IL34217A - 17-aminoalkoxy-androst-2-enes - Google Patents
17-aminoalkoxy-androst-2-enesInfo
- Publication number
- IL34217A IL34217A IL34217A IL3421770A IL34217A IL 34217 A IL34217 A IL 34217A IL 34217 A IL34217 A IL 34217A IL 3421770 A IL3421770 A IL 3421770A IL 34217 A IL34217 A IL 34217A
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- IL
- Israel
- Prior art keywords
- androstene
- acid
- formula
- aoid
- ether
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N45/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Steroid Compounds (AREA)
Description
->andr oa eae-17-θ tbers .; .¼' ·/ This invention is concerned with 2-androstene- -9 17-ethers, with processes for their preparation, and with compositions containing them.
We have found that 2-androstene-17~ethers of the formula: in whioh R and R , which ma be the same or different , are alkyl groups containing 1 to 3 carbon a oms or, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, hexamethyleneimine , piperazine or raorpholine radical, and n is 2, 3 or 4-, and their physiologically acceptable acid addition salts, are well tolerated and have excellent antihyperoholesterolaemio, oestrogenic, anti-oestrogenio and contraceptive activities, together with good fungistatic or fungicidal (antimyootic) and bacteriostatic or baotericidal properties.
For example , an oral dose of 10 mg/kg of the hydrochloride of 17β-( -diethylaminoetho y)- -androθ θne, given to rats (method of Oounsell et al., J. Med« Pharm, Chen , 5, 270, 1224· (1962)) reduced the serum oholesterol level by 29%. The same substance has, for example, fungistatic or fungicidal effeot on the following microorganisms s Aspergillus fumigatus, Aspergillus niger, Oahdida albicans, Candida parapsjlosis , Epidermophyton in whio Q is dime hylamino or diethylaniino.
The present invention also comprises a process for the preparation of the novel compounds, whioh ooraprises oondensing a steroid of the formula: or oondensihg a compound of the formula: in which n has the above-stated meaning and Z Is an OH group, a functionally modified OH group or Hal, where Hal has the above-stated meaning-, "with an amine of the formula, HNR½2 (VI), in which and R2 have the above-stated meanings, s d in which Z, n, R and R have the above-stated meanings, with a compound capable of splitting off HZ, and, if desired, converting the base of Formula I obtained by treatment with an acid into a physiologically acceptable acid addition salt thereof or treating the aoid addition salt of a oompound of Formula I obtained with a base to liberate the free base.
In the oompounds of Formulae I, III, IV, V and VII, the group -Oj^H^- is preferably -(CH2)a-, particularly -QH2CH2-, -CH2CH2CH2- or-CH2CH2CH20H2-. But it may also represent -OH(OHj)-, -CH(CH5)CH2-, -0H20H(0H5 -, -OHCCgH^)-, -0H(0H5)CH20H2-, -CH2CH CH5)CH2-, -CH2CH2CH CH5)-, -CHCCgH^OH^ -CH20H(02H5)-, -ΟΗζη-Ο^)- or -CHCiso-O^)-.
In the compounds of Formulae II, III, V and VII, X, Y and Z may represent functionally .modified OH groups, in addition to Hal and free OH groups, Suoh functional modified OH groups include, for example, .esterified, particularly "reaotively" esterified, OH groups, for example esters formed with a sulphonic acid (for example containing 1 to 10 carbon atoms, such as methanesulphonio, ethanesulphonic, benzenesulphonic, p-toluenesulphonio or naphthalenesulphonic acid) or a carboxylic acid (for example containing 1 to 18, preferably 1 to 7 oarbon atoms, for example a fatty acid, such as formic acid, aoetio aoid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic aoid, caproic aoid, isocaproic acid, oenanthic acid, caprylic acid, pelargonic acid, oaprio aoid, lauric acid, myristio acid, palmitio aoid, and stearic acid; also, for example, crotonio aoid, oleic acid, oyclohexanecarboxylic acid, oyclohexyiacetio acid, oyclohexyipropionic acid, benzoio aoid, phenylacetio aoid, phenylpropionic acid, picolinic aoid, nicotinic aoid, isonicotinic acid or furan-2-carboxylio acid).
In the compounds of Formula II, the sinuous line in the 17-position means that the substituent X may be attached in a or β configuration. Substituents in the a position include, for example, 01, Br, I and sulphonic aoid ester groups, such as p-toluenesulphonyloxy. In these cases, a Walden inversion takes place on reaotion with the amine III, and the desired 173-others are obtained.
In the compounds of Formula VII, the substituenii - Z may also be in the a or β positions. Starting compounds of Formula VII in which Z is in the β position are preferred, because they are easier to prepare. · · . The 2-androstene-17-ethers of Formula I can be prepared by reacting compounds of Formulae II and III, It is advantageous to start with either two alcohols or one aloohol and a reaotive ester of the other alcohol.
