LectureLecture №21 №21Hormones of the sexual glands: Hormones of the sexual glands:

androgens and their semi-synthetic androgens and their semi-synthetic derivatives, estrogens and their derivatives, estrogens and their

synthetic analogues. Prostaglandins synthetic analogues. Prostaglandins as pharmaceuticals, their as pharmaceuticals, their properties, application.properties, application.

ass.ass. Medvid I.I.Medvid I.I.

Androgenic hormonesAndrogenic hormonesMale sex hormones called androgens (from the Greek word 'Andros' Male sex hormones called androgens (from the Greek word 'Andros' - a man and "Genetic" - - a man and "Genetic" - birthbirth). Androgenic hormones are are produced produced by male gonads (testicular) during by male gonads (testicular) during the the pubertypuberty (sexual maturity (sexual maturity period)period).Androgens are necessary for the formation of sexual sphere and Androgens are necessary for the formation of sexual sphere and development of secondary sexual characteristics in mendevelopment of secondary sexual characteristics in men. They also They also affect affect on on various biochemical processes, not related tovarious biochemical processes, not related to the the characteristics of sex - cause anabolic effects, affectcharacteristics of sex - cause anabolic effects, affect on on the the exchange of carbohydrates, lipids, cholesterol, electrolytes and exchange of carbohydrates, lipids, cholesterol, electrolytes and other staffother staff.Natural androgen is testosterone, which was Natural androgen is testosterone, which was at at first dedicated in first dedicated in 1931 y. and synthesized in 1934 1931 y. and synthesized in 1934 yy.Testosterone creates male and his lack Testosterone creates male and his lack in thein the old age in man old age in man destroys the body, creating destroys the body, creating the the conditions for heart attacks and conditions for heart attacks and strokesstrokes.Testosterone - unstable substance and is not used as a medicineTestosterone - unstable substance and is not used as a medicine. In In medicine, testosterone derivatives (esters) medicine, testosterone derivatives (esters) are used, are used, which are which are absorbed slowly and absorbed slowly and are more stanle;are more stanle; and and also also synthetic substitutes, synthetic substitutes, such as methyltestosteronesuch as methyltestosterone. They all have medicinal properties of They all have medicinal properties of the natural hormonethe natural hormone.

Subsequent research established that the testosterone Subsequent research established that the testosterone effect is prolonged after effect is prolonged after the the esterification esterification by by fatty acidfatty acid. Ester creates original depot at the injection site from Ester creates original depot at the injection site from which they were gradually absorbed, while testosterone is which they were gradually absorbed, while testosterone is quickly removed from the body by the kidneysquickly removed from the body by the kidneys. One of the One of the most active and stable most active and stable at theat the stor storage of age of testosterone esters testosterone esters isis testosterone propionate testosterone propionate.MethyltestosteroneMethyltestosterone (17αα-methyltestosteronemethyltestosterone), although although by by the force of action the force of action is weaker thenis weaker then testosterone propionate, testosterone propionate, but not destroyed by enzymes of the gastrointestinal tract but not destroyed by enzymes of the gastrointestinal tract and remains activand remains activity at theity at the oral admission oral admission.Androgens are used for men with sexual Androgens are used for men with sexual underdevelopment, functional disorders of sexual sphere underdevelopment, functional disorders of sexual sphere (eunuchoidism(eunuchoidism) and in old age with vascular and nerve ) and in old age with vascular and nerve disordersdisorders.Applied Applied by by older women (over 60) older women (over 60) at theat the tumors of tumors of reproductive organs, mammary glands of uterine bleeding, reproductive organs, mammary glands of uterine bleeding, as well as radiotherapy as well as radiotherapy of of ovarian cancer and breast ovarian cancer and breast cancercancer.

Chemical signs of androgens

1. Derivatives of androstane;

2. Availability of oxo-group(=О) in position 3;

3. In position 4 – double bond;

4. Hydroxy-group (-ОН) (can be esterificated) in position17.

Androstane

Testosterone

CH3

CH3

1

2

3

4

5

6

7

89

10

11

12

13

14 15

16

17

18

19

O

CH3

CH3OH

General identification reactions onGeneral identification reactions on androgenic hormonesandrogenic hormones

On steroid systemOn steroid system : : Boscot’s reaction and reaction with Boscot’s reaction and reaction with concentrated sulfate acidconcentrated sulfate acid..

On keto-group in the position On keto-group in the position 3: 3: reactions of the oximes, reactions of the oximes, hydrazones, isonicotinoyl hydrazones, phenyl hydrazones hydrazones, isonicotinoyl hydrazones, phenyl hydrazones formationformation..

Esters of androgenic hormonesEsters of androgenic hormones ( (testosterone propionatetestosterone propionate): ): alkaline hydrolysisalkaline hydrolysis; ; hydroxamic reactionhydroxamic reaction..

Alcoholic hydroxyl inAlcoholic hydroxyl in 17 17ββ--position:position: formation of esters with formation of esters with character melting temperature.character melting temperature.

Testosterone propionate (Testosteroni propionas) (SPhU 1.2)

3-Oxandrost-4-ene-17β-yl propanoate or 17β-propioneoxyandrostene-4-one-3

Produce synthetically, based on cholesterol, which is produced with the processing of lanolin and pork fat of animals.

