DE2212197A1 - In 3 position etherified or acylated 3 hydroxyazasteroids and means for fighting insect larvae and nymphs - Google Patents

Description

DR ₁ JiIR ₁ DI- ¹ UCHEM-WALTERBEIE

DR. JL:?. [; 1 ^, ~., Ϊ́: · Λ. Π.-i. WOLFF

DR. JUK. lu \ ', i $ J »·! Λ EXAMPLE ¹ '

March 13, 1972

FRANKFURT AM MAIN-HÖCHST

ADEIONSJ-KASS £ 58

Our no. 17 722

G.D. Searle & Co. Skokie, 111., V.St.A.

3-hydroxyazasteroids etherified or acylated in the 3-position and agents for combating insect larvae and nymphs .

The present invention relates to new compounds, new agents and new methods of combating Insects in their early stages of development under Use of hypocholesterolemic azasteroids etherified in the 3-position and 3-acyloxyazasteroids. As used herein and throughout the specification, the term "azasteroid" refers to a Steroid with a nitrogenous cholesterol or a cholesterol-like side chain on the carbon atom 17 of the steroid nucleus.

Various biological and chemical methods have been used to control undesirable insects. Some of these procedures are on the port reproductive control as well as on the chemical Targeted combat. In the fight against port plantability, organic compounds are

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applies to different degrees of in the insects Achieve sterilization. When used for such purposes, they are called chemosterilants. Strong chemical control consists in the use of various chemicals, such as Gastric poisons, contact poisons, systemic poisons, incense, repulsive or attractive agents. A A recent proposal to control insects provides for the use of chemicals that selectively reduce the Affect development in the early stages of development.

Certain nonsteroidal and 3-hydroxysteroid hypocholesterolemic agents are said to inhibit the growth of insect larvae that convert phytosterols to cholesterol, triparanol and 22,25-diazacholesterol inhibit the growth of larvae of Protoparce sexta C Man due a sexta (Johannson)] Svoboda and Robbins, Science , Vol. I56, p. 1637 (1967). 25-Azacholesterol and 20,25-Diazacholesterol inhibit the growth of capsule beetle larvae ( Anthonomus grandis , Boheman), Earle et al. J. Econ. Entomol., Vol. 60, p. 291 (1967).

Surprisingly, it has now been found that hypocholesterolemic, etherified in 3-position and in 3-position Acylated 3-hydroxyazasteroids are potent growth inhibitors of larvae and nymphs of insects that are dietary Convert phytosterols into cholesterol, or use dietary cholesterol in their metabolism. this is surprising, because despite the fact that the activity of 3-hydroxyazasteroids as hypocholesterolemic Agent seems to run parallel with its activity as larval and nymph control agent, one

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Considerable increase in the effect as a larval and nymph control agent in hypocholesterolemic in 3-position etherified and 3-hydroxyazasteroids acylated in position 3 compared to the underlying alcohols. This potency increase is surprising in that apparently no decrease or change in hypocholesterolemic Activity occurs after etherification or esterification of a 3-hydroxyazasteroid.

The present invention therefore relates to a method for inhibiting the growth of insect larvae and nymphs, that convert dietary phytosterols into cholesterol, or use dietary cholesterol in their metabolism. The method consists in administering an effective amount of a 3-position hypocholesterolemic etherified or 3-hydroxyazasteroids acylated in the 3-position to the aforementioned larvae or nymphs.

The term "hypocholesterolemic" as used herein 3-hydroxyazasteroid etherified in the 3-position or in the 3-position acylated 3-hydroxyazasteroid "refers to a Connection to the following framework;

(D

as hypoeholesterolamisch.es means, in particular in a standard hypocholesterolemic experiment

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-u-

sam, which includes the treatment of male rats, made hypocholesterolemic and hypothyroid by propylthiouracil.

In the above formula, the broken line shows the possible presence of a Δ 'unsaturated bond on, the wavy line in the 3-position indicates the possible α and ß configuration, R means a hydrocarbon residue having 1 to 19 carbon atoms or an acyl radical of a hydrocarbon carboxylic acid with 1 to 18 carbon atoms and X denotes a saturated radical with 1 or 2 nitrogen atoms and at least Jj carbon atoms.

Except for the substituents shown on the structure of the formula (I) various groups can be substituted in the 1-, 2-, 6- and 11-position without thereby affecting the hypocholesterolemic potency of the compound in question is impaired. For example, the 1 position by a hydroxy or an acyloxy group, the 2-position by a lower alkyl group, the 6-position by a lower alkyl group and the 11-position can be substituted by a hydroxy or acyloxy group be.

The hydrocarbon radicals with 1 to 19 carbon atoms denoted by R include alkyl radicals with 1 up to 12 carbon atoms, for example methyl, ethyl. Propyl. Butyl, pentyl, hexyl, heptyl, octyl, Nonyl, decyl, undecyl and dodecyl radicals and their branched chain Isomers, cycloalkyl radicals with 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl and cycloheptyl radical,

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also (cycloalkyl) -alkyl radicals with 4 to 19 carbon atoms, where the terms "cycloalkyl" and "alkyl" have the meanings given above.

To the hydrocarbon carboxylic acids with 1 to 18 carbon atoms, from which the acyl radicals denoted by R can be derived include saturated and unsaturated aliphatic hydrocarbon carboxylic acids with the specified number of carbon atoms. Examples for such acids are alkanecarboxylic acids, for example acetic acid, propionic acid, butyric acid, isobutyric acid, tert-butylacetic acid, valeric acid, isovaleric acid, caproic acid, capryic acid, capric acid, lauric acid, Myristic acid, palmitic acid, stearic acid; Alkenarboxylic acids, for example acrylic acid, crotonic acid and oleic acid, alkynecarboxylic acids, for example Hexynoic acid and octynoic acid, cycloalkanecarboxylic acids and Cycloalkene carboxylic acids, for example cyclopropanearboxylic acid, Cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, Cyclopentenecarboxylic acid, cyclohexanecarboxylic acid and wench ethylcyclohexanecarboxylic acid, also (cycloalkyl) alkanecarboxylic acids, for example Cyelopentylalkanarbonsäuren, such as Cyclopentylessig-, Cyclopentylpropion-, CyclopentyIbutter- and cyclopentylvaleric acid, cyclohexylalkanecarboxylic acids and cycloheptylalkanecarboxylic acids. If R means a (cycloalkyl) alkanoyl radical, i.e. if the Acyl radical is derived from a (cycloalkyl) alkanecarboxylic acid, then the remainder contains 5 to 18 carbon atoms. The cycloalkyl part of the (cycloalkyl) alkanoyl radical contains 3 to 7 carbon atoms while the alkanoyl part contains 2 to Contains 11 carbon atoms.

For the purposes of the present invention, the free 209839/1243

Bases of the compound of the formula I are equivalent to their acid addition salts. Such salts are derived from pharmacological Usable acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, lactic acid, Benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, Salicylic acid, acetic acid, propionic acid, maleic acid, malic acid, tartaric acid, citric acid, cyclohexylsulfamic acid, Succinic acid, nicotinic acid, ascorbic acid and the like.

A particularly valuable group of compounds that falls within the scope of formula I can be obtained by the general Structural formula are represented:

R ₃ -N-AIk-N-

(ID

in which the wavy line, the broken line and R have the meaning given above, R ₁ and R_ mean lower alkyl radicals with 1 to 8 carbon atoms, R stands for hydrogen or a lower alkyl radical with 1 to 8 carbon atoms and Alk represents a lower alkyl radical with 2 to 8 carbon atoms and separates the groups -NR ₁ R ₂ and R ₅ N- by at least 2 carbon atoms. Lower alkyl radicals under

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the above formula fall, are the ethylene, trimethylene, Tetramethylene and pentamethylene radicals and their branched-chain isomers. The connections of the Formula (II) above, in which R is a lower alkanoyl radical, are described in the USA patent 3 O8 <4 156 write. Examples of those in this Compounds described in the patent are 17ß- [N-methyl-N- (3 ~ dimethylaminopropyl) -amino] -androst-5-en-3ß-ol-3-acetate, 17β- [N- (3-dimethylaminopropyl) -amino] -5a-androstan-3β-ol-3 ~ acetate and the corresponding dihydrochloride and 17β-CN- (3-dimethylaminopropyl) -amino] -5α-androstane-3β-ol-3-propionate.