If the etherification reaction takes place without Walden inversion, preferred starting compounds of Formula II are the well-known 2-androsten-17P-ol and its reaotive . 17-esters, such as the 17-me hanesulphonate, 17-benzenesulphonate, 17-p-toluenesulphonate, and also 17P-chloro-2- androstene, 17P-bromo-2-androstene, 17P-iodo-2-androstene. :: If the etherif cation„reaction takes place with Walden inversion, the corresponding 17a-epimers are preferred. are those : in whi indicated above, thanol, 2-diethylaminoethanol, 2-di-n-propylaminoethanolt 2-diisopropylaminoethanol, 2-pyrrolidinoethanol, 2-piperidino- ethanol, 2-hexamethyleneirainoethanol, 2-morpholinoethanol, 2-pipera25inoethanol, 5-dimethylaminopropanol, 3-diethyl- aminopropanol , 3-di-n-propylaminopropanol, 3-diisopropyl- • aminopropanol , 3-pyrrolidinopropanol, 3-piperidinopropanol, j-hexamethyleneiminopropanol, 3-morpholinopropanol, 3-piperazinopropanol, l-methyl-2-dimethylaminoethanol, 1-methyl-2-diethylaminoethanol, l-methyl-2-morpholino- . ■> .... ethanol, -dimethylaminobutanol, -diethylaminobutanol, 2-methyl-3«-di-methylaminopropanol, and the corresponding chlorides, bromides, iodides, methanesulphonates, benzenesulphonates and p-toluenesulphonates. It is advantageous to carry out the etherifioation in the presenoe of a condensation agent. The condensation agent may be, for example, an alkali metal hydroxide, an alooholate former, such as an alkali metal (such as Na, K or Li in liquid ammonia), an alkali metal hydride (preferably NaH) , an alkali metal amide (preferably ITaNHg), or an organometallio compound, such as OH^Li, Other suitable condensation agents are halogen ion aooeptors, such as lead salts or silver compounds, for example AggO, AggCO^, AgOOCCHj, AgNC , AgOlO^ or AgBF^.
If one starts with two alcohols, a dehydrating agent is used, as the condensation agent, for example aluminium oxide, sulphuric aoid or one of its aoid salts, such as HSO^, borio aoid or organio sulphonic acids, such as p-toluenesulphonic acid. It is advantageous to oarry out the reaotion in the presenoe of a solvent. The solvent used may, for example, be a hydrocarbon, suoh as oyolohexane, benzene, toluene or xylene, or an ether, suoh as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxan, or aoetonitrile , aoetone, nitromethane , dimethylformamide, dimethylsulphoxide or liquid ammonia, or a mixture of two or more of these solvents. If the reaction is carried out under dehydrating conditions, it is advantageous to use solvents by means of which the water forming during the reaotion oan be removed by azeotropio distillation, for example benzene or toluene. The alooholate formation ma be oarried out in liquid ammonia; the liquid ammonia is ^ then removed, and the reaction is then oarried out in the presenoe of one of the above-mentioned higher-boiling solvents. Alternatively, an excess of the oompound III, for example an aminoalcohol, may be used as a solvent.
If a reaotive ester of Formula II (X «» Hal or functionally modified OH) is used for the etherification - reaction, Walden inversion generally takes place during the reaction at the ^^ atom that carries the reaotive group. To prepare the oompound of Formula I, it is therefore advantageous to use as starting material ; · 2-androsten-17 -ol, if the free steroid aloohol of Formula II (X = OH) is to be reacted with the amino alcohol III (Y a OH) or one of its reactive esters. If, on the · othe hand, a reactive ester of the Formula II (X " Hal or functionally modified OH) is used, it is advantageous to use the corresponding derivatives of 2-androsten-17o-ol.
In general, any of the methods described in the " literature, for example Houben-Weyl, Methoden der organ!sohen Chemie. Volume 3, pages 132-169» may be used ■ for the etherification.
The tertiary amino ethers of Formula I may also be prepared from the corresponding primary 'or secondary amines, by introducing the additional radical or radicals by alkylation. For example, a primary or secondary steroid amin of Formula IV may be reacted with an alkylating agent, '■. such as an alkyl halide.
The following are typical steroid amines of , Formula IV: l? -(2-aminoethoxy)-2-androstene , 17β-(2- methylaminoethoxy)-2-androstene , 173-(2-ethylaminoethoxy)- 2-androstene , 17 -(2-n-propylaminoethoxy)-2-androstene , i7 -(2-isopropylaminoethoxy)-2-androstene , 17 -(3-aminopro-poxy)-2-androstene , 1 β^l-methyl-2-aminoetho y)-2-·androB ene , 17 -(^-amino'butoxy)-2-andro8tene and 17 -(2-met yi-3-amino-propoxy)-2-androstene .
Suitable alkylating agents are, for example, methyl chloride, methyl bromide, methyl iodide, dimethyl sulphate , ethyl chloride, ethyl bromide, ethyl iodide, diethyl sulphate, "1 n-propyl chloride, n-propyl bromide, n-propyl iodide, Isopropyl chloride, isopropyl bromide, isopropyl iodide, 1. -dichlorobutane , 1,4-dibromobutane , 1, -diiodobutane , 1.5-diohloropentane, 1,5-dibromopentane , 1,5-diiodopentane ^ 1.6-diohlorohexane , 1,6-dibromohexane , 1,6-diiodohexane , bis-(2-ohloroethyl)-amine , bis-(2-bromoethyl)-amine , bis- (2-iodoethyl)-amine, bis-(2-chloroethyl)-ether , bis-(2-;bromoethyl)-ether and bis-(2-iodoethyl)-ether. The free alcohols may also be used as alkylating agents, for example methanol, ethanol, propanol, isopropanol, 1, -butanediol, 1,5-pentanediol, 1,6-hexanediol, diethanol'amine and diethylene glycol, and their reactive esters may also be used as alkylating agents, for example their methanesulphonates, benzenesulphonates or p-toluenesulphonates.
Conversely, to prepare the tertiary steroid amines of formula I, the corresponding secondary aliphatic amines of Formula VI may be used as starting materials and alkylated with a hydroxyalkoxy steroid of Formula V (Z » OH) or a reaotive derivative of the same.