Characters. White or almost white crystalline powder or colorless crystals. Practically insoluble in water, freely soluble in alcohol and acetone, soluble in fatty oils.

O

CH3

CH3OCOC2H5

Identification of testosterone propionateIdentification of testosterone propionate

1. Absorption spectrophotometry in IR-spectrum..2.2. On steroid systemOn steroid system – – Boscot’s reaction Boscot’s reaction.. I Intense ntense

yellow fluorescence.yellow fluorescence.3.3. The drug is dissolved in СНThe drug is dissolved in СН33СООН СООН concconc..,, add add by by

drops bromine water - its bleaching occurs (reaction drops bromine water - its bleaching occurs (reaction onon double bond). double bond).

4.4. Establish a melting point of testosterone derived Establish a melting point of testosterone derived as a as a result ofresult of alkaline hydrolysis. alkaline hydrolysis.

4.4. On ester groupOn ester group – – hydroxamic reactionhydroxamic reaction (red-brown (red-brown color).color).

5.5. On oxo-group in positionOn oxo-group in position 3 – 3 – oxime formationoxime formation, , which which can be can be identifidentified byied by the temperature of the temperature of melting.melting.

6.6. UVUV--spectrophotometry.spectrophotometry.

Assay of testosteroneAssay of testosterone UVUV--spectrophotometryspectrophotometry ( (index methodindex method).). PhotocolorimetryPhotocolorimetry ( (based on the reaction between the drug with based on the reaction between the drug with isoniazid and establishment iisoniazid and establishment isonicotinoylhydrazonesonicotinoylhydrazone, colored in , colored in yellowyellow).).

Storage and applicationIn tightly corked container, protected from moisture and light actionIn tightly corked container, protected from moisture and light action..

Androgenic drug for Androgenic drug for the the treatment of climacteric, vascular and treatment of climacteric, vascular and nerve disorders and cancers of breast and ovaries in women. Enter nerve disorders and cancers of breast and ovaries in women. Enter by iby i/m/m way way in oil solutions. in oil solutions.IssueIssue – – ampamp. 1,0 . 1,0 and and 5,0 % 5,0 % solution in oilsolution in oil..OmnadrenOmnadren – – oil solution for injectionoil solution for injection ampamp.. 1 1 mlml №5 (contains a №5 (contains a mixture of testosterone esters: propionate, mixture of testosterone esters: propionate, phenylphenylpropionatpropionatee, , capronatecapronate, , isocapronateisocapronate))..Andriol (Andriol (testosterone undecanoatetestosterone undecanoate) – ) – capscaps. 40 . 40 mgmg № 30; № 30;AndrogelAndrogel ( (testosterontestosteron) – ) – gel for the external usagegel for the external usage 2,5 2,5 oror 5 5 gg №10. №10. Proviron (mesterolonProviron (mesterolonee, , derivative ofderivative of 5- 5-androstanoneandrostanone (3)) – (3)) – tabl.tabl. byby 25 25 mgmg №20. №20.

Testosterone enanthate (Testosteroni enanthas)

17-enanthoxyandrostene-4-one-3 Applied in same cases as testosterone propionate. Act slower but

longer as testosterone propionate. Enter by i/m way as 20% solution in oil one time every 2-4 weeks. Included to the Testoenatum mixture pro injectionibus amp. by 1 ml of 10% solution in peach oil (contains 24 mg of testosterone propionate and 111 mg of testosterone enanthate).

O

CH3

CH3OCO(CH2)5CH3

Methyltestosterone (Methyltestosteronum)

17α-methyl-17β-oxyandrostene-4-one-3

Synthetic testosterone replacement.

Characters. White crystalline powder, odorless. Practically not soluble in water, slightly soluble in ether and oils, soluble in acetone, easily soluble in ethanol.

O

CH3

CH3OH

CH3

Identification ofIdentification of methyltestosteronemethyltestosterone1.1. On steroid systemOn steroid system – – Boscot’s reaction Boscot’s reaction.. I Intense yellow ntense yellow

fluorescence.fluorescence.

2.2. At theAt the dissolving dissolving of theof the drug in conc. drug in conc. HH22SOSO44 orange- orange-

yellow color appears, and after adding yellow color appears, and after adding of of water - water - orange-yellow color with green fluorescence (steroid orange-yellow color with green fluorescence (steroid cycle).cycle).

3.3. On alcoholic groupOn alcoholic group ОН – ОН – acetilation reactionacetilation reaction,, acting acting ofof (СН (СН33СО)СО)22О О in pyridinein pyridine; ; at theat the dilution with water dilution with water

select methyltestosterone acetate with melting select methyltestosterone acetate with melting temperature temperature 173-176173-176ºº С ( С (with decompositionwith decomposition).).

4.4. On oxo-groupOn oxo-group in positionin position 3 –the substance is boiled in 3 –the substance is boiled in methanol withmethanol with H H22NOH*HClNOH*HCl – – sediment of oxime falls sediment of oxime falls

((melting temperature –melting temperature – 210-216 210-216ººС).С).

Assay of methyltestosteroneAssay of methyltestosterone

UVUV--spectrophotometry atspectrophotometry at λλ=240 =240 nmnm..

Storage and applicationIn tightly corked container, protected from moisture In tightly corked container, protected from moisture

and light actionand light action..

