DE1793208A1 - New cyclic hydrocarbon compounds - Google Patents

Description

PATENT LAWYERS

DR.-ING. BY KREiSLER DR.-ING. SCHDNWALD 1793208 DR.-ING. TH. MEYER DR. FUES

COLOGNE 1, DEICHMANNHAUS

Dr.-Ing. vcn district: Dr.-kg. S * önwa1d

Dr.-lng.ThJlte> er Or .FussCipi -: ^. Rr,. * I: kvmKrelslef _Ko 'i _{n den} ^ A _Ugus t I968 Dipl.-Chem. Carola Keilet Dr.-Ing. Klopsdi st / V

EGG. Du Pont de Ifemours & Company, Wilmington 98, Delaware USA

Today's cyclic hydrocarbon compounds

Elimination registration III from P 14 68 769.5

lie invention relates to a method for the production of tricyclic compounds from the series of the substituting τβη adamantanes and tricyclo / 4,3,1.1 'tundecanes, insbesonc.ere of new adamantane and tricyclo ^ / 4,3,1,1,1 '_7undecane-79rbindungen, in which an aminomethyl or N-substituted Aminomethyl group on a tertiary or bridgehead ring carbonator is bound.

The class of novel compounds made according to the invention includes preparations having pharmaceutical uses and effective agents for treating Represent virus infections. You have the ability to get infections with the most varied of harmful viruses and to inhibit or prevent the growth of these viruses » In addition, the compounds of this class have a significant stimulatory effect.

The tricyclic compounds prepared according to the invention have the general formula

209816/17

X where A = -C-R and B = H or,

I ■

if a CEL group is inserted between C-3 and C-4,

A = H and B = -C-R.

t X

If the compounds prepared according to the invention are adamantanes, they thus correspond to the formula

and when they are tricyclo / 4,3,1,1 '_7undecane, correspond e of the formula

C t

The substituents R, X and Y in the above formulas have the following meanings:

X and Y can be the same or different and are hydrogen, methyl or ethyl and R is

(CH ₂ ) _n , where η = 1, 2, 3, 4, 5 or 6

-N = CiOL

Herein means in turn

Hydrogen, alkyl with 1-6 carbon atoms, monosubstituted alkyl with 1-6 carbon atoms and the following substituents: OH, alkoxy with 1-2 carbon atoms, -NH ₂ , -NHR. or -NR ₄ R ₅ , where R ₄ and R _{5 can be the} same or different and each is an alkyl radical with 1-4 carbon atoms, an alkenyl radical with 2-6 carbon atoms, an alkynyl radical with 2-6 carbon atoms, cyclopropyl, cyclohutyl, cyclopropylmethyl o <ler Oyolol-iityliri ^ thyl is.

6AO ORIGINAL

R _{2 is} equal to E ₁ , chlorine, bromine, formyl, -CH ₂ COOH, -CH ₂ COOCH ₅ or -CH ₂ COOC ₂ H _5, but with the proviso that in cases in which E _{1 is} alkenyl or alkynyl with the double or triple bond in the 1-position is', R _{2 is} alkyl or monosubstituted alkyl, as defined above, and that in the case of the adamantane _{compounds, when R 1 is} an unsubstituted alkyl radical having 1-6 carbon atoms or hydrogen, Rp is neither a hydrogen atom nor an unsubstituted one May be an alkyl radical.

R ₇ is an aliphatic radical, a monosubstituted aliphatic radical with an aromatic or heterocyclic! Substituent, an aromatic radical or a heterocyclic radical with not more than 12 carbon atoms.

Compounds which are hydrolyzable to the compounds of formula (1) and (2) are for most purposes these compounds equivalent and of course fall within the scope of the invention.

Since the compounds of formula (1) and (2) contain a basic amino group, they naturally form salts easily, and these salts containing a non-toxic anion also fall within the scope of the invention. Representative for these salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, succinates, adipates, propionates, Tartrates, citrates, bicarbonates, pamoates, cyclohexylsulfamates and acetyl salicylates. Of these, the hydrochlorides, acetates and acetyl salicyclates are preferred. The cyclohexyl sulfamates have a pleasant taste and are therefore particularly advantageous for the production of syrups for oral application. In addition, the cyclohexyl sulfamates are advantageous for the production of coated tablets for oral use Applications that do not have an unpleasant bitter taste. Other salts are those with oaprochioron

209815/1743

ORIGINAL

and with penicillin in question. In general, the the aforementioned salts highlight the utility of the relatively "insoluble amines" in pharmaceutical applications.

In the overall framework of the compounds prepared according to the invention, various subclasses of compounds exhibit particularly valuable combinations of properties. For example, it is possible by appropriate ¥ ahl of compounds to achieve the dynamics as medicaments and antiviral efficacy different desired combinations of stimulating and antiviral activity and, depending on the type of disease and the λ patient to be treated ten different desired combinations. Accordingly, compounds according to the invention are preferred in which, for example, the amine on the undecane component is substituted with dialkylated (ϊΤ, Ν-dialkylated compounds) because they have a very favorable combination of antiviral activity with reduced stimulating effect. Of these, the lower alkyl substituents, the dimethyl and diethy derivatives, are most preferred because of their higher antiviral effectiveness. Compounds of the invention in which the amine is monoalkylated on the Undecankomponente show also less stimulatory "not effective than the unsubstituted amine. These reduce monoalkylated {amine derivatives, the stimulative effect in the same degree as the dialkylated amine derivatives, but the mono-alkylated amine derivatives, particularly the monomethyl and Honoäthylderivate, have higher antiviral effectiveness than the dialkylated amine derivatives,

when a combination of antiviral effectiveness and more favorable dynamics as a drug, especially longer If the duration of action is desired before degradation or before excretion, compounds according to the invention are preferred, in which the methylamino group on the adamantane or undecane component is "! -substituted or oc," .- substituted " Within this class of compounds, in general

209815/1743 - ⁶ -

· ■ * · * - · ■■■ '6AD ORIGINAL

The α-substituted compounds have higher antiviral properties Efficacy, but less favorable dynamics than drugs than the rx, # - substituted compounds.

