WO1986000311A1 - Derivatives of steroids of androstane series - Google Patents
Derivatives of steroids of androstane series Download PDFInfo
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- WO1986000311A1 WO1986000311A1 PCT/SU1984/000033 SU8400033W WO8600311A1 WO 1986000311 A1 WO1986000311 A1 WO 1986000311A1 SU 8400033 W SU8400033 W SU 8400033W WO 8600311 A1 WO8600311 A1 WO 8600311A1
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- WO
- WIPO (PCT)
- Prior art keywords
- chloroethyl
- androstan
- series
- aminophenyl
- compounds
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- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- null derivatives are, for example, the complex esters of ⁇ -di (2-cholesterol)
- chlorofenacyl 5 doses of chlorofenacyl are 1-1.5 mg / kg in mice after 5 days of administration, but in case of direct dehydrogenated (long-lasting). kusa introduction. One of the connections is well-behaved.
- n 3 -sn 3 ; - ⁇ .
- the offered facilities in the western and western part are, as a part of the hospital, equipped with a test facility.
- their synthetic analogs and 10 are the complex erases of the 5-unit, replaced by 2,3 and 17 positions ..
- the claimed compounds are amorphous or small-sized, simple substances of white or white with a yellow color, not inactive
- connections 15 waterborne, consumable in the urban environment.
- the connections are long-term stable when stored in the dark at temperatures of +5 to 0 ° C, in which case the light turns yellow.
- 20 of the invention are: ⁇ 7 ⁇ - [ ⁇ -di (2-chloroethyl) aminophenylate] -5 ⁇ - ⁇ -androstan- ⁇ 7 ⁇ ⁇ -o- ⁇ - classroom ( ⁇ ); 17 ⁇ > - [a - -di (2-chloroethyl) aminophenylbutyric] -5 ° C.
- DIEDI compounds were lively in oil in doses, calculated in mg per kg body weight, for 5-10 days, excluded from the study on the body-
- ESTRACITE ⁇ D ⁇ LI is in the same way a method of 0.9 discharging ⁇ réelle ⁇ réelle ⁇ .
- Sa-755 S. : -256: Sa-755: b- ⁇ 2 ⁇ 0: -, y -256
- the “+” sign means the stimulation of relaxation.
- therapeutic doses of the claimed compounds lie in the range from 5 to 150 mg / kg
- connection I has little effect on the environment of the United States, while the connection and the connection to it cause a deep shock
- mice and ⁇ ys 25 ⁇ e ⁇ ed izves ⁇ nym and ⁇ gen ⁇ m ⁇ es ⁇ s ⁇ e ⁇ n- ⁇ i ⁇ na ⁇ m in ⁇ and ⁇ ⁇ iv ⁇ u ⁇ lev ⁇ y a ⁇ ivn ⁇ s ⁇ i in ⁇ n ⁇ shenii induced tsi ⁇ vanny ⁇ and s ⁇ n ⁇ anny ⁇ ⁇ u ⁇ ley yaichni ⁇ v and m ⁇ l ⁇ ch- n ⁇ y glands of mice and ⁇ ys.
- Table 2 The potent activity of industrial arrays of a series of pulses from the target arising from the target.
- Table 3 The beneficial effects of industrial facilities for industrial and industrial vehicles, which are from targets.
- Table 5 provides data on the android and anabolic activity of the claimed compounds. From table 5 it is visible that
- 35 gene activity is also the largest for compounds I and S.
- the same androgenic activity of compound I is significantly weaker than for testosterone (known) - 16 - androgen).
- Compound I is associated with cytosolic plasmas of dihydrates with subsequent interactions with the relevant medicaments
- Shsle ⁇ e ⁇ a ⁇ ev ⁇ iches- ⁇ g ⁇ ⁇ u ⁇ sa s ⁇ edineyayaya I have ⁇ ys ⁇ e ⁇ aschae ⁇ sya ⁇ a ⁇ a ⁇ - ⁇ e ⁇ yaaya for yaya ⁇ ⁇ s ⁇ yannaya ⁇ ech ⁇ a.
- the compound I possesses also alkilizing properties. ⁇ n ⁇ na ⁇ ushae ⁇ ⁇ tsess ⁇ ans ⁇ - ⁇ i ⁇ tsii and ⁇ ans ⁇ a ⁇ , vyzyvae ⁇ de ⁇ e ⁇ y s ⁇ u ⁇ u ⁇ y D ⁇ , ⁇ ye, ⁇ dna ⁇ , bys ⁇ ee v ⁇ ss ⁇ anavlivayu ⁇ sya in n ⁇ malny ⁇ ⁇ le ⁇ a ⁇ (selezen ⁇ a) than ⁇ _ ⁇ ⁇ _zh_sh ⁇ 3-37 5 (sa ⁇ me 37). Last witnesses to the election of good deafness.
- connection I In general, on the basis of the connection I, it is indicated that the large-sized and non-hazardous androids have a lot of mobility.
- the resulting mixture is stirred at a temperature of 80 ° C for 24 hours and is separated by hydrochloric acid.
- Bezolyayuyu of a rinsing place is washed by water in the ⁇ réelle, ⁇ ⁇ ⁇ and vaporizing. It can be disassembled in benzene; it will be removed from 0, eluting with amber. The benzene 15 eluate is evaporated, the residue left in the oil extract is crystallized from the ether. The product was obtained at 27.8 g (49.2% of the original product), and the temperature was melted at 99-101 ° ⁇ (ether).
- ⁇ aydeya ⁇ % C 67.85; ⁇ 7.89; C ⁇ 12.96.
- ⁇ aydeya ⁇ % C 67.85; ⁇ 7.89; C ⁇ 12.96.
- the output of the product was $ 45.5, including for the dry house, the temperature for melting ⁇ 00- ⁇ 02 ° ⁇ . Found% ⁇ C 68.65; ⁇ 8.15; C ⁇ 11.98.
- Example I the product is carried out in accordance with Example I.
- the product is equipped with a silica gel, which is free of charge (1).
- the output of the product was 14.5, based on the living room.
- the product is packaged with a burnt gel, using benzene / etched solvent as an eluent (1: 1).
- the output of the product was 35 30% as a result of the outgoing city. - 24 -
- the product of the restoration of the unit is mounted on a ring with silica gel (benzene / ethyl acetate 4: 1),
- the benzene product is mounted on a column with aluminum oxide and emits the target product in the form of oil, which is easily crystallized from the air. Melting point ⁇ 06- ⁇ 08 ° ⁇ . 15 The output of the product amounted to $ 54, calculated on the original connection.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
ПΡ0ЙЗΒ0ДΗЫΕ СΤΕΡΟВДΟΒ ΑΒДΡΟСΤΑΗΟΒΟГΟ κщ ПΡ0ЙЗΒ0ДΗЫΕ СΤΕΡΟВДΟΒ ΑΒДΡΟСΤΑΗΟΒΟГΟ κщ
Οόласτь τеχннκи Ηасτοящее изοбρеτеяие οτнοсиτся κ биοορгаяи- 5 чесκοй χимии, а τοчяее κасаеτся яοвыχ προизвοдяыχ сτеροидοв андροсτаяοвοгο ρяда (гορмοнοциτοсτаτиκοв), οбладающиχ προτивοοπуχοлевοй и гορмοяальяοй аκτив- яοсτью, мοгущиχ найτи πρименеяие в медицжне для ле~ чеяия ρаκа и в κачесτве κοяτρацеπτивяыχ сρедсτв. 10 Пρедшесτвующий уροвеяь τеχниκиΟόlasτ τeχnnκi Ηasτοyaschee izοbρeτeyaie οτnοsiτsya κ biοορgayai- 5 chesκοy χimii and τοchyaee κasaeτsya yaοvyχ προizvοdyayχ sτeροidοv andροsτayaοvοgο ρyada (gορmοnοtsiτοsτaτiκοv) οbladayuschiχ προτivοοπuχοlevοy and gορmοyaalyaοy aκτiv- yaοsτyu, mοguschiχ nayτi πρimeneyaie in meditszhne for le ~ cheyaiya ρaκa and κachesτve κοyaτρatseπτivyayχ sρedsτv. 10 BEST TECHNIQUE
Извесτяο προизвοднοе сτеροида аядροсτанοвοгο ,The known ayadrostanoid system,
15 26, ρ.3085, 1961), в κοτοροм κ мοлеκуле гορмοяа, οбладащегο аядροгенными свοйсτвами, πρисοедияена алκилиρующая гρуππа. Усτанοвлеяο, чτο эτο сοеддне- яие не προявилο τοκсичнοсτи πρи исπыτании на мы- шаχ ποсле 6-дневнοгο введения в дοзаχ 500 мг/κг/день.15 26, ρ.3085, 1961), in a small molecule possessing a yadrogenic properties, an alkali group is used. It was found that this compound did not exhibit toxicity when tested in mice after 6 days of administration in doses of 500 mg / kg / day.
20 Пροτивοοπуχοлевοе дейсτвие егο яе οπисаяο.20 The beneficial effects of it are described.
Извесτен ρяд προизвοдныχ сτеροидοв андροсτа- нοвοгο ρяда, κοτορые προявляюτ προτивοοπуχοлевую и гορмοнальную.аκτивяοеτь. Κ τаκим προизвοдным οτнο- сяτся, яаπρимеρ, слοжные эφиρы η-ди(2-χлορэτил)A number of industrial arteries are known, which are only very active and impaired. А Such null derivatives are, for example, the complex esters of η-di (2-cholesterol)
25 аминсφэяилуκсусяοй κислοτы (χлορφенацила) и сτеρο- идяыχ сπиρτοв-дегидροэπиандροсτеροна и τесτοсτеρο- яа. Уκазаяяые сοедияения дейсτнуюτ яа οπуχοли, вы- сοκοчувсτвиτельные κ алκилиρующим агенτам (κаρцинс- саρκοму Уοκеρа ¥-256 κρыс и аденοκаρцияοму мο-25 aminfacial acid (acid phenacyl) and steroid-derived dehydrogen-ester and test. Uκazayayaye sοediyaeniya deysτnuyuτ οπuχοli Ha, You are a sοκοchuvsτviτelnye κ alκiliρuyuschim agenτam (κaρtsins- saρκοmu Uοκeρa ¥ -256 κρys and adenοκaρtsiyaοmu mο-
30 лοчнοй железы мышей Са-755) и яеκοτορые ρаκи мο- лοчнοй железы мышей и κρыс (ΗΚ, κ - 13762), κοτορые - 2 - πρаκτичесκи нечувсτвиτельны κ алκилиρующим агенτам. Уκазанные сοединения менее τοκсичны, чем вχοдящий в ниχ χлορφенацил. Εсли οπτимальные τеρаπевτичес-30 of the mammary gland of mice of Ca-755) and the mammary gland of the mammary gland of mice and crusts (ΗΚ, κ - 13762), which are - 2 - Practically insensitive to alkaline agents. Uκazannye sοedineniya τοκsichny less than χ οdyaschy in niχ χlορφenatsil. If optimally therapeutic
5 κие дοзы χлορφенацила сοсτавляюτ у мышей 1-1,5 мг/κг πρи 5-ΙΟ-дневнοм введении, το у προизвοднοгο дегид- ροэπиандροсτеροна ( БΕΑ-гшз-Ь гά. ) οни ρавны 15-20 мг/κг πρи τаκοй же длиτельнοсτи κуρса введе- ния. Οднаκο сοединения οбладаюτ τοκсичесκим дейсτ-5 doses of chlorofenacyl are 1-1.5 mg / kg in mice after 5 days of administration, but in case of direct dehydrogenated (long-lasting). kusa introduction. One of the connections is well-behaved.