Characteristic steroids of Formula V are ?β-(2-hydroxyethoxy)-2-androstene , 1 β-(3-hydroxypropoxy)-2-androstene, 17 -( -hydroxybutoxy)-2-androstene, 1 3-(l-methyl-2-hydroxyethoxy)-2-androstene and 173-(2-methyl-3-hydroxy-propdxy)-2-androstene, and the corresponding reaotive esters, ' .-"'·. e.g. 17 -(2-ohloroethoxy)-2-a dros ene, 17p-(2-bromoethoxy)- 2-androstene, 7β-(2-iodoethoxy)-2-androstene , 17β-(2-ρ- ■ toluenesulphonyloxyethoxy)-2-androstene.
Typical amines of Formula VI are dimethylamine , diethyiamine , di-n-propylamine , diisopropylamine , N-methyl- N-ethylamine , N-methyl-N-n-propylamine , N-methyl-N-isopropyl amine, N-ethyl-TT-n-propylamine , N-ethyl-N-isopropylamine, piperidine.
K-n-propyl-N-isopropylamine , pyrrolidine , hexamethyleneimine , - piperazine and morpholine.
. In these alkylations, a secondary amine is advantageously used in excess, and a primary amine advantageously in approximately the calculated proportion. ■ If alkylation is carried out with a halide, sulphate or sulphonic acid ester, the resulting acid may be intercepted '.: by using a strong base, such as NaOH or KOH, NagCO^ or KgCOj, a silver salt, an alkali metal hydride or an alkali ''·■'·.·' metal amide. Neutral salts and ammonium salts are also / suitable condensation agents, for example LiBr, NaBr, NaNOj, ■ or copper salts. If a bromide or chloride is used, the reaction can be accelerated by adding Nal or.KI. The following may, for example, be used as solvents: hydrocarbons,, such as benzene, toluene or petroleum ether; ketones, such as acetone; or aloohols, such as methanol, ethanol. or isopropanol. In certain oases a solvent may not be used, for example if an excess of an . amine of Formula. VI is being used. Suitable reaction temperatures are, for example, from -30° to +160°0.
If the free alcohols are used to alkylate the steroid amines of Formula IV, it may be advantageous to heat the steroid amine with an excess of the alcohol in the presence of Raney nickel.. Furthermore , the steroid, amines can' be . .• alkylated "by reacting them with an aldehyde, such as formaldehyde, preferably with 30-37% aqueous formaldehyde, in the presence of formic acid, advantageously at a temperature between room temperature and boiling temperature, a suitable temperature being about 100°0. At 100°0, reaotion '. times of from to 24 hours are necessary.
In general, any of the alkylating methods desoribed in the literature, for example, Houben-Weyl loo. cit· , pages 108-112 and 618-639» ∞ay he used for the preparation of the tertiary amines of Formula I. ;■;Λ■ ." : The novel compounds may also be prepared by using as starting materials, steroids that correspond to the Formula I, but contain at least one reducible group instead of hydrogen atoms. For example, the starting compounds may , . contain a carbonyl or thiocarbonyl group in the position adjacent to the oxygen atom or nitrogen atom in the side : chain. .
' These steroid esters or thioesters or.amides or ' thioamides can, for example, be reduced to the desired end products by treatment with a borane, preferably diborane.
The borane is as a rule produced in the reaction solution itself, for example by using as reduoing agent a mixture of B j, for example in the' form of the etherate, with LiAlH^ or NaBH^. But the borane may be introduced into the reaotion . solution, which advantageously contains additional B j.
The borane reduction is advantageously carried out in the . presenoe of a solvent, for example an ether, such as diethyl : . ether, diisopropyl ether, tetrahydrofuran, dioxan or die hyleneglycoldimethyl ether; suitable reaotion temperatures are, for example, from -30° to +150°C.
'■'■"■;.:·. '.':· '.-', Aoid amides that oontain a carbonyl. group in the position adjacent to the N atom, for example compounds of he type of amides of 2-androsten-17p-yloxyacetio aoid, X2- androsten-173-yloxy)-propionic acid or 4(2-andros†en-17P- yloxy)-butyric acid, such as 17P-dimethylaminocarbonylmethoxy- 2-androstene , or N-aoyl derivatives of 17 -(w-N-alkylamino- alkoxy)-2-androstenesj~" such as 17β-(2-N-formyl-N-ethylamino- ethoxy)-2-androstene, can also be reduced with complex metal hydrides, particularly LiAlH^, advantageously in the presence of an inert solvent, for example an ether, such as diethyl ether, tetrahydrofuran or dioxan, a glyool ether, such as ethyleneglyooldimethyl ether, or a mixture of two or more of these solvents. The reaction is suitably effected at a temperature of from -30°0 to the. boiling point of the solvent, preferably between 0 and 100°G.
A 2,3-episulphide, for example 2a, $a-epithio-173- (2-diethylaminoethoxy)-androstene, may be reduced to the corresponding 2-androstene of Formula I with LiAlH^, preferably in ether or tetrahydrofuran. A 2,3-episulphide may also be reduced with zinc and acetic acid. A thioenol ether of the' corresponding 3-ketone, such as 3-benzylmeroapto- 17 -(2-diethylaminoethoxy)-2-androstene, can be reduoed to the 2-androstene of Formula I by boiling for several hours ' ■ '·■ .■ ■ ■■ · , ) ' wit Raney nickel in acetone.