Androgenic medicationAndrogenic medication. . InIn 2-3 2-3 times less active times less active than testosterone propionate, but remains activity than testosterone propionate, but remains activity at the inside usage (sublingualat the inside usage (sublingual).).

IssueIssue: : tabltabl. . byby 5-10 5-10 mgmg..

Anabolic steroid structure meansAnabolic steroid structure means

Anabolic drugAnabolic drugs s called substancecalled substance that that in the body in the body stimulate the synthesis of proteins. Under their stimulate the synthesis of proteins. Under their influence increasing body weight, improves the influence increasing body weight, improves the general condition of patients.general condition of patients. By t By theheir ir structure structure anabolic druganabolic drug are are similar to male sex hormones, which similar to male sex hormones, which havehave anabolic activity anabolic activity as side effectas side effect. . ApplApply of y of androgens androgens with with anabolic action is not anabolic action is not possible to treat women and children. Therefore it possible to treat women and children. Therefore it became necessary to synthesize the substance, which became necessary to synthesize the substance, which would be rather would be rather weakweak androgenic effect but a stronger androgenic effect but a stronger or equal with androgens anabolic activity. It turned out or equal with androgens anabolic activity. It turned out that this can be achieved at some changes that this can be achieved at some changes of of molecular molecular structure of male sex hormones.structure of male sex hormones.

• There are three major ways of androgenic activity lowering :

1) Transfering of double bond from position 4 to position 5 :

2) Introduction of the additional double bond in position 1:

3) Elimination of methyl group at position 19.

Derivatives of 19-nortestosterone

are the best anabolic drug.

CH3

5

CH3

O

1

O

Methylandrostendiol (Methylandrostendiolum) Methandriol*

17α-methylandrostene-5-diol-3β,17β or

3β,17β-dioxy-17α-methylandrostene-5

Characters. White crystalline powder, odorless. Practically not soluble in water, soluble in ethanol, sparingly soluble in chloroform.

HO

CH3

CH3OH

CH3

Identification ofIdentification of methylandrostendiolmethylandrostendiol1.1. At theAt the dissolving dissolving of of the drug in concthe drug in conc.. HH22SOSO44 orange- orange-

yellow color appears, with green fluorescence (steroid yellow color appears, with green fluorescence (steroid cycle).cycle).

2.2. On alcoholic groupOn alcoholic group ОН – ОН – acetylation reactionacetylation reaction, , after after the action ofthe action of (СН (СН33СО)СО)22ОО in pyridine in pyridine –17- –17-monoacetate monoacetate ofof methylandrostendiol appears with melting methylandrostendiol appears with melting temperature –temperature –174-180174-180ºº С. С.

4.4. To the solution of drug inTo the solution of drug in 80% СН 80% СН33СООН carefully СООН carefully add add concconc. . HH22SOSO44 – – on the border of phaseon the border of phasess appears appears orange color, the upper phase is characterized by orange color, the upper phase is characterized by yellow-green fluorescence.yellow-green fluorescence.

5.5. UVUV- spectroscopy.- spectroscopy.6.6. Specific optical rotation.Specific optical rotation.

Assay ofAssay of methylandrostendiolmethylandrostendiol

GravimetryGravimetry..

Storage and applicationIn tightly corked container, protected from moisture and light In tightly corked container, protected from moisture and light

actionaction..By chemical structure resembles methyltestosterone, but has By chemical structure resembles methyltestosterone, but has weaker androgenic anabolic effect and stronger weaker androgenic anabolic effect and stronger anabolic anabolic activity.activity.Apply Apply at the at the disorders of protein metabolism after severe injuries, disorders of protein metabolism after severe injuries, operations, at operations, at the the exhaustion, after infectious diseasesexhaustion, after infectious diseases,, at the lag at the lag growth in adolescents. Treatment of women should be under the growth in adolescents. Treatment of women should be under the supervision of the gynecologist to supervision of the gynecologist to prevent theprevent the effects effects vvirilization.irilization.Adopt in the form of tablets for sublingual absorption Adopt in the form of tablets for sublingual absorption byby 25-50 25-50 mg per day. Not used in prostate cancer, liver diseases.mg per day. Not used in prostate cancer, liver diseases.ReleaseRelease in the form of in the form of tablets tablets byby 10 and 25 mg. 10 and 25 mg.

Methandrostenolone (Methandrostenolonum) Анабол, Methandienone*

17α -methyl-17β-oxy-1,4-androstanediene -3-one or1,2-dihydromethyltestosterone

Characters. White crystalline powder, are allowed a weak yellowish shade. Very little soluble in water, slightly soluble in ether, easily soluble in ethanol, chloroform.

CH3

CH3OH

CH3

O

Identification ofIdentification of methandrostenolonemethandrostenolone1.1. UVUV--spectroscopyspectroscopy..

2.2. At theAt the dissolving dissolving of of the drug in concthe drug in conc.. HH22SOSO44 dark-red dark-red

colorcolor formed formed. .

4.4. On oxo-group in positionOn oxo-group in position 3: 3: after after the interaction of the the interaction of the drug with 2,4-drug with 2,4-dinitrophenylhydrazinedinitrophenylhydrazine 2,4- 2,4-dinitrophenylhydrazone of methandrostenolonw formed, dinitrophenylhydrazone of methandrostenolonw formed, which has orange-red colorwhich has orange-red color. .