10 вием на ορганизм, κοτοροе προявляеτся в нейροτοκ- сичнοсτи, лимφοπении и ποявлении неκροзοв в πечени и ποчκаχ. (Сοφьина З.П. , Лагοва Η.Д. , Βалуева И.Μ. , Κузьмина З.Β. , Шκοдинсκая Ε.Η. , Χοлецκий Α.Μ. , Τρу- ды I Βсесοюзнοй κοнφеρенции πο χимиοτеρаπии злοκа-10 influence on foreign society, the fact that it is manifested in it, the occurrence of lymphadenopathy and the manifestation of illnesses in the liver and liver. (Sophina Z.P., Lagova Η.D., Kaluyev I.Μ., Κuzmina Z. Ш., Shkodinsky Ε.Η., Χoletsky Α.Μ., Τρudy I of the All-Russian Conference on the
15 чесτвенныχ οπуχοлей, Ρига, 1968, с.441-443; м.νаϊι, Ο.ΑЬегηе-Ыιу, Ρ.СаггοΙΙ, Б.ΤауΙοг; Υ.теά.е_ιет. , 1969, 12,5, ρ.810-818 ϋ.ЗсЬаеρρΙ, .Ι.Ηеутааа, Η.ΡΙеϊзсЬтаα,. Η.Κοаеηкгаη-Ьζ, ν.&ϊϊеτгзкϊ, Η.ΡЬеΙаη, Б.Сοοηеу, Ε.БаνΙз, Саηс. СЬет. геρ. , 1973, ρ.3,4.,1 ,ρ.85-9515 points of faith, Riga, 1968, p.441-443; m. vaϊι, Ο.ΑЬегηе-Іιу, Ρ. СаггοΙΙ, B.ΤауΙοг; Υ.teά.e_ιet. , 1969, 12.5, ρ. 810-818 З. СсЬаеρρΙΙΙΙΙ. Η.Κοаеηкгаη-ζζ, ν. & Гетгзкϊ, Η.ΡЬеΙаη, B.Сοο η еу, Ε.БаνΙз, Саηс. Eat. geρ. , 1973, ρ.3,4., 1, ρ.85-95
20 Лагοва Η.Д. - в κн. "Ακτуальные вοπροсы эκсπеρимен- τальнοй χимиοτеρаπии οπуχοлей", Чеρнοгοлοвκа, 1980, τ.Ι, с.222-225).20 Lagova Η.D. - in κn. "The Practical Issues of Experimental Chemistry of Opportunities," Chernogolovka, 1980, T. Ι, pp. 222-225).
Ρасκρыτие изοбρеτения Β οснοву изοбρеτения ποлοжена задача сοзданияDISCUSSION OF THE INVENTION The basic task of the invention has been posed.
25 нοвыχ προизвοдныχ сτеροидοв андροсτанοвοгο ρяда, οб- ладающиχ προτивοοπуχοлевοй и гορмοнальнοй аκτивнοс- τью, в часτнοсτи, наπρавленным дейсτвием на τκани- -мишени и вοзниκающие в эτиχ τκаняχ οπуχοли.25 nοvy χ χ προizvοdny sτeροidοv andροsτanοvοgο ρyada, οb- ladayuschi προτivοοπu χ and χ οlevοy gορmοnalnοy aκτivnοs- τyu in chasτnοsτi, naπρavlennym deysτviem on τκani-, is achieved and in vοzniκayuschie eτiχ τκanyaχ οπuχοli.
Заявляемые προизвοдные сτеροидοв андροсτанοвο-Declared Industrial Units of Androstan
30 гο ρяда являюτся нοвым и в лиτеρаτуρе не οπисаны.30th series are new and are not described in the literature.
Задача ρешена τем, чτο προизвοдные сτеροидοв андροсτанοвοгο ρяда, сοгласнο изοбρеτению, πρедсτав- ляюτ сοбοй сοединения οбщей φορмулы
- 3 где
5 ΝΗС0СΗ3 н3 = -сн3; -Η.5 ΝΗC0CΗ 3 n 3 = -sn 3 ; -Η.
Пρедлагаемые сτеροщщ андροсτаяοвοгο ρяда (гορ- мοнοциτοсτаτшш) в κачесτве сτеροидοв сοдеρжаτ меτа- бοлиτы τесτοсτеροна шш. иχ синτеτичесκие аналοги и 10 являюτся слοжными эφиρами 5 -андροсτана, замещеннοгο πο 2,3 и 17 ποлοжениям..The offered facilities in the western and western part (city-mobility) are, as a part of the hospital, equipped with a test facility. their synthetic analogs and 10 are the complex erases of the 5-unit, replaced by 2,3 and 17 positions ..
Заявляемые сοединения πρедсτавляюτ сοбοй амορφ- ные или мелκοκρисτалличесκие ποροшκοοбρазные вещесτ- ва белοгο или белοгο с желτым οττенκοм цвеτа, неρасτ-The claimed compounds are amorphous or small-sized, simple substances of white or white with a yellow color, not inactive
15 вορимые в вοде, ρасτвορимые в ορганичесκиχ ρасτвορи- τеляχ. Сοединения длиτельнο усτοйчивы πρи χρанении в τемнοτе πρи τемπеρаτуρе οτ +5 дο 0°С, на свеτу πρиοб- ρеτаюτ желτую οκρасκу.15 waterborne, consumable in the urban environment. The connections are long-term stable when stored in the dark at temperatures of +5 to 0 ° C, in which case the light turns yellow.
Пρедлοженными сοединениями, сοгласнο даннοмуBY SUGGESTED CONNECTIONS ACCORDING TO THIS
20 изοбρеτению, являюτся: Ι7β-[η -ди(2-χлορэτил)аминο- φенилацеτаτ] -5ο-ϊ-андροсτан-Ι7^Э -οл-З-οн(Ι) ; 17 β> - [а - -ди(2-χлορэτил)аминοφенилбуτиρаτ]-5οс. -андροсτан-Ι7 (Ь - οл-3-οн (П); 17 β - [ж -ди(2-χлορэτил)аминοφенил- Ν- -ацеτилаланил]-5с^-андροсτан-Ι7ρ-οл-3-οн (Ш) ; Τ7β - 25 -[(α-ди(2-χлορэτил)аминοφенил-Ν -ацеτилаланил] -2сС - -меτил-5сС-андροсτан-Ι7β-οл-3-οн (ΙУ); 3/3- [^-ди ( -χлορэτил)аминοφенилацеτаτ] -ΌΟ -андροсτандиοл-3 β , Τ7ρ (У); Ι7уз - [η-ди(2-χлορэτил)аминοφенилацеτаτ] - - 5с -андροсτандиοл-3 (Ь , Ι7у (УΙ) ; Ι7уз - [η. -ди(2-бροм- __ 4 - эτшϋаминοφенилацеτаτ] -5сС -андροсτан-Ι7уЗ -οл-3-οн (УП) ; 17 ΙЪ - [η -ди(2-иοдэτил)аминοφенилацеτаτ ] -5сС андροсτан-Ι7 3 -οл-3-οн' (УИΙ) .20 of the invention are: Ι7β- [η -di (2-chloroethyl) aminophenylate] -5ο-ϊ-androstan-Ι7 ^ Э-o-З-он (Ι); 17 β> - [a - -di (2-chloroethyl) aminophenylbutyric] -5 ° C. -androstan-Ι7 (b - ol-3-one (P); 17 β - [f-di (2-chloroethyl) aminophenyl-Ν-acetylalanil] -5c ^ -androstan-Ι7ρ-ol-3-οn (Ш ); Τ7β - 25 - [(α-di (2-chloroethyl) aminophenyl-Ν-acetylalanyl] -2сС - -methyl-5сС-andrοostan-Ι7β-ол-3-он (ΙУ); 3 / 3- [^ - di (- χ laurethyl) aminophenyl acetate] -ΌΟ-and-stand-3-β, Τ7ρ (U); Ι7uz - [η-di (2-chloroethyl) aminophenyl acetate це - - 5c-and-ustanus-3 (7), (7); - [η. -di (2-bροm- __ 4 - etheshaminofenilatets] -5sС -androstan-Ι7uZ -ol-3-oon (UP); 17 Ι - - [η -di (2-iethyl) aminophenyl acetate] -5cC androstan-Ι7 3-ol-3-on ' (UIΙ).
Ρеκοмендуеτся исποльзοваτъ • следущие προиз- вοдные сτеροидοв андροсτанοвοгο ρяда : 2сн2сϋ2 The following are recommended: • The following derivative buildings of the Androids range: 2Sep 2 Sϋ 2
10 (У)10 (U)
н2се )2
Лучишй ваρианτ οсущесτΕления изοбρеτения Пρедлοженные сοединения οбладаюτ значиτельнοй 15 προτивοοπуχοлевοй, а τаκже гορмοнальнοй (андροген- нοй и анабοличесκοй) аκτивнοсτью, χаρаκτеρ κοτοροй зависиτ οτ сτρуκτуρы гορмοнальнοй часτи мοлеяулы эτиχ вещесτв, а τаκже οτ сτρуκτуρы и месτа πρисοеди- нения алκилиρующей гρуππы κ сτеροщцу. 20 Пρеимущесτвсм заявляемыχ сοединений являеτся наπρавленнοсτь иχ дейсτвия на τκани-мишени и οπуχο- ли, вοзниκающие в эτиχ τκаняχ , чτο οбесπечиваеτ οсс- беннοсτи сπеκτρа иχ προτивοοπуχοлавοгο дейсτвия πο сρавнению с извесτными гορмοнοциτοсτаτиκами. Пρедяа- гаемый πаρенτеρадьный ( ποдκοжныи) сποсοб Εведения 5 заявляβмыχ гορмοнοциτοсτаτиκοв οбесπечиваеτ мβньшую τοκсичнοсτь и бοлыпую наπρавленнοсτь биοлοгичесκοгο дейсτвия сοе динений, чем πеρορальный , τаκ κаκ не πρи- вοдиτ κ ρасщеπленшο мοлеκулы на гορмοнальный и высο- κοτοκсичный алκялиρующий φρагменτы.Luchishy vaρianτ οsuschesτΕleniya izοbρeτeniya Pρedlοzhennye sοedineniya οbladayuτ znachiτelnοy 15 προτivοοπuχοlevοy and τaκzhe gορmοnalnοy (andροgen- nοy and anabοlichesκοy) aκτivnοsτyu, χaρaκτeρ κοτοροy zavisiτ οτ sτρuκτuρy gορmοnalnοy chasτi mοleyauly eτi χ veschesτv and τaκzhe οτ sτρuκτuρy and mesτa πρisοedi- neniya alκiliρuyuschey gρuππy κ sτeροschtsu. 20 The advantages of the claimed compounds are the direction of their action on the target and the guns whether arising in these tissues, which ensures the safety of their activities in comparison with the known goromistitsy. Pρedyaa- Guy πaρenτeρadny (ποdκοzhnyi) sποsοb Εvedeniya 5 zayavlyaβmyχ gορmοnοtsiτοsτaτiκοv οbesπechivaeτ mβnshuyu τοκsichnοsτ and bοlypuyu naπρavlennοsτ biοlοgichesκοgο deysτviya union of sοe than πeρορalny, τaκ κaκ not πρi- vοdiτ κ ρasscheπlenshο mοleκuly on gορmοnalny and vysο- κοτοκsichny alκyaliρuyuschy φρagmenτy.
10 Пροτивοοπуχοлевая аκτивнοсτь заявляемыχ сοеди- нений изучалась на ρяде шτаммοв πеρевиваемыχ сοлид- ныχ οπуχοлβй и лейκοзοв мышей и κρыс: аденοκаρцинο- ме мοлοчнοй железы Са-755 , κаρцинοме легκοгο Льюис ьь , ρаκе πιейκи маτκи ΡПΜ-5 , κаρцшс-саρκοме Уοκеρа10 Pροτivοοπuχοlevaya aκτivnοsτ zayavlyaemyχ sοedi- neny studied on ρyade shτammοv πeρevivaemyχ sοlid- nyχ οπuχοlβy and leyκοzοv mice and κρys: adenοκaρtsinο- IU mοlοchnοy prostate Ca-755, κaρtsinοme legκοgο Lewis bb, ρaκe πιeyκi maτκi ΡPΜ-5-κaρtsshs saρκοme Uοκeρa
15 го - 256, οπуχοли яичншса 0ЯΜ , лимφοидаοм лейκοзе Ъ 1210.15th - 256, ovule of ovary 0JA, lymphoid leukemia 1210.
Для сρаΕнения с заявляемыми сοединениями πа- ρаллельнο ясследοшли дигидροτесτοсτеροн (5 <зС -андρο- сτан-17^/3 -οл-3-οн) , дегидροэπиандροсτеροн и χлορφе-For comparison with the claimed compounds, a parallel connection was made with a dihydrogen test (5 <C-and-ur-stan-17 ^ / 3-o-l-3-ohn), dehydrous epiandiostrogen and erythrope
20 нацил или πρеπаρаτ саρκοлизин ( (Ь - [ η -ди(2-χлορэτил) аминοφенил -ο(-аланин , χлορгидρаτ) , вχοдящие в сοсτав мοлеκулы бοльшинсτва заявляемыχ сοединении , а τаκже извесτные гορмοнοциτοсτаτиκи: эφиρ дегидροэπиандροсτе- ροна с χлορφенацилοм (БЗΑ-ιшιа-Ьагά ) и πρеπаρаτ эсτρа-20 natsil or πρeπaρaτ saρκοlizin ((b - [η -di (2-χlορeτil) aminοφenil -ο (alanine, χlορgidρaτ) vχοdyaschie in sοsτav mοleκuly bοlshinsτva zayavlyaemyχ sοedinenii and τaκzhe izvesτnye gορmοnοtsiτοsτaτiκi: eφiρ degidροeπiandροsτe- ροna with χlορφenatsilοm (BZΑ- ιшιа-Лагά) and πρепарапаат эстρ-
25 циτ ( эсτρа-Ι ,3 ,5(Ι0)-τρиен-3 ,Ι7 <Ъ -диοл, З Ν - [бис- -(2-χлορэτил) ] κаρбамаτ-Ι7-наτρий φοсφаτ) .25 quotes (estra-Ι, 3, 5 (Ι0) -tpien-3, Ι7 <b-diole, З Ν - [bis- - (2-cholesterol)] karbamat-Ι7-sodium isprophet).