The steroids of Formula VII, which may also be used as starting material, may have a chlorine, bromine or iodine atom or a free or functionally modified hydroxy group in the 3-position. The hydroxy group may be present, for example, as an ester group or as a readily splittable ether group (aoetal-type ether group), such as a tetrahydropyranyl ether group. Among the esters, the sulphonic aoid esters of the corresponding 17-substituted androstan-3-ols, in whioh the sulphonio aoid radical preferably contains 1 to 10 carbon atoms, are preferred, for example the methanesulphonates, ethanesulphonates, benzenesulphonates and, particularly, p-toluene-sulphonates. But carboxylio acid esters, in which the carboxylio aoid radical preferably contains 1 to 18 carbon atoms, and particularly 1 to 7 carbon atoms, for example the formates, aoetates, propionates or benzoates, and also xanthates and carbonates, are also suitable for use in this reaotion.
The introduction of a double bond in the 2(3) position with the separation of HZ is suitably effeoted at a temperature of from 0° to 300°0, preferably between 20 and 200°0. Although the separation can be effeoted by simpl heating, for example in the case of the 3-xanthates, 3-oarbonates or 3-benzoates, it is advisable to add reagents that promote the separation. If the alcohols VII (Z = OH) are used as starting materials, the following are suitable for this purpose: dehydrating agents, such as acids, or Lewis aoids, such as sulphuric acid, polyphosphoric aoid, ^Ο^» oxalic acid, trifluoroacetic acid, p-toluenesulphonio acid, benzenesulphonio aoid, and also dimethyl sulphoxide, potassium hydrogen sulphate or iodine. If esters VII (Z o esterified OH) or halides VII (Z « Hal) are used as starting materials, it is advantageous to add a base for combination with the separated acid HZ, such as pyridine, collidine, lutidine, quinoline, Ν,Ν-dimethyl aniline, triethyl amine, NaOH or KOH. Neutrally reacting salts, suoh BS IiiCl or LiBr, are also suitable as catalysts for the separation* The reaction may be carried out in the presence or absenoe of an additional solvent; suitable solvents are, for example, hydrocarbons, such as benzene, toluene and xylene halogenated hydrocarbons, such as chloroform, oarbon tetrachloride, 1,2-diohloroethane and chlorobenzene ; •-'^ e lphoxides, such as dimethyl aulphoxide; and amides, such as dimethyl formamide. An excess of the eliminating agent, such as the base added, may also be used as a solvent.
A particularly preferred embodiment of this variant . of the process is the heating of the Jp-p-toluenesulphonates VII (Z » -ρ-σ^Η^Ο^Ο-) with excess collidine. This reaction takes about 1 to 12 hours for completion.
In addition, a base of Formula I may be converted with an acid into the corresponding acid addition salt. For , this reaction, aoids that yield physiologically acceptable. , salts should be used. The following organic and inorganio '■,·-.'-; acids are, for example, suitable; aliphatic, alioyolic, araliphatic, aromatic or heterocyclic monobasio or polybasio . carboxylic or sulphonic acids, such as formio acid, aoetio aoid, propionic acid, pivalic acid, diethylacetic acid, ·.. oxalic aoid, malonio acid, succinic aoid, pimelic acid, . fumaric acid, maleic acid, lactic acid, tartaric acid, malio acid, aminocarboxylic acids, sulphamio acid, benzoio ; acid, salicylic acid, phenylpropionic acid, citrio acid, gluconic acid, ascorbic acid, niootinic acid, isonicotinio ' acid, methanesulphonic acid, ethanesulphonic acid, β-hydroxy- e hanesulphonic acid, p-tolienesulphonio aoid, naphthalene- ' monosulphonio acids, naphthalenedisulphonic aoid¾ sulphurio acid, nitric aoid, hydrohallc acids, such as hydroohlorio aoid or hydrobromic acid, or phosphorio acids, such as orthophosphoric acid, Finally, a base of the Formula I can be liberated . from its acid addition salts by treating the latter, advantageously in an aqueous solution, with a strong base, suoh as NaOH or KOH.
The oompounds according to the invention are used in human or veterinary medicine in admixture with solid, liquid or semi-liquid excipients. The exoipient substances are organio or inorganic substances that are suitable for parenteral, enteral or topical application and do not reaot with the novel compounds, for example water, vegetable oils, polyethylene glycols, gelatine, laotose, starch, magnesium stearate, talcum, petroleum jelly or cholesterol. Particularly suitable for parenteral application are solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants. Suitable for enteral application are tablets, dragees, solutions, syrups and the like, and for topical application, ointments, creams or powder. The preparations mentioned may, if required, be sterilized or mixed wit adjuvants, such as preserving, stabilizing or wetting agents, salts to influence the osmotic pressure, buffer substanoes, colourin agents, flavourings and/or perfuming agents. ■ The novel compounds are preferably administered' orally in dosage units containing 2 to 300 mg.
In order that the invention may be more fully understood, the following examples are given by way of ^illustration only:-EXAMPLE 1. , 12.3 g of 2-androsten-17 -ol were dissolved in 90 ml of absolute dimethyl formamide and 120 ml of absolute toluene, and 72 ml of a 20% suspension of NaH in paraffin, oil (b.p, 360°0) were added with stirring. After 15 minutes, 13 ml of 2-diisopropylaminoethyl chloride in 30 ml of absolute toluene were added, and the mixture was stirred for 15 hours at room temperature. The mixture was then filtered, the residue was washed with benzene, and the filtrate and washing liquid ere evaporated. The residue was taken up in 500 ml of petroleum, ether (b.p. 0-60°0), and 100 ml of ether saturated with hydrogen chloride were added. The 173-(2~diisopropylaminoethoxy)-2-androstene hydrochloride that precipitated was filtered off "by suotion, washed with ether and, recrystallized from acetone, M.p. 191-194°C.