Test on purityTest on purity

The presence of The presence of side side steroids steroids as as contaminant contaminant (methyltestosterone) (methyltestosterone) is is establishestablisheded by TLC by TLC.

Selenium Selenium adadmixture (not more than mixture (not more than 0,01%)0,01%) - the method the method of combustion in oxygen followed by of combustion in oxygen followed by spectrophotometryspectrophotometry.

Assay of methandrostenoloneAssay of methandrostenolone UV--spectrophotometryspectrophotometry. . In tabletsIn tablets methandrostenolone is detected methandrostenolone is detected

by photocolorimetric method by the interaction with conc. Hby photocolorimetric method by the interaction with conc. H22SOSO44 . .

Storage andStorage and applicationapplication In tightly corked container, protected from moisture and light In tightly corked container, protected from moisture and light

actionaction..Androgenic action is inAndrogenic action is in100100 times weaker then in times weaker then in testosterone testosterone propionatepropionate,, anabolic anabolic activityactivity –– the same the same . .Apply Apply at theat the protein metabolism disorder, chronic adrenal protein metabolism disorder, chronic adrenal insufficiency, toxic goitre, diabetic angiopathy, steroid insufficiency, toxic goitre, diabetic angiopathy, steroid diabetes, chronic coronary insufficiency and myocardial diabetes, chronic coronary insufficiency and myocardial infarction, rheumatic heart lesions, atherosclerotic infarction, rheumatic heart lesions, atherosclerotic cardiosclerosis, stomach ulcers and duodenal ulcers, cardiosclerosis, stomach ulcers and duodenal ulcers, osteoporosis, bone fractures, eczema, psoriasis and others. osteoporosis, bone fractures, eczema, psoriasis and others. Produce Produce in the form of tablets byin the form of tablets by 1 1 andand 5 5 mgmg..

Phenobolin (Phenobolinum), Nerobolil, Durabolin, Nandronolone phenylpropionate*

17β-phenylpropioneoxy-19-norandrostene-4-one-3 or

19-nortestosterone phenylpropionate

Characters. White, sometimes with a creamy tinct crystalline powder. Practically insoluble in water, slightly soluble in ethanol, freely soluble in chloroform and acetone.

CH3OCOCH2CH2C6H5

O

Identification of phenobolin1.1. Melting temperatureMelting temperature (95-99 °С). (95-99 °С).2.2. IRIR--spectroscopyspectroscopy..3.3. TLCTLC..

Assay UV--spectrophotometryspectrophotometry..

Storage andStorage and applicationapplication In tightly corked container, protected from light action.In tightly corked container, protected from light action.PhenobolinPhenobolin –active anabolic –active anabolic mean with mean with long acti long actionon (7-15 (7-15 days after single injection). Detectdays after single injection). Detectss very weak androgenic very weak androgenic effect,effect, in women in women virilyzation phenomenavirilyzation phenomena almost not almost not observed. Applied in those cases, as metobserved. Applied in those cases, as methhandrostenolonandrostenolone,e, not used not used for the treatment offor the treatment of prostate cancer. prostate cancer.Enter Enter by by the the ii/m/m way way in oil solution in oil solution byby 25-50 mg 1 25-50 mg 1 time time every 7-10 days.every 7-10 days.Issue:Issue: byby 1 1 ml ofml of 1% 1% andand 2,5% 2,5% solutions in oilsolutions in oil..

Retabolil (Retabolilum), Nandrolone

17β-decanoyloxy-19-noradrenostene-4-one-3 or

19-noradrenostene decanoate Strong and long (3 weeks) anabolic effect. Low toxicity, androgenic

effect is lover than in phenobolin. Enter by the i/m way by 25-50 mg 1 time every 2-3 weeks. Produce in the form of 5 % oil solution in amp. by 1 ml.

CH3OCO(CH2)8CH3

O

Female sex hormones and synthetic Female sex hormones and synthetic substitutessubstitutes

Female sex hormones called estrogenFemale sex hormones called estrogenss (from the Greek word (from the Greek word "estrus" - estrus and "Gen"estrus" - estrus and "Gennaonao" - b" - birthirth). These hormones are ). These hormones are produced in maturing ovarian follicles and participate in the produced in maturing ovarian follicles and participate in the implementation of menstruation. They are necessary for the implementation of menstruation. They are necessary for the formationformation of female sex of female sex and female secondary sexual and female secondary sexual characteristics and functions for having children.characteristics and functions for having children.The natural estrogen is estradiol and estron. Among them estron The natural estrogen is estradiol and estron. Among them estron is is a a memedical drugdical drug and estradiol used in the form and estradiol used in the form of of esters and other esters and other derivatives, derivatives, becousebecouse estradiol itself very rapidly inactivate estradiol itself very rapidly inactivatess in the in the body.body.As As medical medical drugs estrogendrugs estrogens s are used in low ovarian function are used in low ovarian function (primary and secondary amenorrhea), underdevelopment of the (primary and secondary amenorrhea), underdevelopment of the uterus, sterility, uterus, sterility, post-castartionpost-castartion disorders, surgical removal of disorders, surgical removal of ovaries. Estrogens ovaries. Estrogens are are used to treat parahormonused to treat parahormonee cancer in men and cancer in men and increased increased of of labor activity (causing contraction of the uterus).labor activity (causing contraction of the uterus).Do not apply to women aged up to 60 years for malignant and Do not apply to women aged up to 60 years for malignant and benign tumors of the genital organs and mammary glands.benign tumors of the genital organs and mammary glands.