A particularly preferred group of compounds falling under formula (II) are compounds in which R _{1 is} a methyl radical and Alk is a trimethylene radical, in particular when R 1 and R «are methyl radicals and especially when R is a cycloalkyl radical or when R is the radical means a cycloalkylalkanecarboxylic acid. Preferred compounds are 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino3-androst-5-en-3β-ol-3- (3-cyclopentylpropionate), the corresponding hydrochloride and 17β- [N-Met hy IN - (3 ~ dimethylaminopropyl) -amino] -androst-5-en-3 "ßol-3-cyclopentylether.

Another preferred group of compounds of the formula (II) are compounds in which Alk is an ethylene _{radical or a trimethylene radical, R 1} , Rp and R are methyl radicals and R is a lower alkyl radical. Preferred compounds of this group are 17β- [N-methyl-N- (3 "dimethylaminopropyl) -amino3-androst-5-en-3β-ol-3-methyl ether and 17β- [N-methyl-N- (2-dimethylaminoethyl) -amino] -androst-5-en-3ß-ol-3-methyl ether,

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especially in the form of their dihydrochloride monohydrate salts.

Another preferred group of compounds of formula (I) for use in the present invention is represented by the general formula below:

RO

(III)

in which the wavy line and the broken line and R have the meaning given for formula (I), R ₁ and R _{2 have} the meaning given for formula II, Alk is a lower alkylene radical with 2 to 8 carbon atoms and the -NR ^ Rp- and separating CH, CH functions by at least 2 carbon atoms. Compounds of this formula or starting materials for them are described in the literature, for example in U.S. Patents 3,257,384, 3,144,471 and 3,326,758 and in J. Med. Chem., Vol. 8, p. 45 (1965) . The representative compounds of the formula III include 3ß-acetoxy-24-dimethylamino-5-cholen and other 3ß-acyloxy-24-dialkylamino-5-cholenes, for example the 3ß-acetates, 3ß-propionates, 3ß-isobutyrates, 3ß-

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Caprylates and 3ß-octanoates of 24-diethylamino, 24-diisopropylamino, 24-dibutylamino-, 24-diisobutylamino- and 24-dioctylamino-3β-hydroxy-4-cholene.

A particularly preferred group of compounds within the framework of the formula (III) consists of compounds in which R ₁ and Rp represent methyl radicals and R represents a cycloalkyl or (cycloalkyl) alkanoyl radical. Preferred compounds include 24-dimethylaminochol-5-en-3β-ol-3- (3-cyclopentylpropionate) and 24-dimethylaminochol-5-en-3β-ol-3-cyclopentyl ether.

Another preferred group of compounds within the framework of the formula (III) consists of compounds in which R ₁ and R "represent methyl radicals and Alk represent an ethylene radical. A particularly preferred compound of this type is 23-dimethylamino-24-norchol-5-en-3β-ol-3-methyl ether.

Another preferred group of compounds which are represented by formula (I) and which are suitable for use according to the present invention, consists of compounds of the general formula:

R -.- CH-AIk-NH-CH ^. CH-I Η-

(IV)

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in which the wavy line and the broken line as well as R have the same meaning as given above for compounds of the formula (I), R, R ₂ and R have the meanings given for the compounds of the formula (II) and Alk has a lower one Is an alkylene radical with 2 to 8 carbon atoms and separates the adjacent 20-carbon atom and the nitrogen atom by at least 2 carbon atoms. A particularly preferred group of compounds represented by this structural formula consists of compounds in which Alk is an ethylene radical. A number of parent alcohols, 3-alkyl ethers of 1 to 4 carbon atoms and 3-acyl esters of 1 to carbon atoms of these compounds are described in J. Med. Chem., Vol. 8, p. 45 (1965) and in the United States patent 3,326,758.

Also within the scope of the formula (I) is another preferred group of compounds which can be used according to the invention; this group is represented by the general formula

RO

R ₃ -CH-CH ₂ -NH-CH ₂ CH J

Ch

CH ₃

(V)

in which the wavy line and the broken line and R are indicated for the compounds of formula (I)

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have given meaning and R, for the compounds of the formula (II) has the meaning given. The parent alcohol in which R, denotes a methyl radical is in J. Med. Chem. Vol. 8, p. 45 (1965).

The new compounds of the invention have the general formula

(VI)

in which R ₁ , Rp, R, as well as the broken line and the wavy line have the meaning given above, Alk means a lower alkylene radical having 2 to 8 carbon atoms and the -NR ^ R «- and the R, A group by at least two Separates carbon atoms, A represents -CH- or a nitrogen atom and R ^ represents a cycloalkyl, (cycloalkyl) -alkyl- or (cycloalkyl) -alkanoyl radical, provided that when R represents a methyl radical, A represents -CH-, Alk denotes a trimethylene radical and the 5 (6) bond is saturated, R ₁ J denotes a cycloalkyl or (cycloalkyl) alkyl radical.

The preferred new compounds of the invention have the general structural formula

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(VII)

in the

R ,, Alk as well as the broken line

¹ I ' ⁿ 2 ^;

and wavy line have the meanings given for formula (VI), A -CH- or a nitrogen atom and Rjein Is cycloalkyl, (cycloalkyl) alkyl or (cycloalkyl) alkanoyl, provided that when A is -CH- and the 5 (6) bond is saturated, R is a cycloalkyl or (cycloalkyl) alkyl radical.

In addition to their hypocholesterolemic action, which is directed against larvae and nymphs, the new compounds of the formula (VI) also have other valuable biological properties. For example, these compounds have an antibiotic effect which has been demonstrated, for example, by their ability to inhibit the growth of bacteria, protozoa such as Tetrahymena pyriformis and Trichomonas vaginalis , fungi such as Trichophyton mentagrophytes , and algae such as Chlorella vulgaris.

Suitable starting materials for the preparation of the compounds of the formula (I) are the 3a- and 3ß-isomers the general structural formula:

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(VIII)

in the X and the dashed line and the wavy line have the meanings given above. The connections of the formula (VIII) given above, in which X

Rv-A-AIk-N

where A, R ₁ , Alk, R 1 and R _{2 have} the meanings given for formula (VI), are suitable starting materials for use in the preparation of the new compounds of the formula (VI).

The 3-acylates of the 3-hydroxy compounds of the formula (VIII) can be obtained by mixing the desired 3-hydroxy compound with the corresponding acid halide or acid anhydride in the presence of a tertiary amine such as pyridine. Will the connections of formula (I), in which R is a (cycloalkyl) alkanoyl radical means, if desired, the preferred acylating agent is a (cycloalkyl) alkanoyl chloride. Acylating agents of this type can be prepared by conventional methods, for example by Reacting the corresponding (cycloalkyl) alkanecarboxylic acid with thionyl chloride.

The 3-ethers of the 3-hydroxy compounds of the formula (VIII)

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22121b /

can be obtained by a number of alternative methods. In one of these procedures, a Alcohol of formula (VIII) reacted with the dimethyl or diethyl ketal of the corresponding ketone. These Ketal starting materials can conveniently thereby be prepared by mixing the selected ketone, e.g., cyclopentanone, with trimethyl or triethyl formate implements. After reacting the steroid alcohol with the ketal, the corresponding 3-alkenyloxy-, cycloalkenyloxy- or (cycloalkyl) alkenyloxysteroid in which the double bond in the 3-substituent is between the an the oxygen atom is bonded carbon atom and the next adjacent carbon atom. After subsequent Hydrogenation, which is expediently carried out using molecular hydrogen in the presence of an appropriate Hydrogenation catalyst can be carried out until the uptake of one mole of hydrogen is complete the desired 3-ethers of the formula (I) are obtained.

In an alternative process for the production of the 3-ether of formula (I) is an alcohol of formula (VIII) with the corresponding alcohol of formula ROH, where R is the for formula (I) has given meaning, in the presence of a small amount of an acid, for example ε-toluenesulfonic acid, in an inert solvent such as toluene or the like.