With: 2-dimethylaminoethyl chloride ■ 2-diethylaminoethy1 chloride 2-di-n-propylaminoethyl chloride 2-pyrrolidinoethyl chloride 2-piperidinoethyl chloride 2-hexamethyleneiminoethyl chloride 2-morpholinoethyl chloride /'.■'■' . ,r .-.· 2-piperazinoethyl chloride 3-dimethylaminopropyl chloride 3-diethylaminopropyl chloride 3-di-n-propylaminopropyl chloride · 3-di sopropylaminopropyl chloride 3-pyrrolidinopropyl chloride . - , : . 3-piperidinopropyl chloride 3-hexamethyleneiminopropyl chloride :. '..,' . · . 3-piperazinopropyl chloride 1-methyl-2-dimethylaminoethyl chloride . 1-methy] -2-diethylaminoethyl ohloride . ..' . ί-methyl-2-morpholinoethyl chloride -dimethylaminobutyl chloride , -diethylaminobutyl chloride . : 2-methyl-3-dimethylaminopropyl ohloride . or with the corresponding "bromides or iodides, the followir^; '-.. may be obtained similarly: 17 -(2-dimethylaminoethoxy)-2-androstene, hydrochloride, m.p. 3££*i5a x 219-221 °C. '··.·'' 1?β-(2-diethylaminoethoxy)-2-androstene, hydrochloride, m.p. 235-236°0. 17 -(2-di-n-propylaminoethoxy)-^2-androstene 17β-(2-pyrrolidinoethoxy)-2-androstene 17 -(2-piperidinoethoxy)-2-androstene , 17 -(2-hexamethyleneiminoethoxy)-2-androstene, hydrochloride, m.p. 200-202°0. ... 17β-(2-morpholinoethoxy)-2-androstene, hydrochloride, m.p. 228-230°C. 17 -(2-piperazinoethoxy)-2-androstene 17β-(3-dimethylaminopropo y) -2-androstene ·' "''·· . ' 17β- -diethylaminopropoxy)-2-androstene hydrochloride, m.p. 198-200°C. 17- -di-n-propylaminopropoxy)-2-androstene 17β-(3-diisopropylaminopropoxy)-2-androstene 17β-(3-ρyrrolidinopropoxy)-2-and ostenθ 17β-(3-piperidinopropo y) -2-androstene .17β-(3-he amethyleneiminopropoxy)-2-androstene . 17β-(3-pipe azinopropoxy) -2-androstene ■'·; .17P~(l-methyl-2-dimethylaminoethoxy)-2-androstene • 17β-Cl-methyl-2-diethylaminoethoxy)-2-androstene , 17β-(l-πlθ'thyl-2-morpholinoethoxy)-2-androstene 17β-(4·-dimethylaminobutoxy)-2-androstene . ^β-ζ^-diethylaminobutoxy)-2-androstene 17β-(2-methyl-3-dimethylaminopropoxy)-2-androstene ■■ : EXAMPIJB 2. . 2,74 g of 2-3ηάΓθ3ΐβη-17 -ο1 were dissolved i > • 100 ml of absolute xylene, and 1 ml of a 20% suspension of NaH in paraffin oil diluted with.50 ml of absolute xylene, were added. The whole was boiled for 90 minutes under ITg and then oooled to room temperature. 6 g of 2-bromoethyldiethyi ammonium bromide were then introduced in portions with stirring. The whole was boiled for 150 minutes, cooled and poured into 200 ml of ice water. 200 ml of chloroform were added to the mixture and the chloroform extract was separated. The extract was washed with water, dried, evaporated and taken up in 100 ml of petroleum ether; 20 ml of ethereal hydrochlorio acid were then added. 17P-(2-diethylaminoethoxy)-2-androstene hydrochloride was obtained. M.p. 235-236°C.
Oyclohexane, benzene ,toluene or dioxan may be used as a solvent instead of xylene; the boiling times should · then be extended according to the boiling point of the solvent. ·> - EXAMPLE * Small pieces of potassium were added to 30 ml of liquid ammonia, until the blue colour remained constant. A trace of iron (III) nitrate and another 500 mg of potassium were then added, and the whole was stirred for minutes at -70°C. 2.7 g of 2-andros en-17P-ol were then introduced, and the whole was stirred for another 30 minutes The ammonia was expelled by passing a current of nitrogen through the mixture, the residue was taken up in 15 ml of absolute dioxan, and a solution of 1.8 g of 2-diethylamino- ethyl bromide in 5 ml of absolute dioxan was added drop by drop at room temperature. The whole was boiled under nitrogen for 10 hours and then diluted with 30 ml of dioxan. The KBr was filtered off and the filtrate was evaporated until dry. The crude 1 roduct was dissolved in petroleum ether and ethereal hydrochloric acid was added. £ -(2-diethyl-aminoethoxy)-2-androstene hydrochloride was obtained. M.p. 235-236°C Instead of 2-diethylaminoethyl bromide, equivalent quantities of 2-diethylaminoethyl iodide may be used, or the methane-sulphonate, ethanesulphonate, benzene-sulphonate, p-toluenesulphonate or 2-naphthalenesulphonate of 2-diethylaminoethanol.