Estrone EstradiolCH3

HO

O

CH3

OH

HO

Earlier estrone (folliculine) and estradiol are obtained from the urine of pregnant women, then - from the urine of pregnant animals. Now them are obtained synthetically from cholesterol.

Chemical signs of estrogens

Estrane

1. Derivatives of estrane.

2. Presence of the tree double bounds in the positions 1, 3, 5(10).

3. Group –ОН (oxy-group) in position 3.

4. Group –ОН (can be esterificated) or oxo-group (=О) in position17.

CH3

1

2

3

4

56

7

89

10

11

12

13

1415

16

17

General identification reaction onGeneral identification reaction on estrogenic hormonesestrogenic hormones

On steroid systemOn steroid system: : Boscot’s reaction and reaction with Boscot’s reaction and reaction with concentrated sulfate acidconcentrated sulfate acid..EstersEsters of estrogenic hormonesof estrogenic hormones ( (estradiol dipropionateestradiol dipropionate): ): hydrolysis with the following identification of the hydrolysis with the following identification of the products of hydrolysisproducts of hydrolysis; ; hydroxamic reactionhydroxamic reaction..Phenolic hydroxylPhenolic hydroxyl - - reactionsreactions::

а) а) electrophilic substitutionelectrophilic substitution ( (brominationbromination, , nitrationnitration, , formation azo-dyeformation azo-dye, , aurin stainaurin stain););

bb) ) saltsalt and complex formationand complex formation with heavy metals salts with heavy metals salts ((for for exampleexample, , FeClFeCl33););

cc) ) Esters formationEsters formation ( (for examplefor example, , with benzoyl chloridewith benzoyl chloride), ), which have character melting temperaturewhich have character melting temperature..

Estrone (Oestronum) Folliculine

3-oxyestratriene-1,3,5(10)-one-17

Characters. White crystalline powder. Practically insoluble in water, soluble in ethanol and ether, easily soluble in chloroform.

CH3

HO

O

Identification of estroneIdentification of estrone1.1. Boscot’s reaction – Boscot’s reaction – green fluorescencegreen fluorescence appears appears..2.2. Estrone solution inEstrone solution in conc. conc. HH22SOSO44 ). has golden ). has golden--yellow yellow

colorcolor with intense green fluorescence (steroid cycle). with intense green fluorescence (steroid cycle). 3.3. At the interaction withAt the interaction with NHNH22OH*HCl oxime precipitate OH*HCl oxime precipitate

falls falls (with melting point 228-233(with melting point 228-233ººС). С). 4.4. At the interaction withAt the interaction with з з diazoreagentdiazoreagent formation of azo-formation of azo-

dye is observed (reaction on phenolic hydroxyldye is observed (reaction on phenolic hydroxyl).).5.5. At the action ofAt the action of CC66HH55COCl phenolic hydroxyl COCl phenolic hydroxyl

esterificates and formed ester has melting temperature esterificates and formed ester has melting temperature of of 220220ººС. С.

Activity of estrone determined biologically (evocation Activity of estrone determined biologically (evocation of oestrus) in neutered female mice and ratsof oestrus) in neutered female mice and rats.. In In 1 mg 1 mg areare 10000 10000 UAUA..

Assay of estroneAssay of estronePolarimetry (solution of the drug in Polarimetry (solution of the drug in dioxanedioxane). ).

PhotocolorimetryPhotocolorimetry (by the reaction of azo (by the reaction of azo--dyedye formation formation). ).

Storage and applicationIn tightly corked container, protected from light actionIn tightly corked container, protected from light action..

Enter Enter by by the the ii/m/m way way in the form of oil solutions in the form of oil solutions at theat the low ovarian function (primary and secondary low ovarian function (primary and secondary amenorrhea), infertility, cancer and underdevelopment amenorrhea), infertility, cancer and underdevelopment of secondary sexual characteristics, overterm pregnancy, of secondary sexual characteristics, overterm pregnancy, the surgical removal of ovaries.the surgical removal of ovaries.

Issue:Issue: amp. byamp. by 1 1 mlml of of 0,05% 0,05% oror 0,1 % 0,1 % oil solutionoil solution..

Estradiol dipropionate * (Oestradioli dipropionas)

3,17-dipropioneoxyestratriene-1,3,5(10)

Characters. White crystalline powder. Practically insoluble in water, very little soluble in ethanol and oils.

CH3

C2H5OCO

OCOC2H5

Identification of estradiol dipropionateIdentification of estradiol dipropionate1. IR- and UV-Spactroscopy.2. At the Boscot’s reaction green fluorescence appears.3. At the heating with conc. H2SO4 there is a brown

coloration, which by dilution with water and heated changes to pink.

4. On esteric groups conducted hydroxamic reaction (look testosterone propionate).

5. At the hydrolysis by КОН in ethanol estradiol forms, which falls in the form of precipitate at the dilution with water and acidification by НСl. Melting temperature of estradoil is 177 ºС.

6. Propanoic acid, which formed after the acidic hydrolysis, can be identified by the reaction with ethanol - ester formed, which has a characteristic odor.