In another alternative process for the production of 3 ~ ethers, a steroid alcohol is first used Formula (VIII) with an aryl or alkyl sulfonyl halide or with an aryl or alkyl sulfonic anhydride implemented. Are especially valuable for this purpose

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p_-Tolylsulfonyl chloride and methylsulfonyl chloride. That 3-arylsulfonyl or 3-alkylsulfonyl steroid obtained in this way is then with an alcohol of the formula ROH, where R has the meaning given above, in Reacted in the presence of a suitable acid acceptor, so that the desired 3 ~ ethers are obtained.

An alternative method for preparing compounds of formula (I) is that one has a 3a- or 3ß-isomer of 3-hydroxyandrost-5-en-17-one or 3-hydroxyandrost-17-one to form a compound of the formula

(IX)

in the R as well as the wavy line and dashed line have the meaning given above, esterified or etherified. The esterification and etherification can be carried out according to the processes for preparation described above of 3-acylates and 3-ethers de_r 3 ~ hydroxy compounds of Formula (VIII) are carried out. Typical of the esterification process is the reaction of 3ß-Hydroxyandrost -5-en-17-one with 3-Cyclopentylpropionylchlorid in pyridine, to obtain 3ß- (3-cyclopentyl-propionyloxy) -androst-5-en-17-one. An example of a suitable etherification process is the implementation of 3ß-Hydroxyandrost-5-en-17-one with Cyclopentanondiethylketal to achieve of 3ß- (l-cyclopentyloxy) -androst-5-en-17-one, which is then formed with the formation of 3ß-cyclopentyloxyandrost-

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5-en-17-one with hydrogen gas in the presence of a catalyst is converted from palladium-on-aluminum oxide.

After the compounds of the formula (IX) have been prepared, the 17-side chain is formed by processes which correspond to the processes previously used in the production of the 3 ~ hydroxysteroids according to the previous one Technique have been used to obtain the desired compounds of formula (I). A preferred one Process of this type which is useful for the preparation of the compounds of formula (II), i.e. the compounds where the 17-substituent has the general formula

R_-N-Alk-N

³ I.

where R

R, and Alk are those given for formula (II)

What is important is that you have a 17-ketone of the formula (IX) with the corresponding dialkylaminoalkylamine in the presence of an acidic catalyst Formation of the corresponding imines condenses. The imines of the general structural formS.

-AIk-I

(X)

where R

u as well as the wavy line and the

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chelte line the meaning given for formula (VI) are new intermediates that are used in the preparation of the new compounds of formula (VI) in the A means a nitrogen atom are valuable. Examples of imine formation are the reactions of 3-Dimethylaminopropylamine with 3ß- (3-Cyclopethylpropionyloxy) -androst-5-en-17-one and with 3ß-cyclopentyloxyandrost-5-en-17-one in the presence of p-toluenesulfonic acid monohydrate with formation of 17- [N- (3-dimethylaminopropyl) timino] -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) or 17- [N- (3-dimethylaminopropyl) -imino] -androst-5-en-3β-ol-3-cyclopentyl ether.

By reducing the imines, for example by treatment with a suitable chemical reducing agent, e.g. sodium borohydride, the corresponding Compounds of the formula (II) in which R 1 denotes hydrogen. Are the special ones, given by formula (X) If the imines shown are used, the new compounds of the formula (VI), in which R, is hydrogen, are obtained and A is nitrogen. The reduction process is carried out by the treatment of the specific, in the above Paragraph mentioned imines with sodium borohydride illustrated. This gives 17β- [N- (3-dimethylaminopropyl) -amino3-androst-5-en-3β-ol-3- (3-cyclopentylpropionate) and 17ß- [N- (3-dimethylaminopropyl) -amino] * androst, 5-en-3β-ol-3-cyclopentyl ether.

The compounds of formula (II), in R., hydrogen means, and the compounds of the formula (VI) in which R, is hydrogen and A is nitrogen, can advantageously are alkylated so that the corresponding compounds are obtained, where R-j is an alkyl radical means. Are the compounds in which R, a

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ORIGINAL INSPECTED

1 2 1 υ:

Methyl radical means, if desired, the alkylation takes place expediently carried out using formic acid and formaldehyde. For example, this is how you get by reductive methylation of the specific compounds mentioned in the previous paragraph with Formic acid and formaldehyde 17ß- [N-methylTN- (3-dimethylaminopropyl) -amino3-androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) and 17ß- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-S-en-Sß-ol ^ -cyclopentylether, A preferred process for the preparation of the compounds of the formulas (II) and (VI), where R is an alkyl radical means with more than one carbon atom, but consists in that one the corresponding compounds, where R .. is hydrogen, preferably with a lower alkanoic anhydride or acid chloride in pyridine, acylated and the resulting amide reduced, for example with lithium aluminum hydride.

In an alternative process for the preparation of the compounds of formula (III) and the compounds of Formula (VI) where A is -CH- become starting materials with the partial structural formula

in which Alk ¹ denotes an alkylene radical having 1 to 7 carbon atoms is used. These acid chlorides can easily be prepared by treating the corresponding carboxylic acids with thionyl chloride in the presence of pyridine. By implementing the acid

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ORIGINAL INSPECTED

chloride with a corresponding secondary amine of the formula RR _? NH, in which R ₁ and R _{2 have} the meaning given above, the corresponding Ν, Ν-disubstituted amides are obtained. These amides are then reduced, for example with lithium aluminum hydride in the presence of an inert solvent, to form the desired amines.

In another method of making the compounds of the formula (III) and the compounds of the formula (VI), where A is -CH-, become starting materials the partial structural formula

-CH-AIk-C ^ CH, ^ O-alkyl

in which Alk is an alkylene radical having 2 to 8 carbon atoms is used. Starting materials of this type can be prepared by known methods. A specific example consists in the esterification of 3ß-hydroxychol-5-en-24-carboxylic acid with methanol in HCl to form 3ß-hydroxychol-5-en-24-carboxylic acid methyl ester which is then reacted with tosyl chloride in pyridine, whereupon the resultant is obtained 3 ~ tosyl steroid is refluxed in methanol in order to obtain 3ß-methoxychol-5-en-2 ¹ J-carboxylic acid methyl ester. The esters of the partial formula given above are then subjected to the Curtius rearrangement. The starting materials are reacted with hydrazine to give the corresponding steroid hydrazides, which by treatment with cold nitrous acid in one

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suitable solvents are converted to the corresponding steroid acid azides. These azides are left Now store in an inert solvent, if necessary with the application of heat, until the Development of nitrogen gas ceases. The so obtained Steroid isocyanates are now using a corresponding process, for example by hydrolysis in the presence an acid or base, converted to the corresponding primary amines. These amines can now too the corresponding tertiary amines of the formula (III) and (IV), i.e. to the compounds with the partial structural formula

in which Alk denotes an alkylene radical having 2 to 8 carbon atoms and R ₁ and R ^ denote alkyl radicals including 1 to 8 carbon atoms, can be converted by known processes. For example, the primary AMines obtained in this way can be subjected to reductive methylation by treatment with formic acid and formaldehyde in order to obtain the corresponding compounds of the formulas (III) and (VI) in which R ₁ and Rp are methyl radicals.

In an alternative method to achieve the 5 <x -androstanes of the formula (I) the corresponding androst-5-enes are hydrogenated. The hydrogenation is preferably catalyzed

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table in the presence of a hydrogenation catalyst, 25.B. Platinum, palladium-on-charcoal, platinum oxide and the like, carried out.

Tests to determine the effect of the azasteroids on insects indicate that the hypocholesterolemic azasteroids of the formula (T) compared. Larvae and nymphs of phytophage, saprophage and zoophage insects which obtain their essential cholesterol either from dietary cholesterol or by dealkylation of dietary phytosterols are effective. The term "saprophagus" is used in the traditional sense and refers to insects that feed on dead organic material. The term "phytophag", as used herein in its conventional sense, refers to insects that feed on living plants. The term "zoophag" used herein in the conventional sense relates to insects that feed on living animals. The term "insect" as used herein refers to the class Insecta of the class of the arthropods, the Arthropoda. The term "nymph" is used to denote the early postembryonic developmental stages of an insect that undergoes gradual metamorphosis, that is, a development during which wings gradually develop as external features. The term "larvae" is used to denote the early stage of development of an insect that undergoes a complete metamorphosis, that is, a development that is characterized by three clearly distinguishable post-embryonic stages of development, the larval stage representing the early form during which the wing rims are

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developed internally. More detailed definitions and explanations of these terms can be found in the literature, for example in A Textbook of Entomology , by Herbert H. Ross, 3rd Edition, John Wiley & Sons, Inc., New York, 1967.