From the above considerations of the compounds prepared according to the invention for pharmaceutical Most preferred uses the following compounds and their hydrochloride salts:

3 ~ (N, 1T Dimethylaniinomethyl) tricyclo / 4 ""3> 1, 1 '_7undecan 3- (N-methylaminomethyl) tricyclo / 4 ", 3.1, 1 ^J" _yundecan 3- (N-Ä "thyl- N-methylaminomethyl) tricyclo / 4 ", 3,1, 1 * 7undecane 3- (aminomethyl) tricyclo ^ 4", 3,1, 1 * _7undecane 3- (N, N ~ diethylaminomethyl) tricyclo _< / 4,3j1, 1 * _7undecan 3- (N-ethylam4nomethyl) tricyclo ^ / 4,3,1,1 '_7undecan ü <-Methyl-3-tricyclo ^ 4,3,1>1' / undecanmethylamine oi, ec-dimethyl-1 -adamantanmethylamine

• ζ ο

i , -x-Dimethyl - ^ - tricyclo / ?, 3.1 »1-7undecanemethylamine

The compounds falling within the scope of the invention can be prepared in various ways.

3-Tricyclo / ?, 3,1, 1 '_7 ^{and ecancar} b ° ^{ns acid} can be converted into the corresponding acid chlorides with thionyl chloride. The unsubstituted amides and a wide variety of N-alkyl- and Ν, Ν-dialkyl-substituted amides can be prepared from the acid chlorides by reaction with the correspondingly substituted amines and ammonia. These amides are then reduced with lithium aluminum hydride to the corresponding amino, N-alkylamino, and NjN-dialkylaminomethyltricycloundecanes.

The oi ~ alkyl-3-tricyclo / 4 ", 3,1,1 '_7undecanme thy! Amine be by reduction of tricyclo ^ / ?, 3,1,1 '_7mdeoyl- (3) -alkylketone oximes made with lithium aluminum hydride. The ketones from which these oximes are derived become useful by reacting the corresponding dialkylcadmium with

- 7 209815/1743

BATH ORIGINAL

p- ^r i'ricyclo / 4,3,1, i ^ 'jftmdecylchloride produced.

The ot, * - Mallsyl-3-trioyclo ^? ! 1 ^J _7uMecanmethanol dialkyl-3-tr icy el 0 ^, 3.1, manufactured - _f 3f 1, i'j ^ undecanme thy amine by reacting acetonitrile and sulfuric acid (Ritter reaction) to the corresponding * "' , whereby the N-acetyl-Xja-dialkyl-S-tricyclo / ^^ i, 1 'JTundecanmethylajnin is obtained. The amine is obtained by alkaline hydrolysis. The starting alcohols for these reactions are prepared by reacting 3-Iricyclo / 4,3,1,1 'J ^ undeaylchlorid with alkyl G-rignard reagents.

A wide variety of amines can be used for the preparation of 1-adanantanearboxamides and 3-iricyclo- / 4,3,1, 1 ^{; >>} ^ 7 ^and 6cancar'boxamiden, with a wide variety of substituent groups on the nitrogen of 1- (aminomethyl) adamantane uii: l 3- (aminomethyl) tricyclo / 4,3,1,1 '_7undecane can be obtained. For example, reactions of the acid chlorides with allylamine and diallylamine give the 2! -Allyyl- and 17,11-diallyl compounds after reduction. By reacting the acid chlorides with propargylamine and dipropargylamine, Ή-propargyl and IT, H-dipropargy compounds are obtained after reduction. Conversions with cyclopropylamine, cyclopropylmethylamine and pyrrolidone give the N-cyclopropyl, IT-cyclopropylmethyl and pyrrolidino compounds after reduction. By reaction with alkoxyalky! Amines, the ii-iilkoxyalky! Compounds are obtained after reduction. Certainly, corresponding ϊί, Ιί-disubstituted amino compounds are obtained by reacting the acid chlorides with amines which contain various li-substituents. The reaction of the acid chlorides with IT-allyl-II-i: Jcthylai.iiii gives, for example, 1 - (IT-allyl-N-methylaminomethyl) adar, iantane and 3- (3 ^ -AlIyI-Iimethylaminomethyl) tricyclo / 4,3,1 , 1 ^

Lini -if: substituted alkyl! Amino compounds can be broken down to Β.τ: ο.οτοι. \ /c.-e easier to manufacture. Hydroxy-ethyl- and bishydroxy · ^:: - "; Γ / '7'-ΓΊ) 1η ·:; ιη-' .- ':.: \' ^ Vi <· ΐι 'lurch Ums ο t t; n-jr . Ληίη. "-; nit J'th ^Γ; · -; .'- '-'''- Y .Ootollt. ^r . ^r - '"! .'- 0'"l.'ril! -: o-: yifiethylrijriiiiov. '' rhinn-iii on wcr'i

2 0 9 B 1 B / 1 7 4 3

8AD ORKSlNAt

produced by alkylation with alkyl chloroacetate and a base. Aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl compounds are produced by alkylation with appropriate aminoalkyl halides and a base, however they can also be replaced by treating the corresponding hydroxyalkyl compound with a thionyl halide the hydroxyl group by a halogen and subsequent replacement of the halogen by the amino, alkylamino or Dialkylamino group can be prepared by reaction with ammonia or a primary or secondary amine.

"In some cases, N-alkyl and IT, N-dialky! Compounds can be used easily by alkylation of 3- (aminomethyl) tricyclo / 4,3,1,1 '^ undecane with alkylating agents (e.g. Alky! Halides) produce without having to reduce takes refuge from N-alkyl and N, N-dialky! amides.

When the reagents are used in molar amounts, the monoalkylamino compound will generally be the major product formed while with larger amounts of the reagents the dialkylamino compound is obtained. This method is not as elegant as amide reduction, which is why it is less so is preferred. However, in some cases it is chosen because it has fewer stages.

To alkylate the amino nitrogen to achieve the Hydroxyethyl and alkoxyalkyl substitutions, ethylene chlorohydrin and bromohydrin and alkoxyalkyl halides can be used will. For the reasons just mentioned, these reactions are less preferred than other methods, but can they may be more beneficial in certain cases, and they illustrate an alternative method of making substituted alkylaminomethyltricyclo / ?, 3,1,1 '_ / undecanes and adamantanes by ordinary alkylation with a substituted alkylating agent.

2 0 9 8 1 R / 1 7 4
BAOORiGiNAl.

By. Implementation of "! - (Aminome thyl) adamantane and 3- (Aminome thy 1) tr icy el 0 ^ / 4.3» 1 »1 * Jvoideoan with aldehydes gives the corresponding alkylidene, arylidene or heterocyclicylidenaminomethyladamantanes and aminomethyltricycloundecanes . For example, the reaction of 1 ~ (aminomethyl) adamantane with formaldehyde N- (I-adamantylmethyl) -azomethin. reaction of 3- (aminomethyl) tricyclo / 4 * »3>1" 1 * & 7wn.ä.eG n Benzaldehyde is obtained 3- (benzylideneaminomethyl) tricyclo / 4 _s 3,1,1 * -7undecane.