CH3

C2H5OCO

OCOC2H5

2H2O

H2SO4

CH3

HO

OH

+ 2 C2H5COOH

C2H5COOH + C2H5OH C2H5COOC2H5 + H2O

CH3

C2H5OCO

OCOC2H5 CH3

HO

OH

+ 2 C2H5COOK

+ 2 KOH

KOH + HCl KCl + H2O

Assay of estradoil dipropionate

Alkalimetry, the reverse titration. Substance is hydrolyzed alcohol by the alcoholic solution of potassium hydroxide, an excess of which is titrated by hydrochloric acid solution by phenolphthalein, Ем = ½ М.m.

Storage and application• In tightly corked container, protected from light actionIn tightly corked container, protected from light action..• In two timesIn two times more active more active thanthan estron estrone,e, has a strong and has a strong and

prolonged effect, apply in those cases, as estronprolonged effect, apply in those cases, as estronee. Enter. Enter by by ii//m way by 1 ml of m way by 1 ml of 0 0,,1% sol1% solutionution in oi in oil everyl every 1-2 days. 1-2 days.

• EstradiolEstradiol is is a a part of the part of the following following preparations“preparations“EstramoneEstramone” (” (transdermtransderm. . plaster, plaster, 4 4 mgmg 20 20 cmcm2 2

№6); “№6); “EstrogelEstrogel” (” (gel for the local usage gel for the local usage 0,6 0,6 mgmg//gg 80 80 gg); ); ““EstrimaxEstrimax” (” (tabltabl. 2 . 2 mgmg №28). №28).

• Complex preparationsComplex preparations – “ – “PausogestPausogest” (” (estradiolestradiol hemihydratehemihydrate and norethisteroneand norethisterone acetateacetate); “); “ClimodieneClimodiene” ” ((estardiol valerate andestardiol valerate and dienogestdienogest).).

• Estriol is a part ofEstriol is a part of “ “OvestineOvestine” (” (tabltabl., ., vagvag. . creamcream, , vagvag. . suppossuppos.)..).

Ethinylestradiol (Aethinyloestradiolum) Ethynilestradiol*

17α-ethinylestratriene-1,3,5(10)-diol-3,17β Characters. White or creamy white fine crystaline powder,

odorless. Practically insoluble in water, slightly soluble in alkali, soluble in alcohol, chloroform, soluble in acetone, ether and dioxane.

CH3

HO

OH

C CH

Identification of eIdentification of eththiinnyylestradiollestradiol1. IR- and UV-spectroscopy, TLC2. To detect ethynil group substance is dissolved in

H2SO4, add FeNH4(SO4)2 solution – reddish-brown precipitate falls after the dilution with water pink-red sediment falls.

3. At the Boscot’s reaction orange fluorescence appears, in 50-100 times stronger than estrone fluorescence.

4. At the action of conc. H2SO4 orange-red color forms with yellow-green fluorescence .

5. At the interaction with benzoyl chloride ethinylestradiol-3-benzoate forms with melting temperature of 199-202ºС (phenolic hydroxyl).

CH3

HO

OH

C CH

CH3

O

OH

C CH

C

O

CO

Cl+

+ HCl

Assay ofAssay of ethinylestradiolethinylestradiol

1.1. Alkalimetry by the Alkalimetry by the substituent(substituent(looklook pregninepregnine).).2.2. Spectrophotometry or photocolorimetrySpectrophotometry or photocolorimetry by the by the

formation of bis-diazocompound in alkaline medium formation of bis-diazocompound in alkaline medium at at the interaction with diazoreagent the interaction with diazoreagent ::

Ethinylestradiol is stored in tightly corked container in a Ethinylestradiol is stored in tightly corked container in a dark placedark place..

Application of Application of ethinylestradiolethinylestradiolEthinylestradiol - one of the most active estrogenic agents. Ethinylestradiol - one of the most active estrogenic agents. Introduction Introduction of ethinyl residueof ethinyl residue to the estradiol molecule to the estradiol molecule increases stability and activity, increases stability and activity, that is why that is why ethinylestradiol ethinylestradiol is is taking internally.taking internally.Apply Apply at theat the h hyypopoggenitalizm (primary amenorrhea, enitalizm (primary amenorrhea, underdevelopment of the uterus), ovarian hypofunction and underdevelopment of the uterus), ovarian hypofunction and secondary amenorrhea secondary amenorrhea byby 0,05-0,1 mg 0,05-0,1 mg;; for elimination of for elimination of neuro-vascular disorders of estrogenic insufficiency neuro-vascular disorders of estrogenic insufficiency receiving receiving by by 0,01-0,02 mg per day0,01-0,02 mg per day;; to treat cancer prostate to treat cancer prostate and breast cancer in women over 60 years - to 3 mg per day and breast cancer in women over 60 years - to 3 mg per day over a long time. In the treatment of prostate cancer in men over a long time. In the treatment of prostate cancer in men may may be be feminization.feminization.Issue:Issue: tabl. bytabl. by 0,01 0,01 andand 0,05 0,05 mg under themg under the “ “MicrofolinMicrofolin” ” andand ““EsterlanEsterlan”.”.Is a part ofIs a part of oral contraceptive preparations. oral contraceptive preparations.