Insects that reduce their essential cholesterol through dealkylation of dietary C _? G and CQ phytosterols are the insects that, when placed on phytosterol, dealkylate it. The term "Cg and Cpg phytosterols" is used in the present case

Term steroid _> he uses substances that are in

Plants are found and contain 28 or 29 carbon atoms, of which 9 or 10 carbon atoms are present in the 17 side chain. The dealkylation of such phytosterols is through the conversion of ß-sitosterol to cholesterol illustrated below

cholesterol

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Insects of the type having the ability to dealkylate dietary CpQ and Cp phytosterols are described in the literature and can be illustrated by the method of Life Sciences , Vol. 6, p. 395 (1967) in which the test insect on a stock diet that is coated with about 0.2 %, based on the dry weight, of the desired sitosterol.

The hypocholesterolemic azasteroids of the formula (I) apparently inhibit the early postembryonic development stages of phytophagous insects, which _{convert C g and C 2} g phytosterols to cholesterol, by hindering the essential cholesterol biosynthesis and by disrupting other pathways of steroid metabolism. Such phytophagous insects include insects of the Lepidoptera species , sub-genus Frenatae , family Sphingidae, for example the Protaparce sexta [Manduca sexta (Johannson)], family Noctuidae ( Phalaenidae ), for example the cotton bollworm [Heliothis zafe (Boddie)] and the army worm Spodoptera frugiperda (JE Smith)], furthermore the family Pyralidae , such as the grain borer found in the southwest [Diatraea grandiosella] (Southwestern corn borer). Insects of the genus Coleoptera , family Curculionidae , for example capsule beetles ( Anthonomus grandis ) (boll weevil) are also representative examples of phytophagous insects that can dietarily convert Cpg and Cpq phytosterols to cholesterol.

In the same way is by the way in which the hypocholesterolemic Azasteroids of formula (I) the early

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By inhibiting postembryonic developmental stages of saprophages and zoophages, apparently the essential steroid metabolism is disrupted. Such saprophagous insects include insects of the genus Dictyoptera , the Blattidae family, such as, for example, the German cockroach [ Blattella germanica (L.)] and the American cockroach [ Feriplaneta americana (L. )} and insects of the Isoptera genus, in particular termites; Such zoophageous insects include certain insects of the genus Diptera , subgenus Nematocera »family Culicadae , in particular the insects of the genus Anopheles and the genus Aedes which transmit diseases such as yellow fever.

Inhibiting the early postembryonic stages of development, i.e., larvae and nymphs, of those listed above phytophagous, saprophagous, and zoophageous insects, is changed by interruption of the altering ^ 8? η. des periodically rejection of the cuticle or "skin" of an insect), a premature prepupa formation that Inability to form a pupa (the postembryonic form that follows the larval stage in insects that undergo a complete metamorphosis) or similar manifestations of abnormal or retarded growth proven. The following describes the procedures used in tests to determine the hypocholesterolemic, antilarvoid and antinymph activity of the azasteroids of formula (I) were applied.

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Hypocholesterolemia test

The anti-hypercholesterolemic usefulness of the compounds according to the invention is evident from the results of a standardized test in which the ability of these compounds to counteract the increased serum cholesterol induced in rats by administration of propylthiouracil was examined. For each compound to be tested, a group of eight male rats, each weighing 220-250 g, was used, the propylthiouracil being administered in a concentration of 0.02 % in the drinking water of the animals over a period of 10 days time was dissolved daily the selected dose of the compound in water or aqueous sodium ϊ 30 # propylene glycol or suspended and administered orally or subcutaneously to each animal. A corresponding group of eight rats each same time and in the same manner propylthiouracil and water or aqueous ί Propylene glycol 30 % but not given the compound served as a control group. On day 10, the surviving animals were anesthetized and blood samples were drawn from the abdominal aorta and analyzed for cholesterol. A compound is considered anti-hypercholesterolemic if the Cholesterol levels in animals treated with this compound are significant (P <0.05 as n after the Wilcoxon Rank Sum Method) is lower than the corresponding control cholesterol levels.

Tests with nymphs of the German cockroach f Blattella germanica (L.) 3

20 newly hatched nymphs of the German kitchen-209839/1243

cockroach - Blattella germanica (L.) - were placed in a 0.288 (half-pint) vessel which was covered with a sieve. The vessels contained a device for adding water, which consisted of a bowl vial filled with 3 % agar gel and which was prepared according to the method of Noland and Baumann [Proc. Soc. Exptl. Biol. And Med., Vol. 70, p. 198 (19 ^ 9) 3 prepared diet. The test compound and β-sitosterol were dieted with dichloromethane or methanol to give a concentration of 0.2 JJ each on a dry weight basis. In order to closely examine the effectiveness of the more effective test compounds, additional tests were carried out at other concentrations, e.g. 0.5 % , as indicated by the initial results. The insects were kept at 25 ° C and 50 % relative humidity and the inhibitory effect was determined after a period of 30 days by comparing the weight of the nymphs raised with the test compound with the weight of the control nymphs.

Tests with nymphs of the American

cockroach
[ Periplaneta americana (L,)]

35 newly hatched American cockroach nymphs - Periplaneta americana (L.) - were tested in the same manner as described above for the German cockroach nymphs, with the difference that the American cockroach nymphs were weighed after a test period of 80 days. The inhibitory effect of the test substance was the same

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Way as determined for the nymphs of the German cockroach.

Tests with larvae of the Protoparce sexta

(Tobacco hornworm) [ Manduca sexta (Johannson)]

Two or more groups of six newly hatched larvae - Manduca sexta (Johannson) - were isolated using a modification of the method of Hoffman et al. [Insect Colonization and Mass Production, Academic Press, Inc., New York ('1966) 3, on the work of Waldbauer et al. [J. Econ. Entomol., Vol. 57> p. 93 (1964)] b? ^ H.ert, bred. The stock diet was covered with β-sitosterol and the test compound, the concentration being 0.026% wet weight (0.2 % dry weight) each. The inhibition was rated as follows: 0 = no effect on development; + = less than half of the insects develop a normal prepupa, larval growth is delayed; ++ = less than a third of the insects develop a normal prepupa, some abnormal prepupa of the 4th stage form (an insect of the "^ stage" is an insect in the period of development between the 3rd and 4th change; ++ + = less than 1/6 of the insects develop a normal prepupa, about 1/3 of the insects form abnormal prepupa of the 4th stage; ++++ = no development beyond the abnormal prepupa stage of the 4th stage; considerable mortality during the first three larval stages.

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Tests with larvae of the army worm

[ Spodoptera frugiperda (JE Smith) J.

Ten larvae of the master worm were tested in the same manner as above for the larvae of Protoparce sexta has been described, with the difference that the larvae of the army worm individually in plastic cups have been tested. The evaluation of the inhibition was carried out in the same way as for the larvae of the Protoparce sexta described.

Tests with larvae of the cotton bollworm [Heliothis zea (Boddie)]

Ten bollworm larvae - Heliothis zea (Boddie) - were tested in the same manner as described above for the Protoparce sexta larvae, except that the bollworm larvae were tested individually in plastic cups. Inhibition was assessed in the same way as described for Protoparce sexta larvae.

Tests with larvae of yellow fever mosquitoes [ Aedes aegypti (L.) 3

20 freshly hatched yellow fever mosquito larvae Aedes aegypti (L.) - were placed in 100 ml of distilled water in a 150 ml beaker. The test compounds, in 0.05-0.2 ml of distilled acetone, were added to the water with careful mixing for at least 2 hours before the larvae onset. The compounds were initially at 1.0 and 0.1

209839/1243

Parts / million tested; those compounds that gave 90 % or greater inhibition at 0.1 parts / million were also tested at 0.01 parts / million. The larvae were fed micropulverized dog food (Gaines Dog Meal) and grown at 25 ° C until fully developed. The inhibition effect of the. Compounds in development were calculated from the number of treated larvae which developed into pupae and adults as compared to the control animals.