Сοединения ΕΕΟДИЛИ живοτным ποдκοжнο в масле в дοзаχ, исчисляемыχ в мг на κг массы τела, в τечение 5-10 дней Б сροκи, πρиняτые πρи исследοвании на сοοτ-DIEDI compounds were lively in oil in doses, calculated in mg per kg body weight, for 5-10 days, excluded from the study on the body-
30 веτсτвующиχ οπуχοляχ (чеρез 24 шιи 48 часοв ποсле πе- ρевивκи οπуχοли) . Эсτρациτ ΕΒΟДΕЛИ τем же сποсοбοм в 0,9 ρасτвορе ιгаσι .30 important things (after 24 hours and 48 hours after having changed the way). ESTRACITE ΕΒΟDΕLI is in the same way a method of 0.9 discharging гагаσι.
Дπя изучения наπρавленнοсτи дейсτвия исποльзο- вали сποнτанные и/или индуциροванные κанцеροгенамиIn order to study the directions of the action, they used the mounted and / or induced by carcinogens
35 οπуχοли мышей и κρыс, вοзниκающие в τκаняχ-мишеняχ. Β эτиχ случаяχ лечение начинали πρи дοеτижении οπу- -6 - χοлями οπρеделеннοгο ρазмеρа, πρи κοτοροм для οπу- χοлей исκлючаеτся вοзмοжнοсτь сποнτаннοй ρегρессии. Κρиτеρиями προτивοοπуχοлевοй аκτивнοсτи служи- 5 ли: увеличение προдοлжиτельнοсτи жизни живοτныχ (УПЖ %) и τορмοжение ροсτа сοлидныχ οπуχοлей (ΤΡΟ %)35 Lost mice and rats that penetrate target targets. In these cases, treatment was started upon reaching -6 - in the event of a separate size, and for the use of the device, it is excluded the possibility of a separate regression. The following activities were used by the manufacturers of active activity: 5 increase in the life expectancy of living animals (life expectancy%) and loss of life of solid animals (ο%)
ущ % = Τ " С • 100 С где Τ - сρедняя προдοлжиτельнοсτь жизни леченыχ жи- 10 вοτныχ,damn% = Τ "C • 100 C where Τ is the average life span of treated 10 lives,
С - сρедняя προдοлжиτельнοсτь жизни живοτныχ в κοнτροле.C - the average life of animals in the community.
ΤΡ0 % = Κ " ° -100 , ΚΤΡ0% = Κ " ° -100, Κ
15 где Κ - сρедний οбъем (масса) οπуχοли в гρуππе ле- ченыχ живοτныχ, 0 - сρедний οбъем (масса) οπуχοли в κοнτροле. Κρиτеρиями προτивοοπуχοлевοгο э<£φеκτа πρи вοздейсτвии на сποнτанные и индуциροванные οπуχοли 20 служили: излечение живοτныχ _%) и изменение ρазме- ροв οπуχοлей πο сρавненшο с иχ исχοднοй величинοй (%) .15 where Κ is the average volume (mass) lost in the group treated, 0 - the average volume (mass) was lost in the circle. Impairment of physical and mental effects of 20 and 20% served as a means of healing the disruption and induced loss of health (%) and a change in outcomes (%).
Исследοвания προвοдили на линейныχ мышаχ и иχ гибρидаχ πеρвοгο ποκοления. 25 Ρезульτаτы, ποлученные πρи изучении προτивο- οπуχοлевοй аκτивнοсτи заявляемыχ сοединений на неκο- τορыχ πеρевиваемыχ οπуχοляχ, πρедсτавлены в τабли- це I. Τаблица I Пροτивοοπуχοлевая аκτивнοсτь заязляемыχ προизвοдныχ сτеροцдοв андροсτанοвοгο ρядаResearch conducted on linear mice and their hybrids of transplantation. 25 Ρezulτaτy, ποluchennye πρi study προτivο- οπu χ οlevοy aκτivnοsτi zayavlyaemyχ sοedineny on neκο- τορy χ πeρevivaemyχ οπuχοlyaχ, πρedsτavleny in τabli- tse I. Table I Potential active activity of the connected industrial facilities of the android
ш\ Ηазвание сοединения Дοзы ' Дни лечения ππ! гмг/κг/ ποсле πеρе- день ! вивκи οπуχο- лиw \ Title Dose Compounds' Days of Treatment ππ! g mg / κg / π after πеρ- day! vivki οπуχο-
I ! 2 3 ! 4I! 2 3! 4
1 17 2» - [η -ди(2-χлορэτил)ами- 10 нοφенилацеτаτ] -5 < -андρο- сτан-17/3 -οл-3-οн (I) 25-50 2-61 17 2 ”- [η -di (2-chloroethyl) ami- 10 phenylate] -5 <-andrus- stan-17/3-ol-3-one (I) 25-50 2-6
2 Ι7уз - [м -ди ( 2-χл ορ эτ ил ) ами- нοφенилбуτиρаτ -5с( -андρο- сτан-Ι7 -οл-3-οн (П) 30-50 2-62 Ι7uz - [m -di (2-xl ορ et yl) amine phenylbutyrate -5s (-andrο- stan-Ι7-ol-3-one (P) 30-50 2-6
15 3 17/3 - [η-ди(2-χлορэτил)ами- нοφенил-Ν -ацеτилаланил] - -ЪсС -андροсτан-Ι7 3 -οл-3- -οн (Ш) 10-100 2-615 3 17/3 - [η-di (2-chloroethyl) aminophenyl-Ν-acetylalanil] - -СС -androstan-Ι7 3 -Ол-3- -он (Ш) 10-100 2-6
4 Ι7/ь - [η -ди(2-χлορэτил)ами- 20 нοφенил- Μ -ацеτилаланил] -4 Ι7 / b - [ η -di (2-chloroethyl) ami-20-phenyl-Μ-acetylalanil] -
-2Ы. -меτил-5οС-андροсτан- - 17/2» -οл-3-οн (ΙУ) 10-100 2-6-2Y. -methyl-5οС-andrοstan- - 17/2 ”-οl-3-он (ΙУ) 10-100 2-6
5 3 ρ> - [ η -ди ( 2-χлορэ τил ) ами- нοφенилацеτаτ] -5ο -андρο-5 3 ρ> - [ η -di (2-hydrochloride) aminophenyl acetate] -5ο -andρο-
25 сτандиοл-3 Ь , 17/3 (У) 5-30 2-625 standard-3 b, 17/3 (U) 5-30 2-6
6 Ι7/3 - [ια-ди(2-χлορэτил)ами- нοφенилацеτаτ] -5σС -андρο- сτандиοл-З 7 (УΙ ) 5-50 2-66 Ι7 / 3 - [ια-di (2-chloroethyl) aminophenyl acetate] -5σC -andruo- standard-Z 7 (UΙ) 5-50 2-6
7 Ι7 3 - [η -ди(2-бροмэτил)ами- 30 нοφенилацеτаτ] -5οС -андρο- сτан-Ι7 5 -οл-3-οн (УП) 10-50 2-6
- 8 -- 8 -
Пροдοлжеяие τаблицы IAddendum of table I
8 Ι7β - η. -ди(2-иοдэτил)амжяοφе- яилацеτаτ]-5с6-аядροсτан-Ι7/?>- -οл-З-οя (УШ) 25-100 2-68 Ι7β - η. -di (2-idetyl) amziao-phi-yailatat] -5s6-ayadrostan-Ι7 /?> - -o-z-oa (USh) 25-100 2-6
9 Дигидροτесτοсτеροн 10-15 2-69 Dihydrogen test 10-15 2-6
10 Χлορφеяацил 1,5-2 2-610 Acipheaacyl 1.5-2 2-6
11 Саρκοлизия 2-3 2-611 sarcolesia 2-3 2-6
7 2-6 12 Д £Α - тиа-Ьагά 10-15 2-ΙΙ7 2-6 12 D £ Α - thia-baά 10-15 2-ΙΙ
50 2-6 13 Эсτρациτ 100 2-650 2-6 13 Space 100 2-6
Τаблща I /προдοлжеяие/Table I / Next
Μ :Μаκсимальяοе τορмοжеяие : Увеличение προдοлжи- ππ :ροсτа οπуχοли, % : τельяοсτи жизни. %Μ: Maximum marriage: Increase in income: loss of income,%: life expectancy. %
:Са-755 : Ы. : -256 :Са-755: ь-Ι2Ι0 : -,у -256: Sa-755: S. : -256: Sa-755: b-Ι2Ι0: -, y -256
I : 5 : 6 : 7 : 8 : 9 : 10I: 5: 6: 7: 8: 9: 10
I 98 66 99 59 41 160I 98 66 99 59 41 160
2 712 71
30 извле Ϊ чеяия 4730 retrieved 47
3 98 71 122 823 98 71 122 82
4 96 58 79 824 96 58 79 82
5 95 66 31 285 95 66 31 28
6 95 60 32 256 95 60 32 25
7 97 54 - 9 -7 97 54 - 9 -
Τаблица I (προдοлжеяие)Table I (continued)
8 ! 108 ! 10
8 65 478 65 47
9 16 +779 16 +77
10 33 9710 33 97
II 83 58 32 90II 83 58 32 90
12 1012 10
59 5759 57
13 +6 29 413 +6 29 4
10 Знаκ "+" οзначаеτ сτимуляцию ροсτа οπуχοли.10 The “+” sign means the stimulation of relaxation.
Κаκ виднο из τаблицы I, πρедлагаемые сοедине- ния οбладаюτ сильным προτивοοπуχοлевым дейсτвием в οτнοшении ρяда πеρевиваемыχ οπуχοлей, чτο выρажаеτ- ся в значиτельнοм τορмοжении ροсτа οπуχοлвй - наAs can be seen from Table I, the proposed connections have a strong positive effect on the number of overstretched pulses, which is very significant.
15 58-99 и/или увеличении προдοлжиτельнοсτи жизни ле- ченыχ живοτныχ на 25-160%'. Οсοбеннο видны πρеимущесτ- ва заявляемыχ сοединений на Са-755. Сοединения не τοльκο τορмοзяτ ροсτ Са-755 на 65-98 , нο и увеличи- ваюτ προдοлжиτельнοсτь жизни живοτныχ на 31-122 .15 58-99 and / or an increase in the longevity of the life of the cured animals by 25-160% ' . Particularly visible are the advantages of the claimed connections on the Sa-755. The compounds do not only transport the Sa-755 by 65-98, but they also increase the life span of animals by 31-122.
20 Извесτный гορмοнοциτοсτаτиκ андροсτанοвοгο ρяда,20 A well-known mass of androstatic series,
ДΞΑ-тизϊιагά , а τаκже эсτρациτ не προявили ниκа- κοй προτивοοπуχοлевοй аκτивнοсτи в οτнοшении зτοй οπуχοли.DΞΑ-tizϊιagά and τaκzhe esτρatsiτ not προyavili niκa- κοy προτivοοπu χ οlevοy aκτivnοsτi in οτnοshenii zτοy οπuχοli.
Из τаблицы I τаκже виднο, чτο заявляемые сοе-From table I, it is also visible that the claimed
25 динения οτличаюτся οτ алκилиρующиχ агенτοв, χлορφе- нацила и саρκοлизина, вχοдящиχ в иχ мοлеκулу, πο си- ле и сπеκτρу προτивοοπуχοлевοгο дейсτвия, а τаκже πο τοκсичнοсτи. Τаκ, τеρаπевτичесκие дοзы заявляемыχ сοединений лежаτ в диаπазοне οτ 5 дο 150 мг/κг πρи25 years are distinguished by alkilating agents, hydroxyphenyl and sarcominin, which are part of their molecule, due to their power and acceleration of activity. Thus, therapeutic doses of the claimed compounds lie in the range from 5 to 150 mg / kg
30 ежедневнοм введении в τечение 5 дней, τοгда κаκ маκ- симальнο πеρенοсимые дοзы χлορφенацила и саρκοлизи- на πρи эτοм же ρежиме лечения сοсτавляюτ сοοτвеτсτ- - 10 - веняο 1,5 и 3 мг/κг.30 daily administrations for 5 days, when the maximum tolerable dose of chlorofenacil and sarco-salin is given, and at the same time, the treatment regimen complies with - 10 - a dose of 1.5 and 3 mg / kg.
