,5-diene 17 | 3-Acetoxy-3-1 {3-1 4-IN, N-6wc (2-chloroethyl) -amino-phenoxy} -propanoyloxy j} 17a-methyl: ndrosta-3,5-que, n Pr, 17p-Diacetoxy-3- (, N-bis (2chloroethyl) - amino - phenylthioacetoxy J-9afluoro-17a-methylandrosta-3, 5-diene, 17p-Acetoxn-3 3, N-6uc (2-chloro-propyl) amino-4-methylbenzoyl-oxy; -7a, 17-dimethylandrost-3, 5-diene 17 | 3-Acetocai-17-allyl-3, N-6 "c (2-chloroethyl) -adino-phenyl) -pentanoyloxy} -estra-3,6-que, n 17p-Acetoxy-3- ((3-, N-6uc (2-chloroethyl) -amino-phenyl-propenoyl)} 17a-ethyn-18-methyl}} es11ra-3,5-diene 21-Acetoxy-3- { {2- {4 -, Н -byc (2 - ethyl chloro) - amino - phenyl - 2 - methylproiodoyl lkgi 1 -fi-iiiTon-l 1B-oxy-16a, 17 - isopropyl 3 - (- 4- (, N -6uc (2-chloroethyl) -amino-utanoyloxy-17 | 3-P: royanoyloxy} estra, 5-cie: H 17 | 3-Aceto.xI-3-i; -i, N-6Mc (2-chlorotyl) -amino1-phenyl 1 -butanoyloxy I -androta-3, 5-diene 17p-Aieto1Xi-3-M 4-, N-6wc (2-chloroethyl) -amino-phenyl} -butanonloxy) -andost-2-en 3- {{(2S) -2-Acetamido-3-4-N, N-bis (2-chloroethyl) -amino-phenyl-1-iropanoyloxy}) -17 p-propanoyl-oxo-androst-3,5-diene 17-Acetoxy-3 -, N-6ac (2-chloroethyl) amine-phenyl-acetoxy} -pregna-3,5-diene-20o; n 17.21 - Diacetocio-3- ((4-, M-bys (2 chloroethyl) amino) fen yl} - butanoyloxy) cregna-3 .5-diene-11,20-dione 17,21 - Diacetoxy-3-1 (4-, N-6wc (2 chloroethyl) amino-phenyl I-butanoyloxy} .pregna-3 , 5-dien-20-one 21 - Acetoxy-3- {{4-4-lN, N-bms (2-chloroethyl) -a; mino-phenyl} -butanoneXi} -pregna-3, 5-diene-20 -one Pip and M er 2. In a mixture consisting of, N - b "c (2-chloroethyl) -amino-4-methylbenzoic acid (26.2 g) and trifluoro-xyloxy angi chloride (21.0 g) was added 17 p-acetoxy-5a-androstan-3-one (16.6 g). After 24 hours, toluene is added at room temperature and the solution is washed with water, with an aqueous solution of MaNSO3 and again with water. After drying and evaporation, an oil is obtained which is subjected to chromatographic analysis of aylsacyl colo: Nke using toluene-ethyl acetate (2: 1) as eluent. The eluate fraction (R / 0.5) gives 17 (5-acetoxy-3-, N-6Mc (2-chloroethyl) -amino-4-methyl-benzoyloxy-androst-2-ene (1). The structure is confirmed by NMR, IR spectra and analysis C1. The distinctive features of the NMR spectrum are the following: b (ppm) 0.79 and 0.81 (singlets, GN each, P-18 and H-19), 2.02 (S, GN, -COCH ), 3.42 (S, 8H, 2-CH2CH2C1), 4.63 (wide t, 1H, H-27), 5.18 (wide S, 1H, H-2), 7.27 and 7.78 (doublets with J 8, 1H each, aromatic H), 7.87 (S, 1P, aromatic H). Similarly, the following compounds are obtained from the corresponding starting products (their structure is confirmed as above): 17P - Acetate hydroxy-3- {, N-6 "c (2-chloroethyl) -amino-phenyl} -butanoyloxy-17-ethynyl-estra-3, 5-day 3-I, (2-chloroethyl) -amino-4-methyl-benzoyloyl-17p -; methoxyester - 3,5diene 17p-Aceto-xi-3-, M-bys (2-chloroethyl) ampho-benzoyloxy) -17a-ethylether - 3.53- ((5-4-D-Bis (2- chloroethyl) -am1-phenyl-pentanoyl. oxy} -2-methyl-17p-prop aioi xy a, nd p opt-2 - en
    3- {, N-5 "c (2 - bromoethyl) - amnno-4metplbenzoyloks | -17r-.hexa, butilox - 4methylandrost-3-ene
    17p-Acetoxn-3- (, N-bis (2-chloroethyl) -amino-4-methylbenzonlops} 17a-ethynylestyl-3, 5 (10) -diene
    3- I, N-J5g / c (2-chloroethyl) -a-mino -4methylbenzoyloxy j -21-diclopentyloxyprene-3a, 5-diene-20-one
    3 - {{3- 1 4- (N, N-Bwc (2-chloroethyl) -amnophenoxy) -propanoyl-Oxy; 1 -17,21-d1-shroopanoyloxypregna-3, 5-diene-11,20-D | IO; H
    11p, 17,21-Triacetoxy-3-4-S, H - bis (2chloroethyl) - aiMHHo - phenylacetoxypregna 3, 5-dien-20-one
    17 - Acetaksn - 3- {, Xb "with (2-chloroethyl) -amino-4-met1ILban30; ILO | Xi} -pregna 3, 5-di, en-20-one
    17-Acetoxn-3-M-chloro-3-ChL-bis (2 chloroethyl) -amino-bexsiloxy} -pregna3, 5-dien-20-one