Example 4- A mixture of 2.7 S of 2-androsten-17^-ol , 1.2 g of 2-diethylaminoethanol, 2.66 g of p-toluenesulphonic acid monohydrate and 150 ml of absolute toluene was boiled for 3 hours on a water separator. The whole was left to cool, the solution was washed with NaHCO^ solution and water and dried with sodium sulphate; this was followed by evaporation. This yielded ^-(2-diethyl-aminoethoxy)-2-androstene; hydrochloride, m.p. 235-236° C.
The corresponding 2-androstene-17-ethers mentioned in Example 1 may be obtained similarly from 2-androsten-17/?-ol and the corresponding aminoalcohols.
Example 5 g of 2-dimethylaminoethanol were added drop by drop with stirring and the passage of nitrogen to a boiling solution of 2 g of 2-androsten-1¾C-ol-p-toluenesulphonate (obtainable by reduction of 2-andros-ten-17-one with NaBH^, chromatographic separation of the epimers and. esterification with p-toluenesulphochloride /pyridine) in 100 ml of benzene. The whole was then boiled for- 1^· hours. After cooling, it was diluted with ether and washed with water. The residue of the ahdrostene; hydrochloride, "m.p. ±$5*-½δχδχ 219-221 °C.
The corresponding 2-androstene-17-ethers mentioned in Example 1 may be obtained similarly with the corresponding aminoalcohols.
Example 6 1.2 g of sodium hydride was added to a mixture of 6 g of 2-diethylaminoethanol and 200 ml of dry xylene, and the suspension was heated under nitrogen for 1 hou until boiling. A solution of 2 g of IT^-bromo-2-androstene (obtainable from 2-androsten-17 -ol-P-toluenesulphonate with Br in tetrahydrofuran) in 50 ml of dry xylene was added drop by drop to the boiling mixture with stirring, and the whole was boiled for a further 7 hours. After cooling, some methanol was added cautiously, the whole was then diluted with ether, and . water was added. (Che usual working-up yielded 17£-(2-diethyiaminoethoxy)-2-androstene ; hydrochloride, m.p. .. 235-236°0.
Example 7 .. To a mixture of 5 g of 90% formic acid and 3.8 g of 35% aqueous formaldehyde solution there were added, . with cooling, 6.3 S of 170-(2-aminoethoxy)-2-androstene (obtainable from 2-androsten-17£-ol by reacting 2-chloroethanol in the presence of NaH to form 17^- (2-hydroxyethoxy)-2-androstene, reacting with SOClg/pyridine to form 17>-(2-chloroethoxy)-2-androstene and heating the same with ethanolic KH^ to 160°C in an autoclave).
Evolution of carbon dioxide began on slow heating. The whole was then heated on a steam bath for 12 hours.
Formic acid and formaldehyde were removed by distillation after the addition of 2 ml of hydrochloric acid.
Crystallization from acietone gave ?β-( 2^ime tb lamino- ethoxy)-2-androstene hydrochloride , m. p . ¾3¾2x3§£xfix 219-221 °c , 7P-(5-dimetlr/laminopropoxy)-2-androstene may be obtained similarly from 17#-(3-aminopropo.xy)-2-androstene (obtainable by cyanoethylation of 2-androsten-17/?-ol , 1 - ;; · '·:· ' followed by reduction) , and , 2-androstene from 17 ?^(4— mi r)obutoxy)-2-androstene (obtainable by reacting the Na derivative of 2-androsten- 17,0-ol with 4— bromobutyric acid nitrile and then reducing) . ' ,f. . .;· ' : Examp e 8 0.3 g" f 17^-(2-ethylaminoethoxy)-2-androstene : \ ■ ■: ■. .;■■<■ (obtainable by reaction of the Na compound of 2-androsten yf?-17 -ol with, bromoacet aldehyde diethyl acetal , hydrolysis with dilute hydrochloric acid to form 1^-formylmethoxy- 2-androstene , reaction w ith, ethyl amine to form the Schiff ' s base and reduction with. NaBH^) was heated for 18 hours on a steam bath with. 0.35 g of 90% formic acid and 0-3 S of 35% formaldehyde . The reaction mixture was diluted with wate brought to pH 3 with, hydrochloric acid and agitated with . ether. Caustic soda solution was then added to the aqueous phase until the reaction was alkaline , and this was followed by extraction with ether.
After drying and evaporation, 17/£-(2-N-methyl-N-ethyl- . aminoethoxy)-2-andr0stene was obtained. To prepare the hydrochlo ide , 0.1 g of the free base was dissolved in a little methanol and excess ethereal hydrochloric acid was added to the solution.
Example 9 0.4· g of crude 17^-(2-ethylaminoethoxy)-2-androstene were boiled for 5 hours in 8 mi of ethanol with 0.12 g of ethyl bromide. After evaporation, the residue was chromatographed on basic aluminium oxide and eluted with benzene/chloroform to give 17^-(2-diethylamino-ethoxy)- 2-androstene; hydrochloride, m.p. 235-·236°0β · The corresponding amino ethers of 2-androsten-173- ol may be obtained similarly from 17fi>-(2-aminoethoxy)- 2-androstene or 17ff-(3-aminopropoxy)-2-androstene by reaction with the calculated quantities of methyl iodide, diethylsulphate, N-propyl bromide, isopropyl iodide, 1 , -dibromobutane , 1 ,5-dibromopentane, 1 ,6—dibromohexane or bis-(2-bromoethyl)-ether.
; Example 10 A solution of 3 S of 17?-(2-chloroethoxy)-2- . . androstene (obtainable by reaction of the Na compound of 2-androsten-17/=<-ol with 1-bromo-2-chloroethane) in 150 ml of ethanol was heated to 100°C for 16 hours in a bomb tube with a fivefold excess of diethylamine.