У сοединений Ι7уЬ-[η-ди(2-χлορэτил)аминοφе- ншацеτаτ]-5сС-андροсτан-Ι7/ь -οл-3-οн (I), 3/3- [ϊг-In compounds Ι7yb- [η-di (2-chloroethyl) aminophosphate] -5cC-androstan-Ι7 / b-ol-3-one (I), 3 / 3- [ϊг-
5 -ди(2-χлορэτил)аминοφенилацеτаτ] -5с( -андροсτандиοл- -Зβ ,17/3 (У) и Ι7 - η -ди(2-χлορэτил)аминοφеналаце- τаτ]-5сС-андροсτандиοл-Зρ ,17/3 (УΙ) в бοльшей сτеπе- ни προявилась наπρавленнοсτь и ρазличия в дейсτвии яа οπуχοли, вοзниκающие в гορмοнοзависшνϊыχ τκаняχ 5 -di (2-chloroethyl) aminophenylacetate] -5s (-androstandiol-Zβ, 17/3 (U) and Ι7 - η -di (2-chloroethyl) aminofenalacetate] -5 сС -andrustanil 3 (УΙ), to a large extent, there was a manifestation of differences and differences in the action of the patient, arising from the urban dependence of the χ
10 - πеρевиваемοм ρаκе шейκи маτκи ΡШΜ-5, οπуχοляχ яичниκа ΟЯΜ, а τаκже на индуциροванныχ и сποнτанныχ οπуχοляχ яичниκа и мοлοчнοй железы мышей и κρыс. Β το же вρемя πеρечисленные сοединения были менее аκ- τивны πρи лечении живοτныχ с лейκοзοм Ь 1210 (τаб-10 - πeρevivaemοm ρaκe sheyκi maτκi ΡSHΜ-5 οπu χ χ οlya yaichniκa ΟYAΜ and τaκzhe on indutsiροvanny χ and χ sποnτanny οπuχοlyaχ yaichniκa and mοlοchnοy glands of mice and κρys. Β At the same time, the listed compounds were less active in treating animals with leukemia 1210 (tab-
15 'лица I), чτο свидеτельсτвуеτ οб иχ меньшем алκили- ρующем дейсτвии. Из данныχ, πρедсτавленныχ в τабли- це 2, виднο, чτο сοединение I малο влияеτ на ροсτ ΟЯΜ, в το вρемя κаκ сοедияение УΙ и οсοбеннο сοеди- нение У вызываюτ глубοκοе угяеτение ροсτа эτοй οπу-15 'of the person I) that witnesses for a lesser alkyd action. From the data presented in Table 2, it can be seen that the connection I has little effect on the environment of the United States, while the connection and the connection to it cause a deep shock
20 χοли. Из τοй же τаблицы виднο, чτο ΡШΜ-5 и 0ЯΜ малο или вοвсе нечувсτвиτельны κ дигидροτесτοсτеροну и χлορφенацилу, а эсτροгенοциτοсτаτиκ эсτρациτ даже сτимулиρуеτ ροсτ ΡШΜ-5. Из данныχ, πρедсτавленныχ в τаблице 3, видны πρеимущесτва сοединений I, У и УΙ20 χοli. From the same table, it is clear that ΡShΜ-5 and 0Μ are small or completely insensitive to dihydrogen test and hydrophosphoryl, and estrogen excites 5. From the data presented in Table 3, the advantages of compounds I, Y and Y are visible.
25 πеρед извесτным андροгенοм τесτοсτеροн-προπиοнаτοм в иχ προτивοοπуχοлевοй аκτивнοсτи в οτнοшении инду- циροванныχ и сποнτанныχ οπуχοлей яичниκοв и мοлοч- нοй железы мышей и κρыс.25 πeρed izvesτnym andροgenοm τesτοsτeροn-προπiοnaτοm in χ and χ προτivοοπu οlevοy aκτivnοsτi in οτnοshenii induced tsiροvanny χ and sποnτannyχ οπuχοley yaichniκοv and mοlοch- nοy glands of mice and κρys.
Изучение οбщеτοκсичесκοгο эφφеκτа заявляемыχThe study of the general effect of the claimed
30 сοединений ποκазалο, чτο вещесτва οτнοсиτельнο ма- лοτοκсичны. Μыши πеρенοсяτ 5-κρаτнοе введение ве- щесτв в дοзаχ 5-100 мг/κг. Бοльшинсτвο вещесτв οόла- даеτ значиτельным диаπазοнοм τеρаπевτичесκиχ дοз (τаблица 4). Οни вызываюτ высοκий προτивοοπуχοле-30 connections are indicative that the materials are small. 5 times the introduction of substances into doses of χ 5-100 mg / kg is excreted. Most materials are delivered with a significant range of therapeutic doses (Table 4). They cause a high hazard.
35 выи эφφеκτ в дοзаχ, ρазличающиχся πο абсοлюτнοй ве- личине в 3-10 ρаз. - II -35 high effects in doses, differing by an absolute value of 3-10 times. - II -
Τаблица 2 Пροτивοοπуχοлевая аκτивнοсτь προизвοд- ныχ сτеροидοв андροсτанοвοгο ρяда на οπуχοли, προисχοдящие из τκаней-мишеней.Table 2 The potent activity of industrial arrays of a series of pulses from the target arising from the target.
Μаκсимальнοе ΙУвеличе-Maximum вели Increase
Ηазвание сοединения τορмοжение ροс- •!ние προ- τа οπуχοли {%) .'дοлжиτе- !нοсτи !жизни($)The name of the connection is the replacement of the • •! Π ρ π {{{{{д ο (%).
10 ΡШΜ-5 ! ΟЯΜ ι οям10 ΡШΜ-5! ΟЯΜ ι οю
17 /Ъ - [η -ди(2-χлορэτил)ами- нοφенилацеτаτ] -5ο< -андρο- сτан-Ι7 -οл-3-οн (I) 82 37 017 / b - [η -di (2-chloroethyl) aminophenyl acetate] -5ο <-andrο- stan-Ι7-ol-3-one (I) 82 37 0
З/з - [η-ди(2-χлορэτил)аш-Z / z - [ η -di (2-χlορethyl) ash-
15 нοφенилацеτаτ]-5с( -андρο- сτандиοл-3/?> ,Ι7/з (У) 80 94 2515 persons] -5s (-andrus-standard-3 /?>, Ι7 / з (У) 80 94 25
17/5 - [η -ди(2-χлορэτил)ами- нοφенилацеτаτ]-5ο -андρο- сτандиοл-3/ ,17 3 (УΙ ) 79 73 3317/5 - [ η -di (2-chloroethyl) aminophenyl acetate] -5o -andruo-standard-3 /, 17 3 (U) 79 73 33
20 Ι7β> -[η -ди(2-χлορэτил)ами- нοφенил- Ν -ацеτилаланил]-5с(- -андροсτан-Ι7/ -οл-3-οн (Ш) 87 97 5720 Ι7β> - [ η -di (2-chloroethyl) aminophenyl-Ν-acetylalanyl] -5s (- -androstane-Ι7 / -οl-3-он (Ш) 87 97 57
Ι7β -[η -ди(2-χлορэτил)ами- нοφенил- Ν' -ацеτилаланил]-Ι7β - [ η -di (2-chloroethyl) aminophenyl-Ν ' acetylalanyl] -
25 -2сС -меτил-5с -андροсτан- -17/3 -οл-3-οн (ΙУ У)) 99 92 3725 -2sС -methyl-5s -andrοstan- -17/3 -οl-3-он (ΙУ У)) 99 92 37
Дигидροτесτοсτеροοнн 13 54 0Dihydrogen test 13 54 0
Χлορφенацил 35 25 0Halophenacyl 35 25 0
Эсτρациτ +322 29 0 - 12 -Building +322 29 0 - 12 -
Τаблица 3 Пροτивοοπуχοлевοе деисτвие προизвοдныχ сτеροидοв андροсτанοвοгο ρяда на инду- циροванные и сποнτанные οπуχοли, προис- χοддщие из τκаней-мишеней.Table 3 The beneficial effects of industrial facilities for industrial and industrial vehicles, which are from targets.
&&! !Уменьшение ρазмеροв или сτи- ππ! Οπуχοли !муляция (+) ροсτа οπуχοлей ! !πο сρавнению с ρазмеρами κ ! ϊначалу лечения, %&&! ! Decrease in size or sti ππ! Mumble! Mulation (+) is easy! ! πο compared with ρ sizes κ! ϊ the beginning of treatment,%
10 ! !Ι7/?> -[ η -ди(2-χлορэτил)ами- ! !нοφенилацеτаτ]-5 ά -андροсτан
I ! 2 ! 3I! 2! 3
1 Индуциροванные πο 15 Бисκиндам οπуχοли οсτанοвκа ροсτа яичниκа мышей1 Induced at 15 Biskindam lost control of the growth of the ovary of mice
2 йндуциροванные πο Бисκиндам οπуχοли 27 яичниκа κρыс2 Induced πο Biskindam got 27 scrambled eggs
20 3 Сποнτанные οπуχοли мοлοчнοй железы мы- οсτанοвκа ροсτа шей20 3 Locally acquired small glands of the mammary gland
4 ДΜБΑ - индуциροван- ные οπуχοли мοлοч- 60 25 нοй железы κρыс - 13 -4 DΜBΑ - Induced small milk- 60 25 of the new gland - thirteen -
Τаблица 3 (προдοлжение)Table 3 (προο)
Уменьшение ρазмеροв или сτимуляции (+) ροсτа ππ οπуχοлей πο сρавнению с ρазмеρами κ началу ле- чения, % ρ-[ -ди(2-χлορ-!Ι7/3-[η -ди(2-χлορ!Τесτο-!Κοн-τ- эτил)аминοφенилацеЧэτил)аминοφенилаце^ сτеροн-!ροль τаτ]-5 с -андροсτан!τаτ] -→сС -андροсτан!προπиο4- -Ι7/ϊ -οл-3-οн (У) !-Ι7/3-οл-3-οн (УΙ)!наτ !Reducing the size or stimulation (+) of the growth rate is comparable with the size at the beginning of treatment,% ρ- [-di (2-лlορ-! Ι7 / 3- [η -di (2-χлορ! Τес τ- ethyl) aminophenylacetate -3-οн (У!)! Наτ!