Synthetic steroidal structure estrogensSynthetic steroidal structure estrogensSubstances that have estrogenic activity, were found not only Substances that have estrogenic activity, were found not only among the steroid, but in some aromatic compoundsamong the steroid, but in some aromatic compounds. Admitting that the effect of estrogen depends on the presence Admitting that the effect of estrogen depends on the presence of aromatic nuclei in the moleculeof aromatic nuclei in the molecule. Important role Important role belongs to belongs to hydroxyl hydroxyl and keto-groups and keto-groupsgroups groups that can form hydrogen bonds and interact with proteins in the that can form hydrogen bonds and interact with proteins in the bodybody. For the detection of estrogenic For the detection of estrogenic action is importantaction is important the the distance distance betweenbetween the the functional groups functional groups. It is determined It is determined that the that the distance between the hydroxyl groups (in position 3 and 17) in distance between the hydroxyl groups (in position 3 and 17) in estradiol is 1estradiol is 1,,1 nm, in meso-form 1 nm, in meso-form of synestrolof synestrol 1 1,,2 nm, 2 nm, in in the the trans-isomertrans-isomer of of dietdiethylstilbestrol hylstilbestrol – 1– 1,,22 nm22 nm. At the same At the same cis-cis-isomerisomer of of didiethylstilbestrolethylstilbestrol, , in which thein which the distance between the distance between the hydroxyls is 0hydroxyls is 0,,75 nm, 75 nm, is is physiologically inactive. physiologically inactive. The formation of ethers and esters do not reduce estrogen The formation of ethers and esters do not reduce estrogen activity, but increases the activity, but increases the period of actionperiod of action.

Synestrol (Synoestrolum)Hexestrol

Meso-3,4-di-(p-oxyphenyl)-hexane

Characters. White crystalline powder, can have a yellowish tint, odorless. Practically insoluble in water, soluble in ethanol, chloroform, vegetable oils, alkali solutions.

Estrogenic activity of synestrol is equal to estrone activity. Is used for the treatment of those diseases as estrone.

Issue: tabl. by 1 mg; amp by 1 ml of 0,1% and 2% oil solutions.

HC C

HOH

C2H5

HO

C2H5

Diethylstilbestrol (Diaethylstilboestrolum)

Trans-3,4-di-(p-oxyphenyl)-hexene-3 Characters. White crystalline powder, odorless. Practically insoluble in water, soluble in ethanol, ether,

vegetable oils, alkali solutions. Two times more active than estrone, but due to the side effect it is

used only for the treatment of breast cancer in women older than 60 years.

Issue: amp. 3% oil solutions by 1 ml.

C C OH

C2H5

HO

C2H5

Identification ofIdentification of synestrol andsynestrol and diethylstilbestroldiethylstilbestrol

1. At the interaction of synestrol chloroform solution with conc. H2SO4 (In the presence of formalin) chloroform layer is painted in a cherry-red color (phenyl radicals). Diethylstilbestrol solution in conc. H2SO4 has the orange color, which gradually disappears after the dilution with water.

2. When you add bromine water solution to synestrol in conc. СН3СООН yellow precipitate forms. Diethylstilbestrol with bromine water in the presence of liquid phenol at the heating forms the emerald-green color, after adding of few pieces of sugar and heating coloration turns into dark blue, and cherry-brownish.

3. At the adding of to the synestrol chloroform layer FeCl3 solution and pyridine – there is a blue coloration, which by the adding of pyridine in excess turns green. Alcohol solutions of diethylstilbestrol colored in green, which gradually turns into yellow (phenolic hydroxyl).

4. At the interaction of drugs with (СН3СО)2О or С6Н5СОСl diacetates (dibenzoates) form, which have characteristic temperature of melting.

Assay of synestrol and diethylstilbestrol1. Method of acylation. Based on the obtaining of esters (diacetyl

derivatives) by heating with acetic anhydride in the presence of pyridine. Excess of (СН3СО)2О is transformed to СН3СООН and titrate acid by NaOH solution, indicator - phenolphthalein, Еm = ½ М.m. In parallel control experiment is conducted:

2. Assay of synestrol in oil solution is conducted solution solution after after the the extraction extraction by by aqueous solution of sodium aqueous solution of sodium hydroxide by the rehydroxide by the reverseverse bromatom bromatometry methodetry method with with control experimentcontrol experiment, Еm = 1/8 М.m.:

HO CH CH OH

C2H5

C2H5

HO CH CH OH

C2H5

C2H5

Br

Br

Br

Br

4Br2

4HBr

KBrO3 + 5KBr + 6HCl 3Br2 + 6KCl + 3H2O

Br2 + 2KCl I2 + 2KBr

I2 + 2Na2S2O3 2NaI + Na2S4O6

3. Synestrol and diethylstilbestrol can be determined by photometric method by the reaction of azoconnection with diazotated sulfanilic acid:

Storage of synestrol and siethylstilbestrolStorage of synestrol and siethylstilbestrolIn tightly corked container, protected from light actionIn tightly corked container, protected from light action..