The minimum effective amount of the active ingredient to inhibit the growth of larvae and nymphs is around 0.25 to 100 parts of the active ingredient per million parts of putter, depending on the compound selected, the amount (crop) and the insects to be controlled. Higher amounts can be used if necessary will.

According to the invention directed against larvae and nymphs Agents or mixtures are prepared by carefully mixing the active substances of the general formula (I) prepared with suitable carrier materials. Suitable agents include dust powder, sprinklers, Coated and impregnated granulates, wettable powders, pastes, emulsions, solutions, aerosols and the same.

To produce the solid agents, the active substances are mixed with solid carrier materials or extenders organic or inorganic composition mixed. Typical inorganic carriers include diatoms

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earth, puller earth, bentonite, talc, Kieseiguhr, bolar earth, Kaolin, tricalcium phosphate and calcium carbonate. Suitable organic extenders include ground vegetable products such as bran, bark dust, sawdust, ground nutshells and the same. Each of these carriers can be used alone or mixed with any other carrier material will.

In addition to the solid carrier material and the active ingredient, these agents can also contain substances that stabilize the active ingredient and / or the surfactants that promote adhesion of the active ingredients to the plants or parts thereof and better wettability or achieve dispersibility of the active ingredient.

The concentrates of the active substance that can be dispersed in water (i.e. wettable powders), Paste and emulsion concentrates consist of the active substance and the solid carrier and can optionally also contain stabilizers, surface-active substances, anti-foaming agents and solvents. Wettable powders and pastes are obtained by Mix the active substances with dispersants and fine powder carriers until the mixture is homogeneous Mixture received. The active substances are mixed, ground, sieved and mixed with the dispersants and Carriers so that the size of the pest particles in the wettable powders is in the range of 0.02 to 0.04 mm and in the pastes at 0.003 mm or

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less lies. To emulsion concentrates and pastes too dispersants, organic solvents and water are used. Examples of solvents are benzene, toluene, xylene, alcohols, dimethyl sulfoxide and mineral oil fractions. The solvents should of course not be phytotoxic.

In addition, the agents according to the invention can be in the form can be used by solutions. For this purpose, the compound of formula (I) is used in a suitable organic Solvent, a mixed solvent or dissolved in water. Aliphatic and aromatic hydrocarbons as well as chlorinated derivatives thereof are examples of usable organic solvents.

The agents according to the invention described above can be used to enlarge the area of action, for example with insecticides, fungicides, bactericides, fungistatic agents, bacteriostatic agents, nematocidal agents or fertilizers mixed will. In addition, the active agents can be used together with attractants and baits.

The following examples, which explain the preparation of the compounds of the invention, are merely intended to be used For the purpose of illustration, in these examples the temperatures are given in C and the amounts of material in parts by weight, unless otherwise stated. That The ratio between parts by weight and parts by volume is the same as the ratio between grams and Milliliters. The specific rotations were determined using the D-line of sodium (5893A) as the wavelength

209839/1243

of the light. The nuclear magnetic resonance spectra were determined by means of a 60 megahertz instrument using tetramethylsilane as the internal standard * and given in Hertz (Hz). The infrared absorption maxima are given in microns (μ),
^ (inter-al reference)

Example 1

A mixture of 288 parts of 3ß-Hydroxyandrost-5-en-17 ~ on and about 2,450 parts of pyridine were stirred and cooled in a cold water bath, 177 parts of 3-cyclopentylpropionyl chloride added. The mixture was stirred with cooling for about 1.5 hours. Afterward were 15 more parts of 3-cyclopentylpropionyl chloride added. The resulting mixture was further stirred for 1/2 hour. Aqueous methanol was added to the reaction mixture which was then cooled to about 5 ° C and gave a precipitate in the form of needle-like crystals. The crystals were caught on dried in air and then recrystallized from methanol. 3ß- (3-Cyclopentylpropionyloxy) -androst was obtained -5-en-17-one with a melting point of around 104 - 105 ° C.

By substituting molecular equivalent amounts of the corresponding Acyl chloride instead of the 3 "cyclopentylpropionyl chloride used above, being essentially the same procedure as above was repeated, 3ß- (2-Cyclohexyläthanoyloxy) -androst-5-en-17-one was obtained, 3ß- (3-cyclobutylpropionyloxy) -androst-5-en-17-one and 3ß- (4-cyclopentylbutyryloxy) -androst-5-en-17-one.

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Example 2

A mixture of 290 parts of 3ß- (3-cyclopentyl-propionyloxy) -androst-5-en-17-one, 107 parts of 3-dimethylaminopropylarain and about 3,900 parts of benzene was heated to remove the remaining water. 13 parts of p-toluenesulfonic acid monohydrate were added to this mixture. The resulting solution was heated at reflux temperature for about seven hours, then the solvent was evaporated to give an oil as a residue, which solidified after standing. The oil was recrystallized from ethyl acetate to give 17- [N- (3-dimethylaminopropyl) -imino3 ~ androst-5 ~ en-3.beta.-ol-3- (3-cyclopentylpropionate) having a melting point at about 84-86 ⁰ C.

To 33 parts of the imine prepared above, 16 parts of sodium borohydride and 240 parts of methanol were added over about 1/2 hour while the mixture was stirred at room temperature and cooled in a water bath. Water was added to decompose excess sodium borohydride and the reaction mixture was extracted with ether. The ether extract was washed three times with water, then dried over sodium sulfate and evaporated to dryness to give a pesticide which was recrystallized from acetone. To d ± se 17ß- [N- (5-di-methylaminopropyl) -amino3-androst-5-en-3.beta.-ol-3- (3-cyclopentylpropionate) was obtained with melting point at about 76-78 ⁰ C.

A mixture of about 30 parts of 17β- [N- (3-dimethylaminopropyl) -aminoJ-andrQst-5-en-3β-ol-3- (3-cyclopentylpropio ·

2 09839/12 4

nat), about 37 parts of formic acid and about 30 parts by volume of a solution of formaldehyde and water in a volume ratio from 36:64 became an hour on one Steam bath heated and then left to stand at room temperature for two days. After this period, about 100 parts of aqueous methanol were added to the reaction mixture with stirring and cooling in an ice bath. That mixture thus obtained was neutralized with aqueous sodium hydroxide. Then 10 # aqueous Sodium carbonate added to make the solution basic. The basic solution was extracted with ethyl ether, the extract was washed with water and then over an anhydrous mixture of sodium sulfate and Dried charcoal. The solution was decanted from the pests and evaporated in vacuo; one received 17ß- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) with a melting point of about 89 - 91 ° C. After treating this free base in ethyl ether with isopropanolic hydrogen chloride 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino3 was obtained -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) hydrochloride.

Example 3

By substituting molecular equivalent amounts of the corresponding Amine instead of the 3-dimethylaminopropylamine used in the first paragraph of Example 2, wherein essentially repeating the sequential procedures of the first and second paragraphs of Example 2 were obtained 17β- [N- (3-diethylaminopropyl) -aminoJ-androst-5-en-3β-ol-3- (3-cyclopentylpropionate), 17ß- [N- (3-

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Dipetylamino-propyl) -amino] -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) and 17β- [N- (2-dimethylaminoethyl) -amino3-androst-5-en-3β-ol-3- (3-cyclopentylpropionate).

Example 4

By substituting molecular equivalent amounts of the corresponding 17β- [N-dialkylaminoalkyl) -amino] steroid in place of the 17β-CN- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3 used in the third paragraph of Example 2 - (3-cyclopentylpropionate) and essentially repeating the process described there, 17β- [N-methyl-N- (3-diethylaminopropyl) -amino] -androe ^3- t-5-en-3β-ol-3 was obtained - (3-cyclopentylpropionate), 17β- [N-. ! " ¹ C thy! -Ν- (3-dipenty laminopropyl) -amino] -androst-5-ene-3ßol-3- (3-cyclopentylpropionate) and 17ß- [N-methyl-N- (2-dimethylaminoethyl) - amino] -androst-5-en-3β-ol-3 ~ (3-cyclopentylpropionate).