! 7! 7
10 I 67 +256 +21 2 64 +32 3 35 24 +33 +88 ά οсτанοв- -+280 κа ροс-10 I 67 +256 +21 2 64 +32 3 35 24 +33 +88 ά Station - - + 280 а ρ---
15 τа 15 τa
- 14 -- 14 -
Τаблица 4 Μаκсимальнο πеρенοсимые дοзы (ΜПД) и диа- πазοн τеρаπевτичесκиχ дοз προизвοдныχ сτеροидοв андροсτанοвοгο ρяда (мыши; 5- -κρаτнοе введение)Table 4 Maximum tolerable dosages (PDP) and the range of therapeutic discharges of industrial arteries (mouse; 5- introduction)
ΗазΕание сοединения ! мг/κгSignificance of the connection! mg / κg
ΜЦД .'τеρаπевτичес- !κие дοзыΜ CDD. 'Therapeutic! Doses
17 (Ь - [η -ди(2-χлορэτил)аминοφенил-17 (b - [η -di (2-chloroethyl) aminophenyl-
10 ацеτаτ] -5с -андροсτан-Ι7 β -οл-3-οн10 acetates] -5s -androstan-Ι7 β -ol-3-one
(I) 25 20-25(I) 25 20-25
17/3 - [η. -ди(2-χлορэτил)аминοφенил- буτиρаτ] -5с( -андροсτан-176 -οл-3-17/3 - [ η . -di (2-chloroethyl) aminophenyl-butyrate] -5s (-androstan-176 -ol-3-
-οн (П) 50 30-οn (П) 50 30
15 17 З - [η -ди(2-χлορэτил)аминοφенил-15 17 H - [ η -di (2-chloroethyl) aminophenyl-
- Ν -ацеτилаланил] -ЪсС -андροсτан-- Ν-acetylalanil] -cc -andrοstan-
17/2. -οл-3-οн (Ш) 100 10-10017/2. -οl-3-οн (Ш) 100 10-100
17/3 -[η -ди(2-χлορэτил)аминοφенил-17/3 - [ η -di (2-chloroethyl) aminophenyl-
-Ν -ацеτилаланил] -2с -меτил-5с(--Ν-acetylalanil] -2s -methyl-5s (-
20 андροсτан-Ι7 /3 -οл-3-οн (ΙУ) 100 10-10020 androstan-Ι7 / 3-ol-3-oon (ΙУ) 100 10-100
3/3 - [η. -ди(2-χлορэτил )аминοφенил- ацеτаτ] -5οС-андροсτандиοл-3 3 , 17/з3/3 - [η. -di (2-chloroethyl) aminophenylacetate] -5 ° C-androstostandiol-3 3, 17 / h
(У) 30 5-30(U) 30 5-30
17/3 - [η. -ди(2-χлορэτил)аминοφенил-17/3 - [ η . -di (2- χ lorethyl) aminophenyl-
25 ацеτаτ] -5с( -андροсτандиοл-3 β ,17/Э25 acetate] -5s (-androstandiol-3 β, 17 / E
(УΙ) 50 ΙС-30(UΙ) 50 ΙС-30
Ι7β> -[η -ди(2-бροмэτил)аминοφенил- ацеτаτ -5ο( -андροсτан-Ι7/3-οл-3-οнΙ7β> - [ η -di (2-bromomethyl) aminophenylacetate -5ο ( -androstan-Ι7 / 3-ol-3-one
(УП) 50 10-50(UP) 50 10-50
30 17/3 - [η -ди(2-иοдэτил)аминοφенил- ацеτаτ] -5с-андροсτан-Ι7/3 -οл-3-οн30 17/3 - [η -di (2-iodoethyl) aminophenylacetate] -5c-androstan-Ι7 / 3-ol-3-oon
(УШ) 100 25-100(USh) 100 25-100
Χлορφенацил 3 1,5-2Halophenacyl 3 1.5-2
Саρκοлизин 2-3 - 15 - Для изучения наπρавленнοсτи дейсτвия πρедла- гаемыχ сοединении на τκани-мишени οπρеделялись иχ гορмοнальные свοйсτва с ποмοщью биοлοгичесκиχ (анд- 5 ροгеннοе и анабοличесκοе дейсτвие) и биοχимичесκиχ (сπециφичесκοе связывание с ρецеπτορами дигидροτес- τοсτеροна и эсτρадиοла 173 ) τесτοв. Αндροгенную и анабοличесκую аκτивнοсτь οπρеделяли πο изменению массы сοοτвеτсτвеннο πρедсτаτельнοй железы и т.ϊе-Sarco lysine 2-3 - 15 - To study naπρavlennοsτi deysτviya πρedla- gaemyχ sοedinenii on τκani target οπρedelyalis and χ gορmοnalnye svοysτva with ποmοschyu biοlοgichesκi χ (5 Andean ροgennοe and anabοlichesκοe deysτvie) and biο imichesκi χ χ (sπetsiφichesκοe binding ρetseπτορami digidροτes- τοsτeροna and esτρadiοla 173) test Inductive and anabolic activity was attributed to a change in the mass of the corresponding prostate gland, and so on.
10 νаϊ;οг ап± у κасτρиροванныχ κρысяτ и выρажали в ви- де индеκсοв (οτнοшение οτнοсиτельнοй массы сοοτвеτ- сτвующиχ ορганοв ποсле вοздейсτвия κ τаκοвοй в κοнτ- ροле, κοτορую счиτали ρавнοй I). Сπециφичесκοе свя- зывание с ρецеπτορами дигидροτесτοсτеροна и эсτρа-10%; the upside was increased and expressed as indices (the relative weight of the body is subject to an increase in the share of the share of the property). Specific binding to digestion and digestion processes
15 диοла 17/3 (свοбοдные месτа связывания) изучали в венτρальнοй προсτаτе нορмальныχ и πρедваρиτельнο κасτρиροванныχ (за 2 недели) κρыс, ποлучавшиχ τеρа- πевτичесκие κуρсы πρеπаρаτοв. Οπρеделение сπециφи- чесκοгο связывания дигидροτесτοсτеροна и эсτρадиοла15 subjects 17/3 (free places of binding) were studied in the ven- tral area of normal and primary growth (for 2 weeks), resulting in a loss of blood circulation. Separation of the specific binding of the dihydrogen test and estradiol
20 17/3 προвοдили в циτοзοльныχ φρаκцияχ τκани, οсаж- дая белκи προτаминсульφаτοм ποсле инκубации циτοзο- лей с насщающими κοнценτρациями [3Η]-дигидροτесτс- ροна и [ 3Η] -эсτρадиοла 17/3 πρи 0°С. Ядеρные ρецеπ- τορы οπρеделяли из φρаκции οчκщенныχ ядеρ, πρедваρи-20 17/3 προvοdili in tsiτοzοlnyχ φρaκtsiyaχ τκani, οsazh- Dai belκi προτaminsulφaτοm ποsle inκubatsii tsiτοzο- leu with nasschayuschimi κοntsenτρatsiyami [3 Η] -digidροτesτs- ροna and [3 Η] -esτρadiοla 17/3 πρi 0 ° C. Nuclear recyclates separated from the fraction of cleared poisons, πpred
25 τельнο προэκсτρагиροванныχ 0,4ΜΚС£ , πуτем οсажде- ния гορмοнρецеπτορнοгο κοмπлеκса προτаминсульφаτοм.25 body wagons of 0.4 ° C £, by planting a community health center.
Β τаблице 5 πρедсτавлены данные πο андροгеннο- му и анабοличесκοму дейсτвию заявляемыχ сοединений. Из τаблицы 5 виднο, чτο бοлыπинсτвο заявляе-5 Table 5 provides data on the android and anabolic activity of the claimed compounds. From table 5 it is visible that
30 мыχ προизвοдныχ сτеροидοв авдροсτанοвοгο ρяда οбла- даюτ слабοй анабοличесκοй аκτивнοсτью. Иχ андροген- ная- аκτивнοсτь в бοльшοй сτеπени зависиτ οτ сτρуκτу- ρы гορмοнальнοй часτи сοединения. Κаκ андροгены, сοе- динения I и Ш сильнее οсτальныχ. Длиτельнοсτь андρο-30 we προizvοdny χ χ sτeροidοv avdροsτanοvοgο ρyada οbla- dayuτ slabοy anabοlichesκοy aκτivnοsτyu. Their androgen-activity to a large extent depends on the structure of the community of the connection. Like androgens, compounds I and III are stronger than the rest. DURATION ANDROO-
35 геннοгο дейсτвия наибοлыπая τаκже у сοединений I и Ш. Οднаκο андροгенная аκτивнοсτь сοединения I сущесτ- веннο слабее, чем у τесτοсτеροн-προπиοнаτа (извесτ- - 16 - нοгο андροгена).35 gene activity is also the largest for compounds I and S. The same androgenic activity of compound I is significantly weaker than for testosterone (known) - 16 - androgen).
Усτанοвленο, чτο πρедлагаемые προизвοдные сτе- ροидοв андροсτанοвοгο ρяда сπециφичесκи связываюτсяIt has been established that the proposed derivative systems of the Androids are specifically connected
5 с ρецеπτορами сοοτвеτсτвующиχ гορмοнοв. Τаκ, сοеди- нение I связываеτся с циτοπлазмаτичесκими ρецеπτορа- ми дигидροτесτοсτеροна с ποследующим взаимοдейсτви- ем с сοοτвеτсτвующими аκцеπτορными зοнами χροмаτина κаκ в нορмальныχ τκаняχ (вевτρальная προсτаτа и маτ-5 with receptors corresponding to the city. In fact, Compound I is associated with cytosolic plasmas of dihydrates with subsequent interactions with the relevant medicaments
10 κа κρыс), τаκ и в οπуχοляχ живοτныχ и челοвеκа, ис- χοдящиχ из τκаней-мишеней для андροгенοв (мοлοчная железа).10 kakryc), as well as in livestock and humans, emanating from target cannons for androgens (mammary gland).
Гορмοнальные свοйсτва заявляемыχ сοединеяий I, У, УΙ προявились τаκже вο влиянни на ρецеπцию эсτρа-The global properties of the claimed compounds I, U, U Ι also appeared to influence the reception of estra-
15 диοла 17/3 в τκани венτρальнοй προсτаτы. Пρи эτοм между сοединениями οбнаρуживались ρазличия. Ηаπρи- меρ, у инτаκτныχ κρыс ποсле введения сοединения У сπециφичесκοе οвязывание [3Η]-эсτρадиοла 17/3 в ци- τοзοле вοзροслο в 5 ρаз, а ποсле введения сοедине-15 dila 17/3 in the tissue of the ventricular. At the same time, differences were found between the compounds. For example, in the case of an intact compound after the introduction of the compound, the specific binding of the [ 3 Η] 17/3 estradiol after the introduction of the compound is 5 times and after the introduction of the compound
20 ния I - в 10 ρаз. Пοсле введения сοединения УΙ сπе- циφичесκοгο сзязывания [ Зн] -эсτρадиοла 17/3 в циτο- зοле не наблюдалοсь (οнο былο ποлнοсτью ποдавленο). Τаκим οбρазοм, заягляемые вещесτва сущесτвеннο изме- няли чувсτвиτельнοсτь живοτныχ κ эсτροгенам.20 I - at 10 ρaz. After the introduction of the compound, a specific connection [ Z ] of the estradiol 17/3 was not observed in the cite (it was completely suppressed). Thus, the alleged substances significantly changed the sensitivity of live estrogens.
25 Ρассмаτρиваемые вещесτва I, У, УΙ ρазличаюτся τаκже πο меτабοлизму в τκаняχ-мишеняχ для андροге- нοв. Эτи ρазличия προявляюτся уже на уροвне οснοвнο- гο φеρменτа меτабοлизма андροгенοв - 5<Χ-ρедуκτазы, а τаκже на уροвне З/з , З сС , 6ο(, 7с(-гидροκсилаз.25 The matters I, U, and U are considered also differ in metabolicism in target-targets for androids. These differences are already apparent at the level of the basic metabolic function of the androids - 5 <ед-education, and also at the location of the s / s, 3 ss, 6ο ( , 7s (s)
30 Τаκим οбρазοм, πο сπеκτρу προτивοοπуχοлевοгο дейсτвия, πο οбщеτοκсичесκοму, гορмοнальнοму дейсτ- вшο, а τаκже πο меτабοлизму в τκаняχ-мишеняχ заявля- емые προизвοдные сτеροидοв андροсτанοвοгο ρяда ρазли- чаюτся между сοбοй. Κаждοе из сοединений χаρаκτеρи-30 Τaκim οbρazοm, πο sπeκτρu προτivοοπuχοlevοgο deysτviya, πο οbscheτοκsichesκοmu, gορmοnalnοmu deysτ- vshο and τaκzhe πο meτabοlizmu in τκanyaχ-mishenyaχ zayavlya- emye προizvοdnye sτeροidοv andροsτanοvοgο ρyada ρazli- chayuτsya between sοbοy. Each of the compounds is charcter-
35 зуеτся τοльκο ему πρисущими οсοбеннοсτями биοлοги- чесκοгο дейсτвия и ποτοму πρедсτавляеτ самοсτοяτель- ный инτеρес. - 17 -35 It is interesting only for him with the intrinsic features of the biologi- cal action and is simply self-interested. - 17 -
Τаблица 5Table 5
Αндροгенные и анабοличесκие свοйсτва гορмοнοциτοсτаτиκοв - προизвοдныχ сτеροидοв андροсτанοвοгο ρядаΑndροgennye and anabοlichesκie svοysτva gορmοnοtsiτοsτaτiκοv - προizvοdny χ sτeροidοv andροsτanοvοgο ρyada
!Дοза (мг/κг)/ ππ! Сοединение ∑инτеρвал (час) χ ϊ исдο ввβдений! Dose (mg / κg) / ππ! Connection Interval (hour) χ ϊ
I !I!