HO CH

C2H5

CH OH 2

C2H5N

SO3H

N

HSO4

HO3S N N

HO CH

C2H5

CH OH

NN SO3H

C2H5

2H2SO4

ProstaglandinsProstaglandins Prostaglandins - biologically active substancesProstaglandins - biologically active substances that are that are contained contained in various organs and tissues (blood, lung, kidney, intestine, in various organs and tissues (blood, lung, kidney, intestine, uterus, etc.). They are uterus, etc.). They are a a sort of intracellular hormones that sort of intracellular hormones that have have influence influence on on many body functionsmany body functions . Produced in the body in very . Produced in the body in very small quantities (about 100 micrograms per day). Most small quantities (about 100 micrograms per day). Most accumulate in the seminal fluid.accumulate in the seminal fluid.

The first data The first data was was in 1913, when in 1913, when from from the male prostate extract the male prostate extract was was isolated, whichisolated, which puts puts down Adown APP in dogs in dogs . .

Discoverer of prostaglandins is the Euler (Sweden), who Discoverer of prostaglandins is the Euler (Sweden), who investigated these matters since 1934investigated these matters since 1934 year. H year. He proposed the term e proposed the term "prostaglandins" that "prostaglandins" that is from is from the Latin name of the prostate gland the Latin name of the prostate gland (Glandula prostata(Glandula prostata))..

Like vitamins, prostaglandins are divided into groups with Like vitamins, prostaglandins are divided into groups with similar chemical structure. Each one has a Latin index E, F, A, B similar chemical structure. Each one has a Latin index E, F, A, B (abbreviated writing PGE, P(abbreviated writing PGE, PGGF, PGA, PF, PGA, PGBGB).).

ProstaglandinsProstaglandins - a compounds - a compounds without azotwithout azot, , in the in the base base of its of its structure is prostanostructure is prostanoic ic acid:acid:Individual prostaglandinsIndividual prostaglandins

distinguish by the number and distinguish by the number and placing of radicals placing of radicals ( (HydroxylHydroxyl, , carboxylcarboxyl) ) and double bonds and double bonds in the moleculein the molecule..

Extraction of prostaglandins 1.1. Extraction from animal sources (semen body fluids, animal Extraction from animal sources (semen body fluids, animal

tissue, etc.). The method is laborious, long and expensive. tissue, etc.). The method is laborious, long and expensive. 2.2. Biosynthesis of precursors - polyunsaturated fatty acids in the Biosynthesis of precursors - polyunsaturated fatty acids in the

presence of appropriate enzymes. Almost biosynthesispresence of appropriate enzymes. Almost biosynthesis is is conductedconducted by incubation of by incubation of unsaturated unsaturated fatty acids from fatty acids from homogenate tissues of cattle (mostly seminal glands).homogenate tissues of cattle (mostly seminal glands).

3.3. Synthetic methods for prostaglandinSynthetic methods for prostaglandinss extraction extraction i include up to nclude up to 29 stages. It is difficult to provide the necessary isomers that 29 stages. It is difficult to provide the necessary isomers that havehave biological activity. biological activity.

CharactersCharactersSelected asSelected as individual compounds prostaglandins - a white crystalline individual compounds prostaglandins - a white crystalline substances which are easily dissolved in organic solvents.substances which are easily dissolved in organic solvents.To study the chemical structure of prostaglandins UV, IR, NMR To study the chemical structure of prostaglandins UV, IR, NMR spectroscopy, massspectroscopy, mass--spectrometry, X-ray analysisspectrometry, X-ray analysis are used are used..

IdentificationIdentification For the analysis of prostaglandins are widely used various types of For the analysis of prostaglandins are widely used various types of chromatography: column, paper, thin layer, gas-liquid (chromatography: column, paper, thin layer, gas-liquid (GLCGLC) and ) and others. Especially effective for the quantitative analysis others. Especially effective for the quantitative analysis is is combination of GLHcombination of GLH and mass and mass--spectrometry that spectrometry that allows to allows to detect detect 9-9-1010 g g of of prostaglandins.prostaglandins.For quantitative determination UVFor quantitative determination UV--spectrophotometryspectrophotometry are used are used..To evaluate the physiological activity and the content of To evaluate the physiological activity and the content of prostaglandins in the tissues biological methodsprostaglandins in the tissues biological methods are used are used, , which are which are based based onon their ability to affect their ability to affect on on the smooth muscles (stomach, the smooth muscles (stomach, intestine, uterus), blood pressure and other functions. Useintestine, uterus), blood pressure and other functions. Use also also enzymatic and radioimmunological methods of analysis.enzymatic and radioimmunological methods of analysis.

Usage of prostaglandinsProstaglandins affect on the contractile activity of smooth muscle, functions of the nervous and cardiovascular systems, blood circulation, support the tone of urinary tract and bladder, and exhibit bronholitic bronhodilatation action, involved in the inflammation processes. The most active groups of prostaglandins are E, F and A. Prostaglandins E1 and E2 affect on the function of the bronchi; PGE inhibits the secretion of gastric juice; PGE and PHF cause reduction of uterine muscle; PGA1 and PGA2 during the action on blood vessels, make lower a blood pressure .Various pharmacological activity of prostaglandins hampering their practical application in medicine, so it is nessesary to search their synthetic analogs, which are available obtained and are selectively derived on the specific systems and functions.Obtained in the present analogs contain in the molecule structure cyclopentane nucleus and are 7-oxyanalogs, 15-ketoanalogs, contain esteric group at the positions 1 and 15. Some analogues contain instead of cyclopentane other cycles, and shortened or elongated alkyl chains.

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