The reaction of 1- (aminomethyl) adamantane or 3- (aminomethyl) tric3icLo ^ i, 3, 1 _f 1 'J7 ~ wn.d.eos.n or the corresponding I-Cl-alkjriaminomethyl) compounds with butyl formate gives the pormamido compounds.

Representative of the compounds prepared according to the invention are the following compounds and theirs Salts:

i-CiT-Cyclopropylaminomethyljadamantane 1- (N, IT-di-cyclopropylaminomethyl) adamantane 1- (N-cyclobutylaminomethyl) adamantane 1 ~ (IT, l ~ dicyclobutylaminomethyl) adamantane 1- (iT-Cyclopropylmethyl-laminomethyl) adamantane 1 ~ (N-Cyclopropylmethyl-N-methylaminomethyl) adamantane 1- (N-oyclobutylmethylaminomethyl) adamantane 1- (H-methyl-N-vinylaminomethyl) adamantane 1- (N-Alylaminomethyl) adamantane

1- (N-allyl-N-methylaminomethyl) adamantane 1- (N, IT-Di-ally laminomethyl) adamantane 1- / N- (Hexen-3-yl) aminomethyl ^ adamantane i-CN-ethynyl-N-methylaminomethyl) adamantane 1- (N-propargylaminomethyl) adamantane

1- (1!, N-Di-prο pargylaminomethyl) adamantane 1- (N-hydroxymethylaminomethyl) adamantane 1- (N-methoxymethylaminomethyl) adamantane 1- (N-ethoxymethylaminomethyl) adamantane

{ 2 ~ 14ethoxyethyl) aminomethyl7adamantane . _Q

209815 / 17A3

: \ .. =.-.- ,. SADORIOINAL.

1 -ß $ - ( 2 ~ hydroxyethyl) aminomethyl / adamantane 1 - £ Έ - (2-hydroxyethyl) -N-methylaminomethyl / adamantane 1 - / Έ , N-di- (2 ~ hydroxyethyl) aminomethyl / adamantane 1- (H. -Aminoraethylaminomethyl) adamantan i-ClJ-Aminomethyl-lI-methylaminomethylJadamantan 1- / f- (Methylaminomethyl) aminomethyl / adamantan 1 - / Sf- (Butylaminomethyl) aminomethyl / adamantan 1 - ^ f- (Is obu ty laminome thy 1) aminome thy l / adamantan 1 ~ / Έ- ( sec, -Butylaminomethyl) aminomethyl / adamantan 1 - / ß- ( tert-butylaminomethyl) aminomethyl / adamantan k 1 - / ß- ( dimethylaminomethyl) aminomethyl / adamantan - ^ N- (Ii '-Butyl-N' -me thylaminome thyl) aminome thy l / adamantan - ^ f- (DiTDU ty laminome thyl) aminome thy l7adaman tan - / ff- (Diis obutylaminome thyl) aminomethyl / adamantan -g- ^ Si- (1 -methylpentyl) aminomethyl7 ^a minomethyladamantane

(Di-tert-butylaminomethyl) aminomethyl / adamantane - (6-Hydroxyhexy1) aminomethyl7adamantane 1 - </ N- (3-Hydr oxyhexy 1) aminomethyl / adamantane 1- ^ f- (6-methoxyhexyl) aminomethyl / adamantane 1- / N- (3-methoxyhexyl) aminomethyl / adamantan 1 - / Έ- (6-ethoxyhexyl) aminomethyl / adamantan 1- ^ H- (3-ethoxy-2-methylpentyl) aminomethyl / adamantan 1 - / ϊί- (2-aminoethyl) aminomethyl / adamantane 1- ^ f- (2-methylaminoethyl) aminomethyl / adamantane

- (3-dimethylaminopropyl) aminomethyl / adamantane - ( 2-dimethylaminoethyl) -N-methylaminomethyl / adamantane - (6-aminohexyl) aminomethyl / adamantane ~ ( 1-amino-1-ethyltmtyl) aminomethyl / adamantane - (6-methylaminohexyl) aminomethyl / adamantan 1 - / ß- ( 4-butylaminohexy 1) aminomethyl / adamantan 1 - ^ - (6-iso "butylaminohexyl) aminomethyl / adamantan 1 -Ή - /] ο- ( 1-methylpentyl) aminohexyl / aminomethyladamantane 1 - ^ fJf - (6-Tert.Butylaminohexyl) aminomethyl / adamantane 1 - £ ß , N-di- (2-diethylaminoethyl) aminomethyl / adamantane 1 - / $ - ( 6-dimethylaminohexyl) aminomethyl / adamantane 1 - / ß- ( 3- Dimethylaminohexyl) aminomethyl / adamantane 1 - / ß- ( 6-dibutylaminohexyl) aminomethyl / adamantane 1- / f- (6-diisobutylaminohexyl) aminomethyl7adamantane

_ 11 _

209815/174 3

1 - ^ ü- (6 -M-ter t. -Butylaminohexyl) 8 minomethyl / adamantan 1 - (IT-chloraminomethyl) adamantan 1- (li-Ohlor-N-methylaminomethyl) adamantan i- (F-chloro-lI -hexylaminomethyl) adamantan 1- (li-bromoaminomethyl) adamantan 1- (Ii-Br om-N-me thy laminomethyl) adamantan 1 ~ (> i-bromo-N-hexylaminomethyl) adamantan 1 ~ (lOrmamidomethyl) adamantan 1- ( H-ethylformamidomethyl) adamantane 1 - (N-hexylformamidoinethyl) adamantane N- (1 -adamantylmethyl) glycine lJ- (1 -adamantylmethyl) sarcosine E- (1-adamantylmethyl) -N-hexylglyc in l- (1- Adamantylmethyl) sarcosine, methyl ester i ;-( 1 -Adamantylmethyl) -N-hexylglycine, methyl ester Ή- { 1-adamantylmethyl) glycine, ethyl ester N- (1-adamantylmethyl) sarcosine, ethyl ester U- (1-adamantylmethyl) - N-hexylglycine, ethyl ester 1- (3enzylidenaminomethyl) adamantan 1- (ethylideneaminomethyl) adamantan 1- (isohexylidenaminomethyl) adamantan i- (naphthylidenaminomethyl) adamantan 1- (l? Urf-urylidenmethyl) adamantanyl tT- (1 -Adamantylmethyl) azetidine II- (1-Ada mantylmethyl) pyrrolidine H- (1-Ädamantylmethyl) piperidine li- (1 -Adamanty lmethyl) hexamethyleneimine 3- (aminomethyl) tricyclo / ?, 3,1,1 * ^ 7 ^un deean? - (lT-methylaninomethyl) tricyclo ^ ?, 3,1,1 '_7undecane 3- (1 · 1, N-13imethylamethylaminomethyl) tricyclo / 4,3,1,1,1' 7undecane 3- (iT-ethyl-1 _{-methylaminomethyl) tricyclo / 4,3,1 s 1} '_7undecan 3- (K, W-Uiäthylaminomethyl) tricyclo ^ / 4,3, 1, 1 "®7undecan 3- (KI ^J ropylarnino: iexhyl) tricyclo / 4, 3,1, 1'_7" undecan 3- ( N-Methyl-N-propy laminome thyl) tr icyclo, / ^, 3,1,1 '' 7 ^im decan () ^ 4, 3,1,1 ^J ' ^t ' 7