After evaporation, water was added to the residue, and the mixture was extracted with ether. The extract was washed with water and dried over sodium sulphate, the ether was evaporated, and the remainder was chromatographed over silica gel. 17>?-(2-diethylaminoethoxy)- 2-androstene was eluted with chloroform; hydrochloride, m.p. 235-236°C.
The corresponding ethers of 2-androsten-17i?-ol may '■· be obtained similarly from 17/i-(2-bromoethox^-2-androstene or 17^-C3-bromopropoxy)-2-androstene or from the corresponding chloro, iodo or p-toluenesulphonyloxy compounds by. reaction with dimethylamine , diethylamine, di-n-propyl amine, diisopropyl amine, pyrrolidine, piperidine, hexamethylene irnine, morpholine or piper- ' Example 11 g of 17/9-(2-chlo:roethoxy)-2-androstene were , dissolved in 50 ml of dioxan 10 ml of diethylamine were added, and the mixture was heated to 100°C in a tube for 5 hours. The whole was then left to cool , diluted with 500 ml of water and worked up as in Example 10. This yielded 17^-(2-diethylaminoethoxy)-2-androstene hydrochloride , sup. 235-236°C.
Example 12 3 g of 17^-pyrrolidinocarbonylmethoxy-2-androstene (obtainable from 2-androsten-17 ?-ol and chloroacetic acid pyrrolidide in the presence of NaH) in 4- ml of absolute ether were added drop by drop at 0°C to a suspension of 700 mg of LiAlH^ in 30 ml of absolute ethers The whole was boiled for 3 hours and decomposed with 10 ml of water while being cooled with ice. The mixture was added to 60 ml of solution, and this was followed by extraction with ether. After evaporation of the ether, 17 ~(2-pyrrolidinoethoxy)-2-androstene was obtained. .
Example 13 2 g of 17/e-diethylaminocarbonylmethoxy-2-androstene (obtainable from 2-androsten-17 ?-ol and chloroacetic acid diethyl amide) were dissolved in 70 ml of absolute dioxan and added to a suspension of 1 g of LiAlH^ in . 35 ml of absolute dioxan. After boiling for 18 hours, the excess LiAlH^ was destroyed with aqudous dioxan, the mixture was boiled with 0.8 ml of 20% caustic soda solution, and a little water was added. The precipitated salts were removed . by filtration, the filtrate was washed with dioxan, crude 17^-(2-diethylaminoethoxy)- dissolved in methanol, ' and precipitated in the form ■> of the hydrochloride with ethereal hydrochloric acid; sup. 235-236°C. The free base was obtained by adding UT-caustic soda solution until a strongly alkaline reaction was obtained, and then precipitating with water. '".'·'■ The corresponding amino ethers of 2-androsten-17 -ol may also be obtained with LiAlH^ from: 17^-dimethylaminocarbonylmetho3QT-2-androstene l7^-di-n-propylaminoca^bonylmethoxy-2-androstene 17 -diisopropylaminocarbonylmethoxy-2-and:rostene 17p-pyrrolidinocarbonylmethoxy-2-androstene - 17£-piperidinocarbonylmethoxy-2-androstene 17β-hexamethyleneiminocarbonylmethoxy-2-androstene 170-morpholinocarbonylmethoxy-2-androstene .. 17?-piperazinocarbonylmethoxy-2-androstene Ί7/9-(2-dimethylaminocarbonylethoxy)-2-androstene 1 β-( -diethylaminocarbonylethoxy)-2-androstene Λ70-(2-di-n-propylaminocarbonylethoxy)-2-androstene 7β-(2-diisopropylaminocarbonylethoxy)-2-androstene 1 /9-(2-pyrro1idinocarbonylethoxy)-2-androstene 17S-(2-piperidinocarbonylethoxy)-2-androstene 17/?-(2-hexamethyleneiminocarbonylethoxy)-2-androstene 7^-(2-morpholinocarbonylethoxy)-2-androstene 7β-(2-piperazinocarbonylethox )-2-androstene· Example 14 ...
A solution of 10 ml of boron trifluoride etherate and 500 mg of 17^-(2-N-acetyl-K^ethylaminoethoxy)-2-androstene (obtainable by acetylation of (2-ethylami,noethoxy)-2-androstene) in 25 ml of tetrahydrofuran was added over a period of 50 minutes, under nitrogen, to an ice-cooled suspension of 400 mg of LiAlH^ in 25 nl of tetrahydro cooled with ice and then toiled for 1 hour. After cooling, ethyl acetate and 50 ml of 2N hydrochloric acid were added; the whole was then stirred thoroughly, made alkaline with NaHCO, and extracted with chloroform. (The chloroform extract was evaporated and the residue dissolved in petroleum ether. Ethereal hydrochloric acid was added, and this yielded 17 ?-(2-diethylaminoethoxy)-2-androstene hydrochloride , m.p. 235-236°C.
Example 15 2 g of morpholinoacetic acid-(2-androsten-1¾3-yl)-ester (obtainable from morpholinoacetic acid and 2-androsten-17/8-ol in the presence of dicyclohexylcarbo-diimide) were dissolved in 100 ml of tetrahydrofuran containing 21 g of boron trifluoride etherate, and the solution was added drop by drop in 30 minutes with stirring at 0°0 under Mg to a mixture of 0.37 S oi aBH^ in 25 ml of diethylene glycol dimethyl ether, The whole was left to stand for 3 hours while coolin , and then boiled for 1 hour. After cooling, some methanol was added, the whole was acidified with dilute hydrochloric acid, and then diluted with water. After extraction wit ether, washing to neutrality and drying, the residue was chromatographed on aluminium oxide. Elution with petroleum ether gave 17/6'^2-morpholinoethox3^-2-androstene. Hydrochloride, m.p. 228-230°0.