Example 5

The diethyl ketal of cyclopentanone was prepared by reacting 78 parts of cyclopentanone with 144 parts of triethyl formate in 138 parts of ethanol containing 2 % dry hydrogen chloride at room temperature for about 24 hours. 30 parts by volume of pyridine and then an ether-benzene mixture in a volume ratio of 1: 1 were added. The mixture was washed with a solution of 15 parts of sodium hydroxide in 300 parts of water and then with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and that

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Product was distilled at 79-80 ° C under a pressure of about 30 mm Hg.

A mixture of 4 parts of 3ß-Hydroxyandrost-5-en-17-one, 0.04 parts of p-toluenesulfonic acid and about 1,440 parts Benzene was heated to reflux temperature. Heating was continued until about 180 parts Benzene had been distilled off. 9 parts of cyclopentanone diethyl ketal were then added to this mixture. The distillation was continued until about 620 parts of benzene had been collected. The reaction mixture was cooled, about 4 parts of pyridine were added and the resulting mixture was concentrated in vacuo, an oil was obtained as residue. This oil, namely 3ß- (l-cyclopentenyloxy) -androst-5 ~ en-17-one, was recrystallized from methanol containing a small amount of pyridine.

3.15 parts of 3β- (1-cyclopentenyloxy) -androst-5-en-17-one were dissolved in tetrahydrofuran, and the solution thus obtained was dissolved with hydrogen gas in the presence of 0.8 part of a catalyst composed of 5 % palladium. Alumina reacted at atmospheric temperature and atmospheric pressure until the theoretical amount of hydrogen had been absorbed. The tetrahydrofuran was removed in vacuo to give an oil which solidified on standing. The oil was first made from aqueous methanol and then

re-crystallized from methanol alone, 3β ~ was obtained Cyclopentyloxyandrost-5-en-17-one with a melting point of 158 - 162 ° C.

2U9839 / 1243

A mixture of 13 parts of 3ß-cyclopentyloxyandrost-5-en-17-one, 8 parts of 3-dimethylaminopropylamine, 1.5 parts of p-toluenesulfonic acid monohydrate and 234 parts of anhydrous Benzene was refluxed for about seven hours, then the solvent was removed in vacuo and as residue crystals of 17- [N- (3-dimethylaminopropyl) -imino-3-androst-5-en-3β-ol-3-cyclopentyl ether obtain. This compound is by infrared maxima in chloroform solution at about 3.4, 6.1, 9.25 M. and by a specific rotation (in chloroform at 25 ° C) marked by -24.78 °.

A mixture of about 16 parts of 17- [N- (3-dimethylaminopropyl) -imino] -androst-5-en-3β-ol-3-cyclopentyl ether and 40Q parts of methanol was given 10 parts of sodium borohydride for about half an hour with stirring and cooling added in a water bath. Stirring was continued for an additional half hour. Water was added to replace excess sodium borohydride; The reaction mixture was then extracted with ether. The ether extract was washed three times with water and then dried over anhydrous sodium sulfate. After evaporation of the solution to dryness, 17β- £ N- (3-bimethylamineQpropyl) -amineQ3-andrast ~ 5-en-3β-ol-3-cyclopentyl ether was obtained as a pesticide 9.25 μ and by a specific © rotation (in chloroform at 26 ⁰ C) of * 2 & ₉ 6 ^Ο:

A mixture of 10 parts 17ß-EN- (3- ⁱ DdiRethylamin, QprQpy / l> aminoJ-androst-5-en-3ß-ol-3 "Oylop @ n: fey / lclth ^ r _Ä share aqueous 3? Y £ - igera Forraalde & y / d. and. XZ

221219 /

Formic acid was heated on a steam bath for about 16 hours. At the end of this period it became aqueous Methanol added. The mixture was made basic by the addition of aqueous sodium hydroxide and then cooled to about 5 ° C. A precipitate was obtained which was washed with water in air was dried and then recrystallized from acetone to give 17β- [N-methyl-N- (3-dimethylaminopropy1) .amino] -androst · To give 5-en-3ß-ol-3-cyclopentyl ether. This compound is at 3.4 by infrared maxima in chloroform and 9.25 μ and characterized by a specific rotation (in chloroform at 25 C) of -37> 9 °.

Example 6

By substituting a molecular equivalent amount of the corresponding acyl chloride for that in example 1 used 3-cyclopentylpropionyl chloride, where essentially the sequential procedures described in detail in Examples 1 and 2 were used were obtained 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino] -anörost-5-en-3β-ol-3-cyclopentyl- carboxylate, 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino3-androst-5-en-3β-ol-3-cyclohexylcarboxylate and 17β ~ CN-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3-cycloheptylcarboxylate »

Example 7

By substituting molecular equivalent amounts of the corresponding Acyl chloride instead of the ^ -CyclQpen.tylpropionylchlorids used in Example 1 »where im

- 39 - "5" 9 1? 1 Q 7

essentially the sequential procedures described in Examples 1 and 2 were used one 17β- [N-methyl-N- (3 "dimethylaminopropyl) .amino] -androst-5-en-3β-ol-3- (3-eyclobutylpropionate) and 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3- (3-cyclohexylpropionate).

Example 8

By substituting a molecularly ^{equivalent amount of 2 i} l-dimethylaminochol-5-en-3 [beta] -ol (commonly referred to as "25-aza-cholesterol") for the 3 [beta] -hydroxyantiroiät- used in the first paragraph of the procedure of Example 1 ^{: i} 5 ^i; * en- = 17 "on and repetition of the process described in Example 1 gave 2 ⁱ * -dimethylaminochol-5-en-3β-ol-3- (3-cyclopentylpropionate).

In the same way, by substitution of an equivalent amount of 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol instead of the 3β-hydroxyandrost-5-en-17-one used in the procedure of the first paragraph of Example 1 and repetition there described method 17β- £ N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3- (cyclopentylpropionate ).

Example 9

By substituting an equivalent amount of 24-dimethylaminochol-5-en-3ß-ol (commonly referred to as "25-aza-cholesterol") in place of that in the second paragraph of Example 5 used 3ß-Hydroxyandrost-5-en-17 ~ one, whereby

209839 / 12U

essentially the procedures used in the second and third paragraphs of Example 5 have been repeated, 24-dimethylaminochol-5-en-3β-ol-3-cyclopentyl ether was obtained.

In the same way, by substitution of an equivalent amount of 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol instead of the 3β-hydroxyandrost-5-en-17-one used in the procedure of the second paragraph of Example 5, being essentially the procedures used described in the second and third paragraphs of example 5 have been repeated, 17β- [N-Methy1-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3-cyclopentyl ether.

Example 10

A mixture of 6.8 parts of 3ß.Methoxyandrost-5-en-17-one, 3.96 parts of 2-dimethylaminoethylamine, 0.86 parts of p-toluenesulfonic acid monohydrate and 220 parts of anhydrous benzene was heated at reflux temperature for about 16 hours, the water formed being distilled off. The mixture thus obtained was dried under reduced pressure concentrated, 17- [N- (2-dimethylaminoethyl) -imino] -androst-5-en-3ß-ol-3-methyl ether being obtained as the crude residue received.

The crude material obtained above was dissolved in 200 parts of methanol and mixed with 7.0 parts of sodium borohydride added for about an hour. The resulting mixture was allowed to stand overnight, concentrated it then under reduced pressure and let ether and

209839/1243

Separate water. The ether layer was separated and washed twice with water, then over anhydrous Dried potassium carbonate and concentrated under reduced pressure. This is how you got. 17β- [N- (2-dimethylaminoethyl) amino] androst-5-en-3β-ol-3-methyl ether as an oil that solidified when left standing. This connection has characteristic nuclear magnetic resonance bands, in deuterochloroform, at around 44, 60, 132, 200 and 320 Hz.

7.5 parts of 17β- [N- (2-dimethylaminoethyl) amino] androst-5-en-ol-3-methyl ether, 50 parts by volume of aqueous 88 # formic acid and 50 parts by volume of aqueous 36 # formic acid Formaldehyde were combined and heated on a steam bath for three hours. After this time it became Mixture concentrated under reduced pressure, then water and ether separated and crushed with ice containing concentrated sodium hydroxide solution made alkaline. The mixture thus obtained was washed with ether extracted, the ether extract was dried over anhydrous potassium carbonate and under reduced pressure concentrated. The oil thus obtained was 17β- [N-methyl-N- (2-dimethylaminoethy1) -amino] -andros t-5-en-3β-ol-3-methyl ether. This product showed characteristic nuclear magnetic properties Resonance bands in deuterochloroform at around 48, 60, 134, 201 and 322 Hz.