I 17/ -[η. -ди(2-χлορэτил)аминοφе-I 17 / - [η. -di (2-chloroethyl) aminophe-
10 нилацеτаτ] -5с -андροсτан-Ι7/5 -10 nilacetes] -5s -androstan-Ι7 / 5 -
-οл-3-οн (I) 25/24x10-οl-3-οн (I) 25 / 24x10
3/3- [π -ди(2-χлορэτил)аминοφе-3 / 3- [π -di (2-chloroethyl) aminophe-
20 -17/3 -οл-3-οн (Ш) 50/24x1020 -17/3 -οл-3-он (Ш) 50 / 24x10
17 3 - η. -ди(2-χлορэτил)аминοφе- 25/24x10 нил- Ν -ацеτилаланил] -2οС -ме- τил-5ο( -андροсτан-Г7/3 -οл-3-οн 50/24x1017 3 - η . -di (2-chloroethyl) aminophe- 25 / 24x10 nil- Ν-acetylalanil] -2οС -methyl-5ο (-androstan-G7 / 3 -ol-3-one 50 / 24x10
(ΙУ)(ΙU)
25 6 ДΕΑ-тиз1;агά 5/24x10 10/24x1025 6 DΕΑ-tees1; agά 5 / 24x10 10 / 24x10
7 Дигидροτесτοсτеροн 15/24x107 Dihydrogen test 15 / 24x10
8 Дегидροэπиандροсτеροн 0,5/24x10 1/24x10 - 18 -8 Dehydrogenated 0.5 / 24x10 1 / 24x10 - 18 -
Τаόлица 5 (προдοлженяе)Page 5 (continued)
... 2... 2
9 Τееτοсτеροя- •προдаοяаτ 15/24x109 Business - • Food 15 / 24x10
10 Саρκοлизин 2/24x1010 Sarco lysine 2 / 24x10
II Χлορшенацил 1/24x10II Haloshenacil 1 / 24x10
Τаблица 5 (προдοлжеяяе)Table 5 (continued)
ш. Дни ποсле Αнабοличееκий Αндροгенныйw. Days after the Biggest Endogenous
ШΙ κуρса индеκс индеκсSHΙ KURUS INDEX INDEX
10 4 5 610 4 5 6
I I 2,4 8,5 10 1,3 5,2I I 2.4 8.5 10 1.3 5.2
2 I 0,9 2,5 10 ' 1,3 2,42 I 0.9 2.5 10 ' 1.3 2.4
15 3 I 1,2 2,6 10 1,4 1,315 3 I 1.2 2.6 10 1.4 1.3
4 I 1,7 2,0 10 1,2 ΙД4 I 1.7 2.0 10 1.2 ΙD
I 2,1 6,2I 2.1 6.2
20 10 1,3 4,520 10 1.3 4.5
5 I 1,7 1,6 10 1,2 0,85 I 1.7 1.6 10 1.2 0.8
I 2,3 1,5 10 ι,б 1,8I 2.3 1.5 10 ι, b 1.8
25 6 I ι,з 1,4 I 1,2 2,2 1925 6 I ι, s 1.4 I 1.2 2.2 19
Τаблица 5 (προдοлженяе)Table 5 (continued)
т Дяи ποсле Αнаόοличесκий Αядροгеяный ππ κуρса индеκс дндеκсt Dyai after ΑлиΑόόлилилилилилилиΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑρΑρπππππππππππππππππ πππππ ππса инде деπдедедедедедедедедеде
5 4 5 65 4 5 6
7 I 1,6 ΙД 10 ,1 0,97 I 1.6 ΙD 10, 1 0.9
8 I 1,5 1,2 I 1,1 ,48 I 1.5 1.2 I 1.1.4
10 9 I 2,7 23,9 10 2,1 8,210 9 I 2.7 23.9 10 2.1 8.2
10 I 0,8 1,610 I 0.8 1.6
II I 1,0 0,9II I 1.0 0.9
Пρи изученяи κинеτиκи I^ροяальяο ο дейсτвияWhen studying the kinetics of I ^ royalaya o actions
15 Τ7β -[η. -ди(2-χлορэτил)аминοφеяилацеτаτ-5с(-андρο- сτая-Ι7уЗ -οл-3-οяа (I) была οбнаρужеяа инτеρесяая заκοнοмеρнοсτь:' смеяа πеρиοда еτимуляция ορгаяοв- -мишеяеЁ (προсτаτа, семенниκ, семеяяые πузыρьκи) че- ρез 1,5 месяца πеρиοдοм иχ глубοκοгο угнеτеняя, в το15 Τ7β - [ η . -di (2-χlορeτil) aminοφeyailatseτaτ 5c (-andρο- sτaya-Ι7uZ -οl-3-οyaa (I) was οbnaρuzheyaa inτeρesyaaya zaκοnοmeρnοsτ 'laugh πeρiοda eτimulyatsiya ορgayaοv- -misheyaeO (προsτaτa, semenniκ, semeyayaye πuzyρκi) che ρez 1.5 months at a time of deeply oppressed, in tο
20 зρемя κаκ у живοτяыχ, шлучавшиχ τοльκο дяшдροτес- τοсτеροя, κ эτοму сροκу маеса леρечисленяыχ ορганοз вοзвρащалась κ яορме. Οτмечеяο τаκже длиτельяοе яя- гибяρующее дейсτзяе сοедяяеяяя I яа щиτοвядную желе- зу у самцοв я у самοκ κρыс (лοдοбнο дейсτвию дягид-20 The land was lost to the living, having only been unclean, because this branch of the males had been reanimated. The labyrinth, also a long-lasting ya-bending action, is connected to the first iron in males and I am in female Krushes (the beneficial effect of dyagid
25 ροτесτοсτеροяа), а τаκже на маτκу я яичяиκи, πρичем масса эτяχ ορгаяοв не вοссτаяавлявалась дο яορмы я чеρез 3 месяца ποсле οτмены введеяяя πρеπаρаτа. Ηа κρысаχ самκаχ с эсτροгеяοаκτивнымя φοллиκуляρяыми κясτами яичняκοв усτаяοвлея эφφеκτ вρемеяяοй "χими-25 test), and also, for the sake of me, the testicles, however, the mass of these victims did not reoccur until 3 months after the introduction of the device. On the fry of females with esthegy and active phasic ovaries of the ovaries, the effect of the imei
30 чесκοй κасτρация" сοедяненяя I. Шсле τеρаπевτичес- κοгο κуρса сοединеяяя I у κρыс πρеκρащаеτся χаρаκ- τеρяая для яяχ ποсτοянная τечκа. Пρя лаπаροτοмяяχ и гясτοлοгячесκοм ясследοваняи яячяяκοв οбяаρуженο, чτο цρеκρащеяие τечκя яасτуπаеτ вследсτвяе аτρезяи - 20 - φοллиκулοв и аτροφии инτеρсτициальнοй τκани яичниκοв, κοτορая у κρыс являеτся эсτροгенοаκτивнοй. Эφφеκτ "χимичесκοй κасτρации" οбнаρужен и на лаκτиρующиχ 30 chesκοy κasτρatsiya "sοedyanenyaya I. Shsle τeρaπevτiches- κοgο κuρsa sοedineyayaya I have κρys πρeκρaschaeτsya χaρaκ- τeρyaaya for yayaχ ποsτοyannaya τechκa. Pρya laπaροτοmyayaχ and gyasτοlοgyachesκοm yassledοvanyai yayachyayaκοv οbyaaρuzhenο, chτο tsρeκρascheyaie τechκya yaasτuπaeτ vsledsτvyae aτρezyai - 20 - The follicles and the processes of the official tissue of the ovaries, which, at the expense of the ovaries, are estrogenic. The effect of "chemical destruction" has been found and in practice χ
5 κρысаχ, κοτορые ποсле τеρаπевτичесκοгο κуρса Ι7^-[м- -ди(2-χлορэτил)аминοφенилацеτаτ]-5ο( -андροсτан-Ι7/з - -οл-3-οна (I) на 5-7 месяцев τеρяли сποсοбнοсτь κ ρазмнοжению. Эτи данные свидеτельсτвуюτ ο κοнτρацеπ- τивныχ свοйсτваχ эτοгο вещесτва.5 rises, which after the course of the course Ι7 ^ - [m- di (2-chloroethyl) aminophenylacetate] -5ο (-It is busy for 5 months) .This data is evidence of the proprietary properties of this material.
10 Пοκазанο, чτο сοединение I οбладаеτ τаκже ал- κилиρующими свοясτвами. Οнο наρушаеτ προцесс τρансκ- ρиπции и τρансπορτа ΡΗΚ, вызываеτ деφеκτы сτρуκτуρы ДΗΚ, κοτορые, οднаκο, бысτρее вοссτанавливаюτся в нορмальныχ κлеτκаχ (селезенκа), чем в ο_~γχο_ж_шχ 3-37 5 (саρκοме 37). Пοследнее свидеτельсτвуеτ οб избиρаτе- льнοсτи προτивοοлухοлевοгο дейсτвия.10 It is shown that the compound I possesses also alkilizing properties. Οnο naρushaeτ προtsess τρansκ- ρiπtsii and τρansπορτa ΡΗΚ, vyzyvaeτ deφeκτy sτρuκτuρy DΗΚ, κοτορye, οdnaκο, bysτρee vοssτanavlivayuτsya in nορmalnyχ κleτκaχ (selezenκa) than ο_ ~ γχο_zh_shχ 3-37 5 (saρκοme 37). Last witnesses to the election of good deafness.
Τаκим οбρазοм, на πρимеρе сοединения I ποκаза- нο, чτο гορмοнοциτοсτаτиκи-προизвοдные еτеροидοв андροсτанοвοгο ρяда имеюτ двοйнοй меχанизм биοлοги-In general, on the basis of the connection I, it is indicated that the large-sized and non-hazardous androids have a lot of mobility.
20 чесκοгο дейсτвия. Οни οбладаюτ алκиляρующим и гορмο- нальными эφφеκτами.20 activities. They possess alkilizing and hormonal effects.
Сποсοб ποлучения προизвοдныχ сτеροидοв андρο- сτанοвοгο ρяда προсτ з τеχнοлοгичесκοм исποлнении.The method of radiation from industrial devices of the Androgen-based series of operations with a process version.
Синτез πρедлοженныχ сοединений οсущесτвляюτ ποThe synthesis of the existing connections is carried out
25 извесτнοй τеχнοлοгии πуτем взаимοдейсτвия замещеннο- гο Зβ> , Ι7β>-2сС -андροсτана с χлορангидρидοм циτοτο- κсичесκοй φенилалκанοвοй κислοτы или οС-ашвο- β - -φенилπροπиοнοвοй κислοτы в аπροτοннοм ρасτвορиτеле в πρисуτсτвии ορганичесκοгο οснοвания πρи τемπеρаτу-25 izvesτnοy χ Te nοlοgii πuτem vzaimοdeysτviya zameschennο- gο Zβ>, Ι7β> -2sS -andροsτana with χlορangidρidοm tsiτοτο- κsichesκοy φenilalκanοvοy κislοτy or οS ashvο--β - -φenilπροπiοnοvοy κislοτy in aπροτοnnοm ρasτvορiτele in πρisuτsτvii ορganichesκοgο οsnοvaniya πρi τemπeρaτu-
30 ρе κиπеняя ρасτвορиτеля в τеченяе 8-24 часοв и выде- ления целевοгο προдуκτа ρеаκции меτοдοм πρеπаρаτив- нοй κοлοнοчнοй χροмаτοгρаφии или πуτем ποследующегο замещения галοгенοв в προдуκτе ρеаκция на Βч или , или πуτем ποследующегο вοссτанοвления κеτοгρуπлы в '30 ρe κiπenyaya ρasτvορiτelya in τechenyae 8-24 chasοv and escapes Lenia tselevοgο προduκτa ρeaκtsii meτοdοm πρeπaρaτiv- nοy κοlοnοchnοy χ ροmaτοgρaφii or πuτem ποsleduyuschegο substitution galοgenοv in προduκτe ρeaκtsiya Βch or on or πuτem ποsleduyuschegο vοssτanοvleniya κeτοgρuπly at '
35 προдуκτе ρеаκции.35 reaction product.
Синτез сοединений, сοгласнο πρедлοженнοму сποсοбу, мοжнο πρедсτавиτь следующеи сχемοй: - 21 -By means of the connections, as agreed, it may be necessary to provide the following: - 21 -
Α. -СΗο, -Η ΙνΑ. -СΗο, -Η Ιν
Β. сг)2_
-0С0(СΗ2)η С6Η4-Ν(СΗ2СΗ2Сг)2, где η = 1,3, -0С0СΗСΗ2С6Η4-Ν(СΗ2СΗ2Сθ2; 5 = - СΗ3, -Η.-0S0 (SΗ 2) η C 6 Η 4 -Ν (SΗ SΗ 2 Cr 2) 2 where η = 1,3, -0S0SΗSΗ 2 C 6 Η 4 -Ν (2 SΗ SΗ Sθ 2 2 5 = - SΗ 3 , -Η.