    Example 3. A mixture consisting of 17a: cethoxy-16-meth, ylen 111g: na-4,6-diene - 20-one (19.1 g), N, bis (2-chloroethyl) amino-4-methylbenzoyl chloride ( 24.4 g) t of pyridine (80 lgl), heated at 50 ° C for 4 hours. After cooling, the reaction mixture was heated (ice was added into ice water and the solution was extracted with a mixture (1: 1) of toluene-ethyl acetate (3X100 ml The combined extracts are washed with 2M HCl solution, water, aqueous NaHCOs solution and again with water, dried and evaporated, which gives an oil, which is subjected to chromatographic analysis on silica gel | Colo, Nke using as a solution It is eluted with a mixture of toluene-ethyladetate (2: 1). The eluate fraction (R / 0.5) gives 17-acetoxy-3-3-S, M-by-2-chloroethyl-amino-4 methyl benzoyl-16- 1methylpredgene - 3,5,7trien-20-one (1).
    Similarly to the corresponding dosage (The following products are obtained in the starting products:
    17-Benzoyloxy- 3- {4-D-bis (2-chloroethyl) -amido-alpha.n., ylacetoxy.-Ji-6-methylpregde-3, 5,7-triene-20yy
    17-Acetoxy.-6-hlar-3-114- {4-IN, N-6uc (2hlsretil) -am alco-fedil-butanodloxy; 1 1a, 2a-1methylenpregna-3,5,7-t, rien-20-one
    1113,17,21-Triadetokoki-Z-, N - bms (2 chloropropyl) -amino-4-methyl benzo: Iloxy I 9a-fluoro-16 | 3-methylpregna-1D5-trien-20-one
    17,21-Diacetoxy-3- {, Y-bis (2-chloro-1Il) -amino-phenylthio-acetoxy 1 -prepna1, 3,5-triene-11,20-dio
    IL, 17,21 - Triacetoxy-Z-1, N byc (2-chloroethyl) - amino - phenyl-butanoyloxy}) pregna-2,3,5-trien-20-one
    11p, 17,21-Triacetoxy-3- {, N-6 "c (2 bromoeth | Il) amino-4-methylb: enzoyloxy} -9afluoro-16a-methylpreg-1, 3,5-triene-20-0 | H
    11p, 21-diacetoxp-3- {, N-6 "c (2-chloroethyl) -amino-phen) L I-propenoyloxy}} 9a-fluoro-16a, 17 - isopropylidenedioxypregna-1, 3.5-tr yen-20-one
    3- ({4- I, N-6Hc (2-chloroeth | Il) -amino phenyl} -butanoyloxy 1} -hydrosta-3,5-dden17r-phosphate
    3-1, X-bns (2-chloroethyl) -amino-4 methylbenzoyl-oxophenol-3,5-di € H - 17 phosphate.
    Ф о ip м у л and invented and
    1. A method for producing steroids enol esters of the general formula
    St-r
    where R is a group of general formula
    20
    NR
    -0-С- (А) к-) п.
    25
    where R is p-halogen-substituted alkyl C3, while halogen - hlar or bromine;
    W A
    hydrogen, lower alkyl; a straight Co-C4 hydrocarbon chain which 1 can be saturated OR can contain one double bond, the drich group A can be mono- or di-substituted by lower alkyl 1LI in the a-position.HI to -C-prop11 O
    ne is monosubstituted by lower alkane o and l and M: P; n ogre ul l o i; X - DZ group is selected, including
    -O- and -S-;
    1 w - to disavow dr} t from each other, equal to 0; 1, moreover, if m 1, then k 1;
    St - steroid residue, such as estra-3,5-diene, aster - 3.5 (10) dden, 5a-androst-2-ene, 5a-androst-3-ene, androsta - 3.5 - diene, Alregna-3,5-diene, Pregna-1,3, B-triene or Pregna-3,5,7-triene, containing max: x maximum of up to 40 carbon atoms, including substituents, the specified steroid residue attached to R in The third report is distinguished by the fact that the acid of the general formula
    60
    one
    kk
    IOOg- (A) to-1X) t
    - R65
    7
    where A, X, R, R2, k, and m are as defined above, or its reactive derivative is reacted with its steroid B, which is the keto form of the compound St-OH, in the presence of an anhydride, such as Trifluoroacetic anhydride, or a catalyst strong organic or inorganic acid, such as arylsulphonic acid or pschloric acid, with keto- and gdro8
    The cmrg groups in Stronghold B, if necessary, are plucked up with a subsequent removal of the zagcytes, after which the pellucid products are isolated.