8.3 parts of 17β- [N-methyl-N- (2-dimethylaminoethyl) -amino] -androst-5-en-3β-ol-3-methyl ether were dissolved in about 20 parts of anhydrous ethanol. 2-propanol, the one containing a slight excess of hydrogen chloride was added. Crystals began to form. It was

209839/1243

mixed with ether. The mixture was cooled to about O C, then filtered, washed carefully with ether and dried. 17β- [N-methyl-N- (2-dimethylaminoethyl) -amino] -androst-5-en-3β-ol-3-methyl ether dihydrochloride were obtained. This amorphous material absorbed one mole of water after exposure to air. In this way 17β- [N-methyl-N- (2-dimethylaminoethyl) -aminoj | -androst-5-en-3β-ol-3-methylether dihydrochloride monohydrate was obtained with a melting point of about 272 ° C with evolution of gas. This connection is also characterized by infrared absorption maxima in potassium bromide at about 2.9, 3.4, 3.5, 3.8, 4.0, 6.8 and 7.2 μ.

Example 11

A mixture of 6.8 parts of 3ß-methoxyandrost-5-en-17-one, 4.6 parts of 3-dimethylaminopropylamine, 0.86 parts of p-toluenesulfonic acid monohydrate and 220 parts of anhydrous benzene were heated at reflux temperature for about 16 hours, during which the water formed was distilled off. The resulting mixture was concentrated under reduced pressure. Crude 17- [N- (3-dimethylaminopropyl) -imino] -androst-5-en-3β-ol-3-methyl ether was obtained.

The crude residue obtained above was used in 200 Parts of methanol dissolved, and 7.0 parts of sodium borohydride were added over the course of about one hour. The thus obtained Mixture was allowed to stand overnight, concentrated under reduced pressure and left ether and Separate water. The ether layer was separated and washed with water, then over anhydrous potassium carbonate

209839/1243

dried and concentrated under reduced pressure. In this way 17β- [N- (3-dimethylaminopropyl ) .aminoJ-androst-5-en-3ß-ol-3-methyl ether in the form of an oil.

7.8 parts of the 17β-tN- (3-dimethylaminopropyl) -amino-3-androst-5-ene-3ßol-3-methyl ether prepared as described above, 50 parts by volume of aqueous 88 % formic acid and 50 parts by volume of aqueous 36 / S Formaldehyde were combined and heated on a steam bath for 1 hour. At the end of this time the mixture was concentrated under reduced pressure, then the water and ether were allowed to separate and made alkaline with a concentrated sodium hydroxide solution containing crushed ice. The mixture thus obtained was extracted with ether, and the ether extract was dried over anhydrous potassium carbonate and concentrated under reduced pressure. In this way, 17β-CN-methyl-N- (3-dimethylaminopropyi) ⁱ -amino-3-androst -5-en-3β-ol-3-methyl ether was obtained in the form of an oil. This product had characteristic nuclear magnetic resonance bands in deuterochloroform at about 48, 60, 132, 200 and 322 Hz.

9.4 parts of 17B- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3-methyl ether were dissolved in about 20 parts of anhydrous ethanol. 2-propanol, the one containing a slight excess of hydrogen chloride was added and crystals began to form. It was mixed with ether and the mixture cooled to about 0 C, then filtered and washed carefully with ether and dried. 17β- [N- i

209839/1243>-; Ϊ \ t? L κ

aminopropyl) amino] dihydrochloride. This amorphous material, when exposed to air, absorbed one mole of water, so that 17β- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-S-en ^ ß-ol ^ -methyl-ether dihydrochloride monohydrate received, whose melting point was about 28l ° C (with evolution of gas). This connection is also characterized by infrared absorption maxima at about 2.9, 3 * 4, 3.5, 3.7, 4.0 and 6.8 μ, as by Measurement in potassium bromide was noted.

Example 12

A mixture of 3 parts of 24-dimethylamino-5a-cholan-3A-ol, 0.04 parts of p-toluenesulfonic acid and about 1,440 parts of benzene were heated to reflux temperature and at this temperature was maintained until about 180 parts of benzene had been distilled off. 9 parts of cyclopentanone diethyl ketal were added. Distillation was continued until about 620 parts of benzene were collected had been. The reaction mixture was then cooled about 4 parts of pyridine were added and the mixture was concentrated under reduced pressure. The residue, namely 24-dimethylamino-5a-cholan-3ß-ol-3- (1-cyclopenty1) -ether, was recrystallized from methanol containing a small amount of pyridine.

3.15 parts of 24-dimethylamino-5-x-cholan-3β-ol-3- (1-cyclopentenyl) ether was dissolved in tetrahydrofuran, and the resulting solution was extracted with hydrogen gas in the presence of 0.8 part of a catalyst 5 % palladium on aluminum oxide at atmospheric pressure and room

209839/1243

temperature implemented until the theoretical amount of hydrogen had been absorbed. The tetrahydrofuran was removed under reduced pressure. Man received 24-dimethylamino-5a-cholan-3ß-ol-3-cyclopentyl ether.

Example 13

A mixture of 10 parts of 3β-methoxy-chol-5-en-24-carboxylic acid methyl ester, 10 parts of hydrazine hydrate and 200 parts of 1-pentanol was heated at reflux temperature for about 44 hours. The solvent was distilled off in vacuo and the residue dissolved in anhydrous ethanol. solved. Water was added and the crystals which formed were filtered and washed with a mixture of ethanol and water. Here to give 3.beta.-Methoxychol-5-ene-24-carboxylic acid, the sinter started at about 156 C and at about 173 - 176 ⁰ C melted.

5 parts of 3β-methoxychol-5-en-24-carboxylic acid hydrazide were dissolved in a mixture of 16.5 parts of glacial acetic acid and 22 parts of methylene chloride. The resulting mixture was cooled to about -10 ⁰ C. A solution of 2.6 parts of sodium nitrite and 8.5 parts of water was then added all at once and the reaction mixture was shaken vigorously for several minutes. The reaction mixture was then left to stand at about 0 ° C. for about 30 minutes. A mixture of 133 parts of methylene chloride and 540 parts of a 1.5 N sodium carbonate solution was then added, and the mixture thus obtained was shaken. The organic layer was separated and dried first over anhydrous sodium sulfate and

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then dried over anhydrous calcium chloride. Methylene chloride was distilled off from the reaction mixture under atmospheric pressure and at the same time replaced with dry benzene until the distillate boiled at about 75.degree. The solution was then heated at reflux temperature until the evolution of nitrogen gas ceased. The mixture obtained in this way was cooled to about 25 ° C. and 3 parts by volume of aqueous 36 % hydrochloric acid were added. The reaction mixture was then stirred vigorously until the evolution of carbon dioxide had ended. The desired product, namely 23-amino-24-norchol-5-en-3β-ol-3-methyl ether hydrochloride, crystallized from the solution and was filtered, air-dried and then recrystallized from a mixture of ethanol and anhydrous ether. This product melted at about 315 ° C. (with evolution of gas).

The free base of 23-amino-24-norchol-5-en-3ß-ol-3-methyl ether was prepared by adding 23-amino-24-norchol-5-en-3ß-ol-3-methyl ether hydrochloride suspended in a water-benzene mixture, this suspension made alkaline with aqueous sodium hydroxide, which Separated organic layer, dried over anhydrous potassium carbonate and reduced the benzene under reduced pressure Pressure removed. In this way, 23-amino-24-norchol-5-en-3ß-ol-3-methyl ether was obtained, which began to sinter at 180 C and melted at 111-114 ° C.