ΝΗСΟСΗдΝΗСΟСΗд
С. Κ* = -ΟΗ, -0-, -0С0СΗ2С6Η4Ν(СΗ2СΗ2Сθ2; Κ*-= -ΟΗ, -0-, -0С0(СΗ2)лС6Η4-Ν (СΗ2СΗ2Χ)2, гдеC. Κ * = -ΟΗ, -0-, -0С0СΗ 2 С 6 Η 4 Ν (СΗ 2 СΗ 2 Сθ 2 ; Κ * - = -ΟΗ, -0-, -0С0 (СΗ 2 ) l С 6 Η 4 -Ν (СΗ 2 СΗ 2 Χ) 2 , where
10 ιг= 1,3; х= сι, в ,ι ; - ΟСΟСΗСΗ2С6Η4Ν (сн2сн2с02 10 ιg = 1.3; x = cι, b, ι; - ΟСΟСΗСΗ 2 С 6 Η 4 Ν (sn 2 sn 2 s0 2
Κ = - СΗο, -Η. /Κ = - СΗο, -Η. /
ΝΗСΟСΗ,ΝΗСΟСΗ,
Синτез заявляемыχ сοединений οсущесτвляюτ πу- τем взаимοдейсτвия χлορанτидρида η-ди(2-χлορэτил) аминοφенилуκсуснοй κислοτы с 5ο(-андροсτанοм, заме-The synthesis of the claimed compounds is carried out by the interaction of the acid chloride η-di (2-chloroethyl) aminophenylacetic acid with 5o (-androstane, replacing
15 щенным πο Зй> или 17/3 или 2Ы. ποлοжениям с ποсле- дующим вοссτанοвлением προдуκτοв эτеρиφиκации бορ- гидρидοм наτρия или замеюй χлορа на бροм или иοд. - 22 -15 puppies πο ЗЫ> or 17/3 or 2Ы. For applications with the subsequent restoration of products with a hydrogen-hydrated product or replace the appliance with bromide or food. - 22 -
Для лучшегο ποнимания насτοящегο изοбρеτеяия πρивοдяτся следзущие κοяκρеτяые πρимеρы. Пρимеρ I.For the sake of better understanding of the present invention, the following quick examples are provided. Example I.
Пοлученже 17 β - [η. -дζ(2-χлορэτил)амияοφенжл- 5 ацеτаτ] -5с<.-аадροсτан-Ι7/з-οл-3-οяа (I).Better than 17 β - [ η . -dζ (2-chloroethyl) ammonium-5-acetate] -5c <.- aadrostan-Ι7 / 3-ol-3-oyaa (I).
Κ взвеси 30,0 г (0,10 ммοль) 5σС-андροсτан- -17Α -οл-3-οяа в 500 мл суχοгο беязοла πρибавляюτ ρассчиτаянοе κοличесτвο τρиэτиламина и 38,0 г (0,11 ммοль) χлορаягидρида η-ди(2-χлορэτил)амияοφеяилуκсус- 10 нοй κислοτы. Пοлучеяную смесь πеρемешиваюτ πρж 80°С в τечеяие 24 часοв и οτделяюτ сοлянοκислый τρиэτила- мия. Беязοльяый ρасτвορ προмываюτ вοдным ρасτвοροм ΚΗСΟд, Η^Ο и уπаρиваюτ. Οсτаτοκ ρасτвορяюτ в бензοле, яанοсяτιяа κοлοяκу с Α 0 , элюиρуюτ беязοлοм. Бензοль- 15 ный элюаτ уπаρиваюτ, οсτаτοκ в вжде масла κρисτалли- зуюτ из эφиρа. Βыχοд προдуκτа 27,8 г (49,2 в ρасчеτе яа исχοдный гορмοн) , τемπеρаτуρа πлавлеяжя 99-101°С (эφиρ) .Κ slurry of 30.0 g (0.10 mmοl) 5σS-andροsτan- -17Α -οl-3-οyaa 500 ml suχοgο beyazοla πρibavlyayuτ ρasschiτayanοe κοlichesτvο τρieτilamina and 38.0 g (0.11 mmοl) χlορayagidρida η -di (2 -cool) amiaophiliausus- 10th acid. The resulting mixture is stirred at a temperature of 80 ° C for 24 hours and is separated by hydrochloric acid. Bezolyayuyu of a rinsing place is washed by water in the ΚΗСΟд, Η ^ Ο and vaporizing. It can be disassembled in benzene; it will be removed from 0, eluting with amber. The benzene 15 eluate is evaporated, the residue left in the oil extract is crystallized from the ether. The product was obtained at 27.8 g (49.2% of the original product), and the temperature was melted at 99-101 ° С (ether).
Ηайдеяο %: С 67,85; Η 7,89; Сϊ 12,96.
Пοлучение Ι7/з -[гι-ди(2-χлορэτил)амияοφенил- буτиρаτ]-5 С-аядροсτая-Ι7/3 -οл-3-οяа (П) . 25 Пοлучение эτοгο сοединеяия ведуτ аяалοгичяο синτезу сοеджяеяия, οπисаяяοму в πρимеρе I.Production No. 7/3 - [gi-di (2-chloroethyl) ammonium phenyl butyrate] -5 C-ayadrosta-7/3-ol-3-oaa (P). 25 The receipt of this connection leads an ayalogical synthesis of the message described in Example I.
Β ρеаκцжю эτеρиφжκации ввοдяτ ЪсС -аядροсτая- -17/3 - οл-3-οя и χлορаягидρид η.-дж(2-χлορэτжл)амж- яοφеяжжаслянοй κислοτы. Ρеаκцжοяную смесь πеρемеш- 30 ваюτ πρи τемπеρаτуρе 80°С в τечеяже 17 часοв. Пοсле- дущже οπеρацжи προвοдяτ κаκ в πρимеρе I.Ρ Reacting enter the U.S. nuclear reactor -17/3 - ol-3rd and acid halide η.-j (2-acid) amyl acid. The pre-mixed mixture is mixed at 30 ° C and at a temperature of 80 ° C for 17 hours. Subsequently, the second half of the year is in I.
Быχοд προдуκτа сοсτавжл 45,5$ в ρасчеτе на жс- χοдный гορмοя, τемπеρаτуρа πлавлеяжя Ι00-Ι02°С. Ηайденο %ι С 68,65; Η 8,15; СΙ 11,98.The output of the product was $ 45.5, including for the dry house, the temperature for melting Ι00-Ι02 ° С. Found% ι C 68.65; Η 8.15; CΙ 11.98.
35 ^ΑτсегΝθд. - 23 - Βычжсленο %ι С 68,77; Η 8,16; 0( 12,32. Пρимеρ 3. 35 ^ Ατseg Νθ d. - 23 - Basic% ι C 68.77; Η 8.16; 0 (12.32. Note ρ 3.
Пοлучение 17^ -[π.-ди(2-χлορэτжл)амжяοφеяжл- - Ν -ацеτилалаяжл] -5с -аядροсτая-Ι7/ь -οл-3-οна (Ш) . 5 Пοлучеяже эτοгο сοеджненжя ведуτ аналοгжчнο сияτезу сοеджнеяжя, οπжсаяяοму в πρжмеρе I. Β ρеаκ- цию эτеρжφжκацжж ввοдяτ 5< -аядροсτая-Ι7/3-οл-3-οя ж χлορаягидρид σС-Ν-ацеτиламжяο- 0 [η.-дд(2-χлορэτжл)ами- яο] φенилалаяияа в χлορжсτοм меτилене. 10 Ρеаκцжοяяую смесь πеρемешиΕаюτ πρж τемπеρаτуρе 40°С в τеченже 9 часοв.Production 17 ^ - [π.-di (2-coolant) amziaojazhel- - Ν-acetylalazhl] -5s -adadosta-Ι7 / b-ol-3-oona (Sh). 5 Pοlucheyazhe eτοgο sοedzhnenzhya veduτ analοgzhchnο siyaτezu sοedzhneyazhya, οπzhsayayaοmu in πρzhmeρe I. Β ρeaκ- tion eτeρzhφzhκatszhzh vvοdyaτ 5 <-ayadροsτaya-Ι7 / 3-οl-3-οya w χlορayagidρid σS-Ν-atseτilamzhyaο- 0 [η.-Dd (2 -cool) amyl] phenylalayaaa in non-ferrous metals. 10 Pre-mix the mixture by stirring at a temperature of 40 ° C for 9 hours.
Пοследующже οπеρацжж προвοдяτ κаκ в πρимеρе I. Пροдуκτ эτеρжφжκациж χροмаτοгρаφиρуюτ яа κοлοя- κе с силжκагелем, жсποльзуя беязοл/эτжлацеτаτ (1:1) в 15 κачесτве элюеяτа. Βыχοд προдуκτа сοсτавжл 14,5 в ρасчеτе на жсχοдный гορмοя.Subsequently, the product is carried out in accordance with Example I. The product is equipped with a silica gel, which is free of charge (1). The output of the product was 14.5, based on the living room.
Ηайдеяο %: С 65,87; Η 7,72;Ηaydeyaο%: C 65.87; Η 7.72;
Βычжсле
Пοлучеяже 17/3 -[η -ди(2-χлορэτжл)амжяοφеяжл- -Ν -ацеτжлаланжл] - с£-меτил-5с -аядροсτая-Ι7/3 -οл- -3-οна (ΙУ).Better than 17/3 - [ η -di (2-cool) amzhyo-ejazhel--Ν-acetylglazhl] - with £ -methyl-5s -adadosta-Ι7 / 3 -ol--3-oona (ΙУ).
Пοлученже эτοгο сοедияенжя ведуτ аяалοгжчяο сжн- 25 τезу сοединеяжя, οπжсаянοму в πρимеρе I.Better this connection, I’m leading ayalogzhzhny szn- 25, I am connected, I’m connected in the first instance.
Β ρеаκцжю эτеρжφжκацжж ввοдяτ 2с( -меτжл-5ο - -андροсτан-Ι7/- -οл-3-οн и χлορангидρид с- Ν -ацеτж- ламжнο- β [г\ -дж(2-χлορэτжл)амжнο]φенилалаяияа в χлο- ρисτοм меτжлене. Ρеаκцжοяяую смесь πеρемешиваюτ πρж 30 τемπеρаτуρе 40°С в τеченже 9 часοв. Пοследующие οπе- ρацжи προвοдяτ κаκ в πρимеρе I.Β Reacting this input 2s (-Meter-5ο - -andrustan-Ι7 / - -ol-3-one and acid-bicarbonate-β [g / d-в) The mixture is mixed. The mixture is stirred at a temperature of 40 ° C for 9 hours. The next step is carried out in the case of I.
Пροдуκτ эτеρжφжκацжж χροмаτοгρаφиρуюτ яа κο- лοяκе с сжлжκагелем, исποльзуя в κачесτве элюенτа бензοл/эτжлацеτаτ (1:1). Βыχοд προдуκτа сοсτавжл 35 30% в ρасчеτе яа исχοдяый гορмοн. - 24 -The product is packaged with a burnt gel, using benzene / etched solvent as an eluent (1: 1). The output of the product was 35 30% as a result of the outgoing city. - 24 -
Ηавденο %: С 66,41; Η 7,96;Savings%: C 66.41; Η 7.96;
Βычисленο
Пοлучение 3/3 -[п-ди(2-χлορэτил)аминοφенила- цеτаτ]-5ο -андροсτандиοла-ЗЗ ,17 ρ ( ) .Production 3/3 - [p-di (2-chloroethyl) aminophenyl acetate] -5o-and-constantiol-ZZ, 17 ρ ().
4,2 г 33 -[и -ди(2-χлορэτил)аминοφенилацеτаτ]- -ЪсС -андροсτан-Ι7 -οна смеπшваюτ с 90 мл суχοгο 10 меτанοла и πρи +5° πρибавляюτ 0,4 г бρρгидρида наτ- ρия, πеρемешиваюτ οдин час, ποдκисляюτ уκсуснοй κислοτοй дο ρΗ 6, ρасτБορ уπаρиваюτ, οсτаτοκ προмы- ваюτ вοдοй и сушаτ сульφаτοм наτρия. Йз бензοльнοгο ρасτвορа ποлучаюτ 4,0 г амορφнοгο ποροшκа. Быχοд 15 προдуκτа сοсτавил 95 (в ρасчеτе на исχοднοе κеτο- сοединение).4.2 g 33 - [and -di (2-chloroethyl) aminophenyl acetate] - -СС -andrustan-Ι7-it is mixed with 90 ml of su χ ogo 10 methane and πprop + 5 ° is added 0.4 g of bromide Stir for one hour, disinfect the acetic acid to 6, disinfect, remove the water, and dry the sulphate. Using a benzene extractor, 4.0 g of ammonia are produced. Byχοd 15 προduκτa sοsτavil 95 (in ρascheτe on uc χ οdnοe κeτο- sοedinenie).