    Source of information taken into account in the examination:
    1. US Patent No. 3,732,260, cl. 260397 .45, publ. 08.05.73.
    权利要求:
    Claims (1)
    [1]
    Claim
    1. The method of obtaining complex enolic esters of steroids of the General formula
    St — R where R is a group of the general formula o
    -o - C - (A) k - ( x ) m. ^ 2 where R 1 is a β-halogen-substituted C 2 - C 3 alkyl, with the halogen being chlorine or bromine;
    R 2 is hydrogen, lower alkyl;
    A is a straight hydrocarbon chain C 2 —Cl, which may be saturated or may contain one double bond; moreover, group A may be mono- or di-substituted by lower alkyl or in the α-position to —C — πρνπII O not monosubstituted by lower alkanol l a min ogre ull oy;
    X is selected from the group comprising —O— and —S—;
    k and m are independently 0; 1, moreover, if m = 1, then k = 1;
    St is a steroid residue such as estra-3,5-diene, estra-3,5 (10) diene, 5a-and.rost-2-ene, 5a-androst-3-ene, androsta - 3,5 - diene, pregna-3,5-diene, pregna-1,3,5-triene or pregna-3,5,7-triene containing up to a maximum of 40 carbon atoms, including substituents, said steroid residue being attached to R in the third position characterized by the fact that an acid of the general formula
    HYO with (-A-) k 1 ^ -) where A, X, R 1 , R 2 , k and m have the above meanings, or its reactive derivative is reacted with steroid B, which is a ketoform of the compound St — OH, in the presence of an anhydride, such as trifluoroacetic anhydride, or a catalyst, a strong organic or inorganic acid, such as arylsulfo, new or perchloric acid, the keto and hydroxy groups in steroid B are protected, if necessary, followed by removal protection, after which the target products are isolated.
    Source of information taken into account during the examination:
    1. US patent He 3732260, CL 260397.45, published. 05/08/73.
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    同族专利:
    公开号 | 公开日
    SE7700170L|1977-08-20|
    US4150126A|1979-04-17|
    ATA111977A|1980-01-15|
    AU511532B2|1980-08-21|
    JPS52100458A|1977-08-23|
    CA1087167A|1980-10-07|
    AT358200B|1980-08-25|
    FR2341594B1|1980-09-19|
    NL7701585A|1977-08-23|
    NO770560L|1977-08-22|
    FI57114B|1980-02-29|
    DK71977A|1977-08-20|
    BE851649A|1977-08-22|
    ES456057A1|1978-06-01|
    NZ183376A|1980-04-28|
    AU2209177A|1978-08-17|
    FR2341594A1|1977-09-16|
    GB1527161A|1978-10-04|
    DE2707121A1|1977-09-01|
    FI770296A|1977-08-20|
    HU176558B|1981-03-28|
    LU76795A1|1978-10-18|
    FI57114C|1980-06-10|
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    US4260736A|1978-08-14|1981-04-07|Kureha Kagaku Kogyo Kabushiki Kaisha|Steroid hormone-antitumor derivatives|
    US4261910A|1978-08-14|1981-04-14|Kureha Kagaku Kogyo Kabushiki Kaisha|Process for the preparation of Chlorambucil derivatives|
    US4512986A|1983-07-26|1985-04-23|Research Triangle Institute|Progrestationally active steroids|
    JPH0156079B2|1985-06-21|1989-11-28|Kureha Chemical Ind Co Ltd|
    JPH0621072B2|1986-11-12|1994-03-23|呉羽化学工業株式会社|Immunomodulator consisting of estradiol derivative|
    GB9003939D0|1990-02-21|1990-04-18|Imperial College|Sulphatase inhibitors|
    US5429934A|1990-08-18|1995-07-04|Schering Aktiengesellschaft|Process for the production of 20-methyl-5,7-pregnadiene-3β,21-diol derivatives using mycobacterium|
    GB9118465D0|1991-08-29|1991-10-16|Imperial College|Steroid sulphatase inhibitors|
    GB0304927D0|2003-03-04|2003-04-09|Resolution Chemicals Ltd|Process for the production of tibolone|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB6512/76A|GB1527161A|1976-02-19|1976-02-19|Enol esters of steroids|
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