2 0 9 8 1 B / 1 7 U 3

BATH ORIGINAL

3- (N, N-Misopropylaminomethyl) tricyclo / 4 ", 3,1,1'7undecane 3- (N-sec-Butylaminomethyl) tricyclo / 4,3,1,1 '_7undecane

^ ς ο ""

3- (N-Isobutylaminomethyljtricyclo / ?, 3,1, 1 'tunde ⁰⁸ · ¹¹ 3- (N-tert-Butylaminomethyl) tricyclo / 4,3,1,1' J ^ indecane 3- (N-hexylaminomethyl) tricyclo / i, 3,1,1'vundecane 3- (N-isoamylaminomethyl) tricycle- / ?, 3,1,1 'tundecane 5- (IST-1-methylpentylaminomethyl) tricyclo / ?, 3,1,1- 7undecane 3 - (N-1,1-Dimethylbutylaminomethyl) tricyolo / ?, 3,1,1 '7undecane 3- (N, N-Dihexylaminomethyl) tricyclo / ?, 3,1,1' JTundecane 3- (N, U-Diisohexylaminomethyl) tricyclo / i, 3,1,1 ⁵ '®7unäecan 3- £ f, N-di- (1-methylpentyl) aminomethyl7tricyclo _< / i, 3,1,1' J ^ undecane

"3- ^ U, U-Di- (I, 1-dimethylbutyl) aminomethyl7tricyclo _< / ?, 3,1, 1 ^5> ^ 7-

■ undecan

3- (N-Oyolopropylaminomethyl) tricyclo / ?, 3,1, 1 '^ undecane 3- (N, IT-Di-cyclopropylaminomethyl) tricyclo _< / ?, 3,1,1' ^ undecane 3- (lT-OycloT-Dutylaininomethyl) tricyclo /? , 3,1,1 'J ^ undeoan. 3- (N, N-Di-cyclobutylaminomethyl) tricyclo / ί, 3,1,1'Vundecane 3- (N-Cyclopropylmetliylaminomethyl) tricyclo / 4,3,1,1'-7undecane 3- (N-Cyclopropylmetliyl-N -methylaminomethyl) tricyclo ^, 3,1,1 J- undecane

■ ζ ο

3- (N-cyclobutylmethylaminomethyl) tricyclo / ?, 3.1, 1 / undecane 3- (N-Met] ayl-N-vinylaniinomethyl) tricyclo / ?, 3.1, 1 * _7undecane 3- (N-allylaminomethyl) trcyclo / ?, 3,1, 1 ^ '^ νκιάβο & η | l 3- (N-Allyl-N-methyiaminomethyl) tricyclo / i, 3,1,1'

3- (N, N-Di-allylaminomethyl) tricyclo / ?, 3,1,1 ^{5> 8} 7 3- / 5f (hexen-3-yl) aminoinethyl7trioyclo / 4,3,1, 1 ^f -7 3- (N - ⁱ -Ätliinyl-li-methylaminomethyl) tricyGlo ^? _> 3,1,1 * '^ Jxuid.eo & n 3- (N-Pr opargylaminome thy l) tr icy clo / i ^, 1,1' Viindecan 3- (N, N-Di-propargylaminomethyl) tricyclo ^ i, 3 , 1,1 * _7undecane 3- (N-hydroxymethylaminomethyl) tricyclo / 4 »3,1,1 * 7undecane 3- (N-methoxymethylaminomethyl) tricyclo / i _f 3,1,1 ^ '_ yundecane 3- (N-ethoxymethylaminomethyl) tricyclo / ?, 3,1,1 '^ and © ⁰⁰¹¹ 3- £ f- (2-methoxyethyl) aminomethyl7tricyclo _</ ?, 3,1,1 ⁵ »^ undecane 3 / N' - (2-hydroxyethyl) aminomethyl7tricyclo ^ ?, 3,1, 1 ⁵ 'yundecane 3- / N- (2-hydroxyethyl) -N-raethylaminomethyl7tricyclo ^ ?, 3, ⁵ tindecane

3- / i?, N-di (2-hydroxyethyl) aminomethyl7tricyclo / ?, 3, 1,1 ³ »^ 7-undecane

209815/1743 -13-

8AD ORiGJNAL

3- (N-Aminome.thylaminomethyl) tricycle ^ / ?, 3,1,1 * __7irndecane 3- (li-Aniinoinethyl-li-inethylainInomethyl) tricyclo ^ 4 | 3,1,1 * ^ J ⁷ -undecane 3- ^ T- (Metliylaminomethyl) aminomethyl7trioyclo ^ ?, 3,1, 1 ³ '^ 7-undecane 3- / 5- (Butylaminomethyljaminomethy ^ tricyclo ^ ?, 3,1, 1 ³ '^ 7-undecane 3- ^ f- (IsobutylaminometliylJaminometliy ^ triGyclo / ?, 3,1,1 ^f _7 "" undecane 3- _< / I- (sec. -Butylaminomethyl) aminomethyl7tricyclo ^ 4,3 _f 1 »1 'imdecan

3- / ß- { tert. -Butylaminometh.yl) aminomethyl7tricyolo ~ ³ f

Z »,, f7 3 - ^ / f- (Dimethylaminomethyljaminomethyl / tricyclo ^ i, 3» 1 »1- * _7-undecane

3 - ^ - (H '-Butyl-U' -methylaminomethyljarainomethy ^ tricyclo- ³ ^

Z »,, ^ 7 3 - ^ - Dibutylaminomethyl) aminomethyl7tr ieyclo ^ 4 ~, 3,1,1 * _7-undecane.