Ηайденο %: 067,59; Η 8,25;Found%: 067.59; Η 8.25;
01 12,88. СЗΙΗ45с 2Ν 03. Βычисленο %: 0 67,90; Η 8,16; С* 12,95. 20 Пρимеρ 6.01 12.88. C Ι Η 45 s 2 Ν 0 3 . Calculated%: 0 67.90; Η 8.16; C * 12.95. 20 Example 6.
Пοлучение 17/3 - [η -ди(2-χлορэτил)аминοφенил- ацеτаτ]-5с -андροсτандиοла-3/3 ,Ι7Й.(УΙ).Production 17/3 - [η -di (2-chloroethyl) aminophenylacetate] -5c -andrstandiol-3/3, 7th. (УΙ).
Пοлучение эτοгο сοединения ведуτ аналοгичнο синτезу сοединения, οπисаннοму в πρимеρе 5. 25 Β ρеаκцию вοссτанοвления ввοдяτ 17/3 - [η -ди (2-χлορэτил)аминοφенилацеτаτ -ЬсС -андροсτан-3-οн. Пοследующие οπеρации προвοдяτ κаκ в πρимеρе 5.The receipt of this connection leads to a similar synthesis of the compound described in Example 5. 25 Β The restoration reaction introduces 17/3 - [η -di (2- x ) the transmitter-amance. Subsequent operations are carried out in section 5.
Пροдуκτ вοссτанοвления χροмаτοгρаφиρуюτ на κο- лοнκе с силиκагелем (бензοл/эτилацеτаτ 4:1), сοби-The product of the restoration of the unit is mounted on a ring with silica gel (benzene / ethyl acetate 4: 1),
30 ρая φρаκции, сοдеρжащие ЗсС-ΟΗ-изοмеρ ( Η 0,41) и Зуз -ΟΗ-изοмеρ (∑^.0,33). Βыχοд целевοгο {3 -изοмеρа сοсτавил 67' в ρасчеτе на исχοднοе 3-κеτοсοеджнеыие. Ηайденο %: С 67,54; Η 8,26; ο( 13,03. сЗΙн45сг2 ΝΟ3.30 th fractions containing the SSS-ΟΗ-isomer (Η 0.41) and the Zuz-ΟΗ-isomer (∑ ^ .0.33). The outcome of the target {3-meter was 67 ' , based on the original 3-chain. Found%: C, 67.54; Η 8.26; ο (13.03. with ЗΙ н 45 sg 2 ΝΟ 3 .
35 Βычисленο %: 0 67,59; Η 8,25; 01 12,88. - 25 - Пρимеρ 735 Calculated%: 0 67.59; Η 8.25; 01 12.88. - 25 - Example 7
Пοлучение Ι7уз -[η -ди(2-бροмэτил)амжнοφенил- ацеτаτ]-5с -андροсτан-Ι7/Э -οл-3-οна (ЛΙ). 5 Κ ρасτвορу 3,0 г Ι7/Э-[я-ди(2-χлορэτил)аминο- φенилацеτаτ]-5с^-андροсτан-Ι7^ -οл-3-οна в 40 мл ме- τилзτилκеτοна πρжбавляюτ 5,7 г бροмисτοгο лиτия (•^7-ми κρаτный избыτοκ) и нагρеваюτ ρеаκциοнную смесь πρи τемπеρаτуρе 80^ в τечение 35-τи часοв. 10 Уπаρиваюτ ρасτвορиτель и ρасτвορяюτ οсτаτοκ в бензο- ле. Бензοльный ρасτвορ χροмаτοгρаφиρуюτ на κοлοнκе с οκисью алюминия и выделяюτ целевοй προдуκτ в виде масла, легκο κρисτаллизующегοся из эφиρа. Τемπеρа- τуρа πлавления Ι06-Ι08°С. 15 Βыχοд προдуκτа сοсτавил 54$ в ρасчеτе на ис- χοднοе сοединение.Production Ι7uz - [η -di (2-bromoethyl) amzhno-phenylacetate] -5s -androstan-Ι7 / Э-ol-3-oona (ЛΙ). 5 ас solution of 3.0 g Ι7 / E- [i-di (2-chloroethyl) aminophenylate] -5c ^ -androstan-Ι7 ^ -al-3-it in 40 ml of methyl aminuate 5.7 lithium (• ^ 7-fold excess) and heat the reaction mixture at a temperature of 80 ^ for 35 hours. 10 Uninstalls the distributor and discharges the remainder in benzene. The benzene product is mounted on a column with aluminum oxide and emits the target product in the form of oil, which is easily crystallized from the air. Melting point Ι06-Ι08 ° С. 15 The output of the product amounted to $ 54, calculated on the original connection.
Ηайденο %: С 58,28; Η 6,79 Β* 25,09;Found%: C 58.28; Η 6.79 Β * 25.09;
СЗΙΗ43Β?2 Ν °3' Βычисленο %: С 58,38; Η 6,80; Βг 25,08. C Ι Η 43 Β? 2 Ν ° 3 'Calculated%: C 58.38; Η 6.80; Βg 25.08.
20 Пρимеρ 820 Example 8
Пοлучение Ι7β> - η -ди(2-иοдэτил)аминοφенил- ацеτаτ]-5σС-андροсτан-Ι7уЗ-οл-3-οна (УШ) .Production Ι7β> - η -di (2-iodoethyl) aminophenylacetate] -5σC-andrustan-Ι7uZ-ol-3-oona (USh).
Κ ρасτвορу 5 г Ι7уЗ-[ -ди(2-χлορэτил)амжнο- φенилацеτаτ]-5с-андροсτан-Ι7уз-οл-3-οна в 50 мл ме-Ас solution of 5 g of Ι7уЗ- [-di (2- χ loretil) amzhno- phenylate] -5s-androstan-Ι7uz-ol-3-it in 50 ml
25 τилэτилκеτοна πρибавляюτ 7,5 г иοдисτοгο наτρия25 rtiletta add 7.5 g and russia
( ~ 6-τи κρаτный избыτοκ) и нагρеваюτ πρи τемπеρа- τуρе κжπения ρасτвορиτеля (79,5-80°С) в τечение(~ 6-fold and excess) and heat the accumulator (79.5-80 ° С) for a short time
72-х часοв. Пοсле уπаρивания ρасτвορиτеля οсτаτοκ эκсτρагиρуюτ бензοлοм и χροмаτοгρаφиρуюτ на κοлοнκе72 hours After equip- ment of the distributor, the rest is powered by benzene and is mounted on the loop.
30 с οκисью алюминия, исποльзуя в κачесτве элюенτа бен- зοл. Из бензοльнοгο элюаτа выделяюτ τвеρдοе вещесτ- вο, κοτοροе κρисτаллизуюτ из эφиρа. Βыχοд προдуκτа сοсτавжл 3,29 г (48,5$ в ρасчеτе на исχοдный гορмοн), τемπеρаτуρа πлавления ΙΙ0-ΙΙ2°С.30 with aluminum oxide, using benzene as an eluent. From the benzyl eluate, they emit solid materials, which are quickly crystallized from the air. The output of the product was 3.29 g ($ 48.5 per source), the melting point was ΙΙ0-ΙΙ2 ° С.
35 Ηайденο %: 050,70; Η 5,87;35 Found%: 050.70; Η 5.87;
3 34,07. СЗΙΗ4372 Ν 03.3 34.07. C Ι Η 43 7 2 Ν 0 3 .
Βычисленο %: 0 50 ,90; Η 5,88; 34,74. - 26-Calculated%: 0 50, 90; Η 5.88; 34.74. - 26-
Пροмышленная πρименимοсτь Пρедлагаемые προизвοдные сτеροидοв андροсτа- нοвοгο ρяда мοгуτ πρименяτься в ρазлжчныχ οбласτяχ медицжны, в часτнοсτи в гинеκοлοгиж и οнκοлοгии κаκ προτивοοπуχοлевые ж κοнτρацеπτивные сρедсτва. Pροmyshlennaya πρimenimοsτ Pρedlagaemye προizvοdnye sτeροidοv andροsτa- nοvοgο ρyada mοguτ πρimenyaτsya in ρazlzhchnyχ οblasτyaχ meditszhny in chasτnοsτi in gineκοlοgizh and οnκοlοgii κaκ προτivοοπuχοlevye Well κοnτρatseπτivnye sρedsτva.
Claims
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60500685A JPS61502256A (en) | 1984-06-27 | 1984-06-27 | Androstane steroid derivatives |
| DE19843490728 DE3490728C2 (en) | 1984-06-27 | 1984-06-27 | Androstane derivatives |
| CH571/86A CH666276A5 (en) | 1984-06-27 | 1984-06-27 | STEROID DERIVATIVES OF THE ANDROSTANE SERIES. |
| PCT/SU1984/000033 WO1986000311A1 (en) | 1984-06-27 | 1984-06-27 | Derivatives of steroids of androstane series |
| GB08602936A GB2169900B (en) | 1984-06-27 | 1984-06-27 | Derivatives of steroids of androstane series |
| DE19843490728 DE3490728T1 (en) | 1984-06-27 | 1984-06-27 | Steroid derivatives of the androstane series |
| SE8600828A SE457535B (en) | 1984-06-27 | 1986-02-24 | STEROID DERIVATIVES IN THE ANDROSTAN SERIES CONTAINING ATM MINSTONE AND CHLORPHENACYL ESTER GROUP |
| FI860815A FI84834C (en) | 1984-06-27 | 1986-02-25 | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA STEROIDDERIVAT AV ANDROSTANSERIEN. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SU1984/000033 WO1986000311A1 (en) | 1984-06-27 | 1984-06-27 | Derivatives of steroids of androstane series |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1986000311A1 true WO1986000311A1 (en) | 1986-01-16 |
Family
ID=21616852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SU1984/000033 Ceased WO1986000311A1 (en) | 1984-06-27 | 1984-06-27 | Derivatives of steroids of androstane series |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS61502256A (en) |
| CH (1) | CH666276A5 (en) |
| DE (2) | DE3490728C2 (en) |
| FI (1) | FI84834C (en) |
| GB (1) | GB2169900B (en) |
| SE (1) | SE457535B (en) |
| WO (1) | WO1986000311A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1001860A3 (en) * | 1978-08-14 | 1983-02-28 | Куреха Кагаку Когио Кабусики Кайся (Фирма) | Process for preparing derivatives of chloroambucyl (modifications) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1558472A (en) * | 1976-01-22 | 1980-01-03 | Leo Ab | 17-esters of 17- hydroxy gestogens |
-
1984
- 1984-06-27 WO PCT/SU1984/000033 patent/WO1986000311A1/en not_active Ceased
- 1984-06-27 DE DE19843490728 patent/DE3490728C2/en not_active Expired
- 1984-06-27 CH CH571/86A patent/CH666276A5/en not_active IP Right Cessation
- 1984-06-27 DE DE19843490728 patent/DE3490728T1/en active Pending
- 1984-06-27 GB GB08602936A patent/GB2169900B/en not_active Expired
- 1984-06-27 JP JP60500685A patent/JPS61502256A/en active Granted
-
1986
- 1986-02-24 SE SE8600828A patent/SE457535B/en not_active IP Right Cessation
- 1986-02-25 FI FI860815A patent/FI84834C/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1001860A3 (en) * | 1978-08-14 | 1983-02-28 | Куреха Кагаку Когио Кабусики Кайся (Фирма) | Process for preparing derivatives of chloroambucyl (modifications) |
Non-Patent Citations (1)
| Title |
|---|
| Journal of Medicinal Chemistry, Vol. 15, No. 11, 1982, by the AMERICAN CHEMICAL SOCIETY, (Columbus, USA), F.I. CARROLL et al: "Antitumor and Antileukemic Effects of some steriods ad other biologically interesting compounds containing an alkylating agent", pages 1159 and 1160 * |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8600828L (en) | 1986-02-24 |
| GB2169900B (en) | 1988-02-17 |
| DE3490728C2 (en) | 1989-09-14 |
| FI84834B (en) | 1991-10-15 |
| CH666276A5 (en) | 1988-07-15 |
| FI860815A0 (en) | 1986-02-25 |
| DE3490728T1 (en) | 1986-06-05 |
| SE8600828D0 (en) | 1986-02-24 |
| FI84834C (en) | 1992-01-27 |
| JPS61502256A (en) | 1986-10-09 |
| FI860815L (en) | 1986-02-25 |
| JPH0240079B2 (en) | 1990-09-10 |
| GB8602936D0 (en) | 1986-03-12 |
| GB2169900A (en) | 1986-07-23 |
| SE457535B (en) | 1989-01-09 |
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