The corresponding 7-ethers of 2-androsten-17 -ol may be obtained similarly from: , dimethylaminoace ic acid-(2-androsten-17^-yl)-ester diethylaminoacetic acid-(2-androsten-17B-yl)-este di-n-propylaminoacetic acid-(2-androsten-17/3-yl)- . ester diisopropylaininoacetic acid-(2-androsten-17 -yi)- ester . - - ester '' ' ■ ·· ' f * piperazinoacetic acid-(2-androsten-170-yl)-este 3-(dinethylamino)-propionio acid-(2-androsten-17/S - yl) -ester 3-(diethylamino)-propionic acid-(2-androsten-17£- yl ) -ester 3- (di-n-propylamino) -propionic acid-(2-androsten- ■ 17]5-yl)-ester 3-(diisopropylamino)-propionio acid-(2-androsten— 17 -yl)- ester 1 3- (pyrrolidino) -propionic acid-(2-ardrosten-17J -yl) -ester 3- (piperidino ) -propionic acid-(2-androsten-17&-yl)- e3tor ' 3-(hexai ethyloneiiiiino )-propi
Claims (1)
1. 27. A prpoess for the preparation of a oompound the formula specified in claim 1, which comprises condensing a oompound of the formula: in which n has the meaning specified in claim 1 and Z is , an OH group, a functionally modified OH group or Hal, , where Hal is CI, Br or I, with an amine of the formula, . HNR R (VI), in which R and R have the meanings specified in claim 1. ,28. A process for the preparation of a compound of Formula I, specified in claim 1, which comprises reducin . a oompound that corresponds in other respects to Formula I "but has at least one reducible group instead of hydroge atoms, by treatment with a reduoing agent. 29. A prooess for the preparation of a compound of the formula spe g a oompound in which n, R and R have the meanings speoified in claim 1 and Z is an OH group, an esterified OH group or Hal, where Hal is CI, Br or I, with a compound oapable of splitting off HZ. 30. A process aocording to any of claims 25 to 29, in which the base of Formula I obtained is converted by treatment with an aoid into a physiologically aooeptable aoid addition salt thereof or the acid addition salt of a oompound of Formula I obtained is treated with a base to liberate the free base. 31. prooess for the preparation of a compound of Formula I or an acid addition salt thereof substantially as herein desoribed in any of the Examples. COHEN ZEDEK & SPISBACH P. 0. Box 1169,. Tel-Aviv Attorneys , f o r A p p | i c a n t
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DE19691918699 DE1918699A1 (en) | 1969-04-12 | 1969-04-12 | 2-Androstene-17-ether and process for their preparation |
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IL34217A true IL34217A (en) | 1973-03-30 |
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IL34217A IL34217A (en) | 1969-04-12 | 1970-03-31 | 17-aminoalkoxy-androst-2-enes |
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AT (2) | AT302546B (en) |
BE (1) | BE748720A (en) |
BR (1) | BR6915479D0 (en) |
CH (1) | CH533607A (en) |
CS (1) | CS149424B2 (en) |
DE (1) | DE1918699A1 (en) |
DK (1) | DK129989B (en) |
ES (1) | ES378469A1 (en) |
FR (1) | FR2042324B1 (en) |
GB (1) | GB1264941A (en) |
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1969
- 1969-04-12 DE DE19691918699 patent/DE1918699A1/en active Pending
- 1969-12-19 BR BR215479/69A patent/BR6915479D0/en unknown
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1970
- 1970-03-19 GB GB1264941D patent/GB1264941A/en not_active Expired
- 1970-03-31 CS CS368A patent/CS149424B2/cs unknown
- 1970-03-31 IL IL34217A patent/IL34217A/en unknown
- 1970-04-01 NL NL7004608A patent/NL7004608A/xx unknown
- 1970-04-03 DK DK169170AA patent/DK129989B/en unknown
- 1970-04-06 CH CH503170A patent/CH533607A/en not_active IP Right Cessation
- 1970-04-08 AT AT1107570A patent/AT302546B/en not_active IP Right Cessation
- 1970-04-08 SE SE04771/70A patent/SE349299B/xx unknown
- 1970-04-08 AT AT321970A patent/AT296515B/en not_active IP Right Cessation
- 1970-04-09 BE BE748720D patent/BE748720A/en unknown
- 1970-04-10 FR FR707012963A patent/FR2042324B1/fr not_active Expired
- 1970-04-11 ES ES378469A patent/ES378469A1/en not_active Expired
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SE349299B (en) | 1972-09-25 |
FR2042324B1 (en) | 1973-08-10 |
NL7004608A (en) | 1970-10-14 |
BE748720A (en) | 1970-10-09 |
ES378469A1 (en) | 1972-06-16 |
CS149424B2 (en) | 1973-07-05 |
FR2042324A1 (en) | 1971-02-12 |
DE1918699A1 (en) | 1970-10-15 |
JPS4843903B1 (en) | 1973-12-21 |
GB1264941A (en) | 1972-02-23 |
AT296515B (en) | 1972-02-25 |
CH533607A (en) | 1973-02-15 |
AT302546B (en) | 1972-10-25 |
DK129989C (en) | 1975-05-20 |
DK129989B (en) | 1974-12-09 |
BR6915479D0 (en) | 1973-01-25 |
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