3- ^ lf-diisole (butylaminomethyl) aminoiiiethyl7tricyclo / 4,3,1,1 '7 ~ ttndecane (1 ~ methylpentyl) aminomethyl7aminomethyltricyclo-

3 ~ ^ S ^! - (Di ~ tert .- 'b'utylamirLomethyl) ainomethyl7tricyclo- ³ f

^ ,,, f7

3- ^ fj- (6-Hydroxyhexyl) am4nomethyl7tricyclo ^ 4,3,1, 1 'tundecane 3- _< / ^ - (3-Hydroxyhexyl) aminomethyl7tricyolo ^ / ?, 3,1,1' 7undecane 3 - / ^ - ( 6-methoxyhexyl) aminomethyl7tricyolo / ?, 3,1,1 · J ^ undecane 3- £ ß- { 3-methoxyhexyl) aminomethyl7tricydo / i, 3 »1,1'7tuidecaii 3 - ^ - (6-lthoxyhexyl) aminometh £ l7trioyclo ^ 4 ", 3,1,1 '_ / undecane 3- / f- (3-ethoxy-2-methylpentyl) aminomethyl7tricyclo- ³ f

- / f? - (2-aminoethyl) aininomethyl7tricyclo / ?, 3,1,1 * __7undecane 3 - ^ - (2-methylaminoethyl) arainomethyl7tricyclo ^ ?, 3,1,1 ³ » ^ undecane

- 14,

209815/1743

3- / ß- { 3-Mmethylaminopropyl) aminomethyl7tricyolo _< / 4 *, 3,1,1 ⁵ »^ ⁷ -undeean

3- / ß ~ ( 2-dimethylaminoethyl) -IT-methylaminomethyl / trioyclo- ³ ^

~ Ζ ^ - (6-aminohexyl) aminomethy l / tricyelo / i, 3,1,1 ^ '_ yundecan 3- ^ T- (1 -amino-1 -ä thy lbu ty 1) aminomethy l7tr icy clo / ?, 3 , 1,1 ^{3 1} ^ J- undeoan 3- / f- (6-methylaminohexyl) aminomethyl7trioyolo / ?, 3,1,1 ³ '^ 7-undecane 3- / f- (4-butylaminofaexyl) aminomethyl7tricyclo / ?, 3 , 1,1 ^{5 f} ^ 7 ~ undecane 3- / S ^! - (6-Isobutylaminohexyl) aminomethyl7tricyolo / ?, 3,1,1 * J- undecane

3-N - ^ - (1-methylpentyljaminohexy ^ aminomethyltrioyolo- ⁵ ®

3- / N- (6-Tert .Butylaminohexyljaminomethy ^ trioyolo- / ?, 3,1,1 J ⁷ undecane 3- / f, II-Di- (2-diethylaminoethyl) aminomethyl7trioyclo-

/ 4,3,1,1 ⁵ * f7imdecane

3- / f- (6-Dimethylaminohexyl) aminomethyl7tricyclo / 4,3,1,1 '^ 7 ~ undecane 3- / f- (3-Dimethylaminohexyl) aminomethyl7trioyolo / ?, 3,1,1 undecane 3- / H- ( 6-ditutylaminohexyl) aminomethyl7tricyclo ^, 3,1, i ^ undeoane 3_ ^ f- (6 -diisobutylaminohexyl) aminomethyl l7tricyclo- / 4 ", 3,1,1 ⁵ 'undeoane

. - "butylaminohexyl) aminomethy l7trioyolo-

3- (N-chloraminomethyl) tricyclo / 4 ", 3.1, 1 ^ ^ / 3- (N-chloro-N-methylaminomethyl) trioyclo / 4", 3.1, 1 * _7undecane 3- (li-chloro -li-hexylaminomethyl) tricyclo _< / 4,3,1,1 * ^ υηο.βα & Ώ. 3- (N-bromoaminomethyl) trioyclo / ?, 3,1,1 '_ / undeoan 3- (N-bromo-N-methylaminomethyl) tricyolo /? _r 3,1,1 '~ 7undecane 3- (N-bromo-N-hexylaminomethyl) tricyolo / 4,3,1 , Ϊ' y 3- (lOrmamidomethyl) tricyclo / ?, 3,1,1 * 7 ^{un (} i ^eoan 3- (N-methylformamidomethyl) tricyclo / ?, 3,1,1 '3- (N-hexylformamidomethyl) tricyclo / ?, 3 _l 1 _f ^

209615/1743

• 7 O

N- (3-Tricyclo / 4,3,1,1 'Jvinu.ecylm.ei; hjl) gljc ± n N- (3-Tricyclo ^ 4 ", 3,1,1' Vund-ecylmethyl) sarcosine

II- (3-Tricy clo / 4,3,1, 1 ⁵ '"tundecylmethyl) -N-hexylglycine

¹ Z TT

H- (3-Tricyclo / 4 *, 3,1, i ^ 'Vundecylmethyl) sarcosine, methyl ester

■ ζ tr

l \ f- (3-Q} ricyclo / 4,3,1, 1 '7 ^ ^{n (} ä ^ec yl ^IIie ' thyl) ~ ^ "" ^ ^iex ylsly ^c: i- ⁿ i methyl ester

• χ ο

N- (3-Tricyclo / 4,3,1,1 'V'undecy! Methyl) glycine, ethyl ester N- (3-Tricyclo / 4,3,1, 1' V ^^^ ei ^ y ^1111613 ^!) sarcosine, ethyl ester ίϊ- (3-Tricyclo ^ ?, 3,1,1 '_7'undecylmethyl) -N-hexylglycine, iithyl ester

3- (Benzylidenaminomethyl) tricyclo ^ i, 3,1,1 '__7undecane 3- (Ethylidenaminomethyl) tricyclo / ?, 3,1,1' JTundecane 3- (l-schexylidenaminomethyl) tricyclo / 4,3,1, 1- ^ '7 ' ⁱ mdecan 3- (l · Iaphthylidenaminomethyl) tricyclo ^ 4 ", 3,1, 1' 7 ^ ¹¹ * ³ - ⁶⁰⁰¹¹ 3- (Furfurylidenaminomethyl) tricyclo ^ 4", 311, 1 '_7undecan li ~ (3-Tricyclo / 4,3,1,1'7un <iecylBiethyl) aziridine N- (3-TricycloA, 3,1,1'Vundecylmethyl) azetidine IT- (3-tricyclo / 4,3,1,1 'V ^ naecylmethyl) pyrrolidine N- (3-Tricyclo / ?, 3,1, 1 '7' ^{un (} i ^eG yl ^me 't ⁿ yl) piP ^{e: r} ic'-i ⁿ N- (3-Tricyclo / 4,3,1, 1 ' ⁸ 7 ^and e.ecylmethyl) hexamethyleneimine

In the following examples, the quantities given are based on weight, unless otherwise stated.

example 1

A solution of 5.8 parts of 3-carboxytricyclo </ 4,3,1, 1 '_7 ~ undecane in 10 parts of thionyl chloride is refluxed until the evolution of hydrogen chloride ceases. The crude acid halide produced in this way is isolated by distilling off the excess thionyl chloride under reduced pressure, adding a small amount of benzene and removing this under reduced pressure. The acid chloride is then dissolved in 200 parts of ether, whereupon excess dry methylamine is added to the stirred

, ;; is conducted at 0 °. The reaction mixture is then

20981 B / 1 Ί U%

BAD ORtGWAL

Stirred for 30 minutes and diluted with water. The layers are separated. The ether layer is washed with water and dried over calcium chloride. After removing the solvent Bmid be 3.7 parts N-Methyltricyclo- / 5,3,1, 1'_7undecyl ~ 3 car'box! Of melting point 133 ⁰ C in the form of white flakes.