A mixture of 1 part of 23-amino-24-norchol-5-en-3ß-ol-3-methyl ether, 15 parts by volume of aqueous 88% formic acid and 15 parts by volume of aqueous 36% formaldehyde was about 5 hours at about 100 ⁰ C heated. The mixture

209839/1243

was then poured onto ice and benzene and made alkaline with aqueous sodium hydroxide. The organic layer was separated and dried over anhydrous potassium carbonate
dried. The solvent was distilled off under reduced pressure. The oil thus obtained was in
Dissolved anhydrous ethanol and added 2-propanol containing a slight excess of hydrogen chloride. The resulting pestilence was gone
recrystallized from a mixture of anhydrous ethanol and anhydrous ether. The 23-dimethylamino-24-norchol-5-en-3β-ol-3-methyl ether hydrochloride obtained as product melted at about 290 ° C. (with evolution of gas).

209839/1243

Claims (1)

Patent claims: 1. Compound of the general formula R ₇ -A-AIk-N in which the dashed line indicates the optional presence of a Δ 'unsaturated bond, the wavy line at the 3-position indicates the optional α- and β-configurations, R ₁ and R_ denote alkyl radicals with 1 to 8 carbon atoms, R, hydrogen or one Alkyl radical with 1 to 8 carbon atoms, Alk is an alkylene radical with 2 to 8 carbon atoms, which separates the -NR.Rp- and R Α groups by at least 2 carbon atoms, A -CH- or a nitrogen atom and R ^, a cycloalkyl, (Cycloalkyl) -alkyl- or (cycloalkyl) -alkanoyl radical, provided that when R is a methyl radical, A -CH- and Alk is a trimethylene radical and the 5 (6) bond is saturated, R ^ is a cycloalkyl or ( Cycloalkyl) alkyl radical, or an acid addition salt thereof. 2. Compound of the general formula 209839/1243 in which the dashed line indicates the optional presence of a Δ -unsaturated bond, the wavy line at the 3-position indicates the optional α- and β-configurations, R and R ₀ alkyl radicals with 1 to 8 1
Carbon atoms, R ₇ hydrogen or an alkyl radical with 1 to 8 carbon atoms, Alk an alkylene radical with 2 to 8 carbon atoms which separates the -NR.Rp- and R-, A groups by at least 2 carbon atoms, A -CH - or a nitrogen atom and R ₁ - is a cycloalkyl, (cycloalkyl) alkyl or (cycloalkyl) alkanoyl radical, provided that when A is -CH- and the 5 (6) bond is saturated, Rj- is a Cycloalkyl or (cycloalkyl) alkyl radical means, or an acid addition salt thereof. 3. Compound according to claim 2, characterized in that that A of the general formula denotes a nitrogen atom, or an acid addition salt thereof. ¹ J. lYß-CN-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) or an acid addition salt thereof. 5. Π & - C N-Methy lN- (3-dimethylaminopropyl) -amino] androst-5-en-3ß-ol-3-cyclopentyl ether or an acid addition salt thereof. 209839/1243 6. 17β- [N- (3-Dimuthylaminopropyl) -aminoI-androst-5 ~ en-3β-ol-3- (3-cyclopentyl propionate). 7. 17β- [M- (3-dimethylaminopropyl) -amino] -androst-5-en-3β-ol-3-cyclopentyl ether. 8. 24-Dimethylaminochol-5-en-3ß-ol-3- (3-cyclopentyl pripionate) or an acid addition salt of the same. '), 2H-DLmefchylaminuühoi-5 "än-3ß-oi-3-cyclopent.yläfchar or an acid additive of the same, LO, compound of the general formula N-AIk-N Ln the the dashed line the optional chamfering 5 (6) a Δ 'unsaturated bond, the wavy line at the 3-position indicates the optional α- and ß-configurations, R. and R _{2 are} alkyl radicals with 1 to 8 carbon atoms, Alk is an alkyl radical with 2 to 8 carbon atoms, which the - NR ₁ Rp and ^! Functions separated by at least 2 carbon atoms, and Rjj is a cycloalkyl, (cycloalkyl) alkyl or (CycLo- 20Ü839 / I243 alkylJ-alkanoyl radical. 11. 17- [N- (3-Dimethylaminopropyl) -iniino3-androst-5-en-3β-ol-3- (cyclopentylpropionate). 12. 17- [N- (3-Dimethylaminopropyl) imino] androst-5-ene 3β-ol-3-cyclopentyl ether. 13 · Means for inhibiting the growth of larvae or nymphs of insects, which _{convert dietary C 2} g and C g phytosterols to cholesterol or use dietary cholesterol in their metabolism, characterized by a. Content of a hypocholesterolemic 3-hydroxyazasteroid etherified in the 3-position or acylated in the 3-position of the general formula in which the dashed line indicates the optional presence of a Δ unsaturated bond, the wavy line at the 3-position indicates the optional α- and ß-configurations, R is a hydrocarbon radical with 1 to 19 Carbon atoms or an acyl radical derived from a hydrocarbon carboxylic acid having 1 to 18 carbon atoms is derived, and X is a saturated residue with 509839/1243 1 or 2 nitrogen atoms and at least 4 carbon atoms means, provided that when X is 5-dimethylamino-2-pentyl radical, R is more than one Must contain carbon atom, or an acid addition salt thereof as an active ingredient. 14. Composition according to claim 13, for inhibiting the growth of insects of the genus Dictyoptera , Lepidoptera or Coleoptera or of the genus Diptera , family Culicadae . 15. Composition according to claim 13, characterized in that the steroid is a compound of the general formula in which the dashed line and the wavy line and R have the meaning given above, R. and R _{2 are} alkyl radicals having 1 to 8 carbon atoms, R is hydrogen or an alkyl radical having 1 to 8 carbon atoms and Alk is an alkylene radical having 2 to 8 carbon atoms and the -NR ₁ R ₂ and R, N group are separated by at least 2 carbon atoms, or is an acid addition salt of this compound. 20 ^ 839/1243 16. Composition according to claim 13, characterized in that the steroid 17ß- [N-methyl-N- (2-dimethylaminoethyl) -aminoJ-androst-5-en-3ß-ol-3-methyl ether or an acid addition salt thereof. 17. Composition according to claim 13, characterized in that the steroid 17ß- [N-methyl-N- (3-dimethylaminopropyl) amino] androst-5-en-3ß-ol-3-methyl ether or an acid addition salt thereof. 18. Composition according to claim 13, characterized in that the steroid is a compound of the general formula CH-AIk-N in which the wavy line and the dashed line, R, R ₁ and R _{2 have} the meanings given above and Alk denotes an alkylene radical having 2 to 8 carbon atoms which has the -NR ₁ R ₅ - and CH-zCH groups through at least 2 carbon atoms separates provided that when Alk is trimethylene, R must contain more than 1 carbon atom, or is an acid addition salt thereof. 209839/1243 2212137 19. Composition according to claim 13 »characterized in that the steroid 2 is 3-dimethylamino-2 ⁱ f-norchol-5-en-3ß-ol-3-methyl ether or an acid addition salt thereof. 20. Agents for inhibiting the growth of larvae or nymphs of insects containing dietary C-g and C-g phytosterols to convert cholesterol or use dietary cholesterol in their metabolism, featured by a content of a hypocholesterolemic etherealized in the 3-position or in the 3-position acylated 3-hydroxyazasteroid according to claim 1 or an acid addition salt thereof as an active ingredient. 21. Composition according to claim 20, characterized in that the steroid is a compound of the general formula according to claim 1, wherein A represents a nitrogen atom or an acid addition salt thereof. 22. Composition according to claim 20, characterized in that the steroid 17ß- [N-methyl-N- (3-dimethylaminopropyl). amino] -androst-5-en-3ß-ol-3- (3-cyclopentylpropionate) or an acid addition salt thereof. 23 · Agent according to claim 20, characterized in that the steroid 17ß- [N-methyl-N- (3-dimethylaminopropyl) -amino] -androst-5-en-3ß "" ol-3-cyclopentyl ether or an acid addition salt thereof. 24. Composition according to claim 20, characterized in that the steroid 24-dimethylaminochol-5-en-3ß-ol-3- (3-cyclopentylpropionate) or an acid addition salt thereof. 209839/1243 25. Composition according to claim 20, characterized in that the steroid 2 ⁱ J-dimethylaminochol-5-en-3ß-ol-3-cyclopentyl ether or an acid addition salt is the same. For: G.D. Searle & Co. Skokie, 111., V.St.A. ' (Dr W. Beil) Lawyer 209839/1243