A solution of this amide in 150 parts of tetrahydrofuran becomes a suspension of 2 parts of LiAlH. given in 100 parts of diethyl ether. After the addition has taken place, the mixture is heated under the reflux condenser for one hour and the solvent is distilled off. After slowly adding water to the dry residue, the mixture is refluxed for 10 minutes and filtered. Both the cooled filtrate and the solid filter cake are carefully extracted with ether. The ether solution is dried with sodium hydroxide and excess dry hydrogen chloride is passed into the solution. The amine hydrochloride which precipitates is isolated by filtration and recrystallized from methanol-ethyl acetate. 3- (N-Methy laminomethyl) tricyclo ^, 3,1,1 ⁵ ^ undecane HCl of melting point 338 ⁰ C is obtained in a yield of 2.1 parts.

Example 2

A sample of 3-carboxamidotricyclo _< / i, 3,1,1 '_yundecane is prepared by using the 3-carboxytricyclo / £, 3,1,1_7-undecane from Stetter (Ber. 92, 1629-1635 (1959)) is converted to the acid amide by treatment with thionyl chloride and subsequent treatment of the crude acid chloride with ammonia. The amide 181 ⁰ C. (9.75 parts) is added as a solution in tetrahydrofuran to a suspension of 3 parts of lithium aluminum hydride in 100 parts of ether - After TJmkristallisation from acetone 'the amide melts at 180th The mixture is refluxed for one hour. After removing the organic solvent, the residue is heated with V / ater for 10 minutes on the reflux condenser to the

209815/1743

! Facilitate filtration, and filtered. Both the filtrate and the solid are carefully extracted with ether. The combined extracts are dried with sodium hydroxide, whereupon hydrogen chloride is passed into the solution. 6.5 parts of 3- (aminomethyl) tricyclo ^ 4 ", 3.1.1 * -7undecane hydrochloride with a melting point of 352-352.5 ⁰ O are obtained as the product.

Example 3

A solution of 19.85 g (0.10 mol) of 1-adamantoyl chloride in 100 cm of dry diethyl ether is ^{stirred at 0} ° C. and a solution of 12.7 g (0.15 mol) of piperidine in ether is slowly added. The mixture is stirred for 30 minutes at room temperature and evaporated to dryness. The solid residue is triturated with water and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and the ether is removed. 1-Adamantoylpiperidide remains as the residue. A solution of 0.10 mol of 1-adamantoylpiperidide in 100 cm of ether is slowly added, with thorough stirring, to a suspension of 4.5 g of lithium aluminum hydride in 300 cm of ether. After the addition, the reaction mixture is refluxed for one hour and the solvent is removed. The residue is then heated for 10 minutes with 250 cm of water in a reflux condenser, cooled and filtered, whereupon the filtrate and the pesticide are carefully extracted with ether. The combined extracts are dried with potassium hydroxide, whereupon hydrogen chloride is passed into the solution. The precipitate is filtered and dried to give N- (1-adamantylmethyl) piperidine hydrochloride.

Example 4

The working instructions given below for the adamantane compound are carried out using 21.3 g of 34-tricyclo / 4 ", 3» 1.1 * _7 undecoyl chloride instead of 19.8 g

209815/1743 -18-

1-adamantoyl chloride, with tricyclo ^ 4 ~, 3,1,1 * ⁸ 7 ~ undecyl- (3) methyl ketone, then tricyclo ^ i, 3,1,1 ^{5 |} ^ 7undecyl- (3) -methylketone oxime and after reduction a-methyl-3-tricyclo ^ 4 ", 3.1, undecanemethylamine hydrochloride is obtained.

A mixture of 3.6 g of magnesium turnings, a small crystal of iodine, 11 cnr of anhydrous benzene and 1 cc of absolute ethanol is heated until a reaction begins. Then the heating is stopped and a mixture of 24.0 g aue Dläthylmolaisfc, 7.0 g of absolute ethanol and 30 cm of benzene was added dropwise at such a rate that Rüok- w flow of the reaction mixture is effected. When the addition is complete, the mixture is refluxed until the magnesium is dissolved. The excess ethanol is removed by azeotropic distillation with part of the benzene.

To the solution of ethoxymagnesium diethyl malonate obtained

3, a solution of 19.8 g of 1-adamantoyl chloride in 30 cm of anhydrous benzene is added dropwise over 50 minutes. The reaction mixture is refluxed for a further hour and then cooled in an ice bath. 50 g of ice and then enough 10% sulfuric acid are added to the cold mixture to form two clear layers. The layers are separated. The aqueous layer is extracted twice with 25 cm of benzene each time. The extracts f 3

are combined with the organic layer, washed with 30 cm of water and dried with anhydrous sodium sulfate. The benzene is removed by concentration under reduced pressure at 4O ⁰ C. After adding a solution of 64 cnr glacial acetic acid, 39 cnr water and 7 cnr concentrated sulfuric acid to the residue (32 g) the mixture is refluxed for 7 hours. It is then cooled and ^{poured into 350 cm 5 of} water. The solid which separates out is filtered and dried and then recrystallized from a methanol-water mixture, 13.4 g of white, crystalline adamantyl- (1) -methyl acetate having a melting point of 53.5-55 ° C. being obtained.

2098 15/1743
- «AD

A mixture of 14 g of hydroxylamine hydrochloride, 65 cm

• 7.

Anhydrous pyridine and 65 cm of anhydrous ethanol are heated on the steam bath "until a clear solution has formed. 13" 4 g of adamantyl (1) methyl ketone are added to this solution. The mixture is refluxed for 2 hours and heated then cooled. This introduces under reduced pressure at 7O ⁰ C to dryness

"■? T * l

steams. The residue is suspended in 150 cm of water and well stirred. The pesticide is filtered and dried, with 14.2 g of adamantyl (1) methyl ketone oxime as white, crystalline compound with a melting point of 180.5 132 C is obtained. The compound can be obtained from a dioxane-water mixture without influencing the melting point be recrystallized.

8.3 δ Adamantyl (1) methyl ketone oxime are added to a mixture of 3.3 g of lithium aluminum hydride in 150 cm of anhydrous tetrahydrofuran. The mixture is stirred and refluxed for 3 hours. After cooling in an ice bath, the excess lithium aluminum hydride is destroyed with a water-tetrahydrofuran mixture. A few cm of a 10bigen sodium hydroxide solution is added to accelerate the coagulation of the pesticides. The contaminants are filtered off, washed with 50 cnr chloroform and discarded. The piltrate, which comprises the tetrahydrofuran solution and the chloroform solution, is saturated with dry hydrogen chloride and then evaporated to dryness ^{at 50 ° C. under reduced pressure.} The residue is placed in a separating funnel and shaken with a mixture of 100 cnr 10big sodium hydroxide and 300 cm iither. The aqueous layer is discarded and the ether solution is dried over potassium hydroxide granules. Dry hydrogen chloride is passed into the ethereal solution until it is completely precipitated. The amine hydrochloride which forms is filtered off and dried. This crude salt is dissolved in water, treated with an excess of 50% sodium hydroxide solution, whereupon the

209815/1743

BATH

free amine is extracted with ether o The ether extract is dried over potassium hydroxide granules, whereupon hydrogen chloride is passed in until it is completely precipitated. The precipitate is filtered off and dried, 5.6 g of white, crystalline oC-methyl-1-adamantanemethylamine hydrochloride with a melting point of 575-575 ⁰ (closed tube) being obtained.

Analysis:

Calculated for found:

66 , 82 10 , 20 6th , 49 66 , 52 10 , 15 6th , 58

Example 5

The working procedure given below for the adamantane compound is carried out using 55.7 g of 5-tricyclo · / 4 ", 5» 1, 1, 1 'J ^ undec ° yl chloride instead of 51.5 g of 1-adamantoyl chloride, where c (, Q (-Dimethyl-5-tricyclo- / ϊ »5,1,1 '~ 7undecanmetfaanol, then N-acetyl-ftjOi-dimethyl-5-tricyclo / 4", 5,1,1'J ^ undecanmethylamine and after hydrolysis CC, Ä-Dimethyl-5-tricyclo / ?, 5,1,1 * ° 7 ' ^tmdecanme ' ^tii y ^laminli y ^d - ^ro ~ chloride is obtained.

5 150 cm of commercially available 5 molar methyl magnesium bromide are added dropwise under nitrogen to a solution of 51.5 g of 1-admantoyl chloride in 500 cnr of anhydrous ether at such a rate that a gentle reflux is maintained. After the addition, the reaction mixture is heated for one hour and then cooled. The metal complex is decomposed by adding 500 cnr of saturated ammonium chloride. The ether layer is separated off and the aqueous layer is extracted with 100 ml of chloroform. This extract is combined with the ethereal layer. The mixture is dried with anhydrous magnesium sulfate and evaporated to dryness ^{at 55 ° C. under reduced pressure.} The residue is the water vapor

209815/1743

ORIGINAL

subjected to distillation until the distillate is no longer milky. About 3 liters of distillate are collected here. Upon cooling the steam distillate crystallized, and the solid is filtered and dried to give 26.9 g of Λ, οί-dimethyl-I -adamantanmethanol are obtained of melting point 77-80 ⁰ C.

35 cm of concentrated sulfuric acid is added dropwise to 160 cm of acetonitrile, cooling so that the temperature remains below 10 ° C. Then 21 g * Χ, λ-dimethyl-1-adamantanemethanol are added. The temperature is increased to 48 ^° C. and kept at this value for 45 minutes. After the reaction mixture has cooled to room temperature, it is slowly poured into 1000 cm of ice water. The solids which separate out are filtered off and dried to give 24.2 g of crude product. This is taken up in 500 cm of ether, whereupon dry hydrogen chloride is passed into the ethereal solution until no further precipitation takes place. The solids are filtered, dried and placed in a separatory funnel containing 200 centimeters of water and 500 cubic centimeters of ether. The mixture is shaken until the solids dissolve. The aqueous layer is separated and discarded. The ether solution is dried with anhydrous sodium sulfate and evaporated to dryness, white crystals of N-acetyl-OjoQ-dimethyl-i-admantanmethylamine being obtained.

A mixture of 2.0 g of N-acetyl-ov ^ -dimethyl-i-adamantanmethylamine, 10g potassium hydroxide and 40 cm methanol Heated at 225 ° C. in a sealed tube for 18 hours

■ 5

and then chilled. The content of the tube becomes 100 enr

Given water. The mixture is twice with 50 cm each Ether extracted. The extracts are combined, dried with potassium hydroxide granules, whereupon dry chlorine

- 22 209815/1743

The precipitate is filtered off and dried to give 1.8 g of crude salt. This is dissolved in 80 cnr of water and treated with excess 50% sodium hydroxide. The precipitated amine is filtered off and dried, melting point ., 103-105 ⁰ C. It is taken up in ether and precipitated with hydrogen chloride The hydrochloride · chloride is filtered off and dried, the melting point of oC, o ^ -dimethyl-1-adamantanmethylaminhydrochlorid is 340-345 C (sealed tube).

An alyse;

C. 1 H 45 6th H 0 67 , 98 1 O, 35 6th ,1 7th 67 , 75 O, ,1

Calculated for found:

Example 6

The working instructions given below for the adamantane compound is made using 4.5 g of F-acetyl <X, "- diemethyl-3-tricyclo ^ ?, 3,1,1 ^ J ^ undeoanmethylamine (manufactured carried out according to Example 5) instead of 4.1 g of N-acetyl- <x, oUdiemethyl-1-adamantanmethylamine, wherein li-ethyl-o (, (X-dimethyl-3-tricyclo- ^ ?, 3,1,1 '_ / and ecanm ethyl amine hydrochloride is obtained.

To a mixture of 1.5 g lithium aluminum hydride in 100 egg of the anhydrous dimethyl etherB of diethylene glycol 4.1 g of the l-acetyl-o ^ Cfc-dimethyl-1-ädamantanmethylamins prepared according to Example 13 given. The reaction mixture is refluxed and heated for 3 hours with stirring then chilled in an ice bath. By adding moist diethylene glycol (Dimethyl ether) becomes the excess lithium aluminum hydride decomposed. To coagulate the precipitate, a few cm 10 sodium hydroxide is added. The precipitation is then filtered off and washed with 50 cnr ether. That The filtrate is treated with dry hydrogen chloride until i.

209815/1743 _ 23 -

no further precipitation is formed. The precipitation will filtered off, dissolved in 100 cnr water and treated with excess sodium hydroxide. The mixture will extracted three times with 30 cm ether each time. The Athere Extracts are combined, dried with potassium hydroxide granules and until complete precipitation with hydrogen chloride treated «The precipitate is filtered off and dried, 3.2 g of N-ethyl-C ^ Or-diamthyl-i-adamantanmethylamine hydrochloride with a melting point of 276-279 ° C. (closed tube).

Analysis;

for C ₁₅ H ₂₈ Nc: C. 10 H 5 N Calculated , 91 11 , 87 5 , 44 Found: , 33 , 00 , 67 L: 69 69

Example 7

The working instructions given below for the adamantane compound are carried out using 21.3 g of 3-tricyclo- / 4! 3.1 1 ^ » ⁸ 7un-decoyl chloride instead of 19» 8 g 1-adamantoyl chloride carried out, with tricyclo / 4 *, 3,1,1 7undecyl (3) ethyl ketone oxime and after reduction <X -ethyl-3 -tricyclo / 4 ", 3,1,1 J- undecanemethylamine hydrochloride is obtained.

A solution of diethylenium in benzene is prepared by adding 19.6 g of powdered anhydrous cadmium chloride to 0.2 mol of ethyl magnesium bromide in 100 cnr of anhydrous ether within 5 minutes at ice bath temperature. The mixture is refluxed for 30 minutes with vigorous stirring. The ether is then removed by distillation on the steam bath, whereupon 65 cnr benzene is added to the almost dry, brown, pasty residue. The distillation is continued reaches 61 ⁰ C until the vapor temperature of the distillate. After adding a further 100 cm of benzene to the diethylcadmium solution, the

*) via the corresponding ketone - 24 -

209815/1743

BATH ORIGINAL

Solution brought to reflux temperature again When the heating is stopped, the mixture is vigorously stirred and a solution of 19 »8 g of 1-adamantoyl chloride is produced as quickly as possible added as it allows the exothermic reaction. The mixture is refluxed for a further 45 minutes with stirring heated. The reaction mixture is cooled in an ice bath and first with 200 g of water and ice and The benzene layer was then mixed with 150 cm of 20% sulfuric acid is separated off and the aqueous layer is extracted with 75 cur of benzene. The benzene solutions are ^ unite and dry with anhydrous sodium carbonate. The benzene is removed under reduced pressure at 50 °, leaving a liquid residue. This residue crystallizes on cooling and yields 21 pounds Adamantyl (1) ethyl ketone with a melting point of 30.5 - 32.5 ° C.

2 hours ethyl ketone, a mixture of 75 cm of anhydrous ethanol, 75 cm ³ of anhydrous pyridine, 16 g of hydroxylamine hydrochloride and 16.0 g of adamantyl (1) was heated under reflux and then evaporated under reduced pressure at 80 ⁰ C for half dryness. After adding 200 cubic centimeters of water, the mixture is again evaporated to semi-dryness. The residue is suspended in 300 cm V / water and the solid is filtered off. The melting point of this crude material is 175 - 177 ⁰ O. After recrystallization from a mixture of dioxane and acetonitrile, 10.3 g of white crystalline Ädamantyl- (1) äthylketonoxim of melting point 177 - 179 ⁰ C obtained.

7.7 g of adamantyl (1) ethyl ketone oxime are added to a mixture of 3.0 g of lithium aluminum hydride and 150 cm of anhydrous diethylene glycol dimethyl ether. The mixture is refluxed with stirring for 3 hours. It is cooled ^{to 10 °} C. with an ice bath. The excess lithium aluminum hydride is destroyed with moist diethylene glycol dimethyl ether. To coagulate the pesticide, 5 cm of 10biges sodium hydroxide is added.

2,098 15/1743
ßÄt) ORIGINAL

given. The solid is filtered off, washed with 50 cm of ether and discarded. The filtrate is saturated with dry hydrogen chloride and concentrated under reduced pressure until precipitation is complete. The concentrated piltrate is cooled and the solid is filtered off, washed with ether and dried. The dried salt is dissolved in 150 cubic centimeters of water. The solution is treated with excess 50% sodium hydroxide and extracted twice with 50 cm of ether each time. The ether extracts are combined, dried with potassium hydroxide granules and treated with dry hydrogen chloride until they are completely precipitated. The precipitate is filtered off and dried to give 5.2 g of white crystalline <.- * - ethyl-1-adamantanmethylaminhydrochlorid of melting point 278 - 282 ⁰ obtained C (sealed tube). "

Analysis:

Calculated for C ₁₃ H ₂ :

Example 8

When the experiment described in Example 3 is repeated, but using 0.10 mol of 3-tricyclo ^ 4% 3.1.1 'Tundeayl chloride (see Example 1) and 0.15 mol of N- (3-methoxypropyl) methylamine instead of 1-adamantoyl chloride and piperidine becomes 3 ~ / N * - (3-methoxypropyl) -N-methylaminomethyl / tricyclo ^? , 3,1,1 * __7undecane hydrochloride obtain.

Example 9

When using 0.15 mol of allylamine instead of the in Example 3 used 0.15 mole of piperidine becomes 1- (N-allylaminomethyl) adamantane hydrochloride obtain"

209815/1743

_Μί i ^, BADOFUGiNAL

C. 1 O H 6th N O 67 , 99 1 O , 45 6th ,1 4th 68 , 55 , 48 ,1

Example 10

When repeating that described in Example 3 " Experiment, but using 0.10 mol 3-tricyclo / ?, 3.1 »1 '_7undecoy! Chloride (see Example 1) and 0.15 moles of diallylamine instead of 1-admantoyl chloride and piperidine becomes 3- (N, N-M-allylaminomethyl) tricyclo ~ / 4 ", 3.1> 1 '_7undecane hydrochloride obtained.

Example 11

When 0.15 mol of PDopargylamine is used instead of 0.15 mol of piperidine in the experiment described in Example 3, 1 - (N ^- -Pr opargylaminomethyl) a damant anhydro chloride is obtained.

Example 12

When using 0.15 mole of cyclopropylmethylamine instead of 0.15 mol of piperidine in the experiment described in Example 3! - (N-Cyclopropylmethylaminomethyljadamantane hydrochloride obtain.

Example 13

When using 0.10 mol of 3-tricyclo / $, 3.1.1 ^ ^r ° 7undecoyl chloride (see Example 1) and 0.15 mol of oyclobutylamine instead of 1-adamantoyl chloride and piperidine in the experiment described in Example 3, 3- (N "-Cyclobutylaminomethyl) · tricyclo ^ / ^, 3,1, 1 '_7unde anhydrochloride obtained.

Example 14

In a 100 cm flask equipped with a magnetic stirrer and reflux condenser, 0.050 mol of 1- (aminomethyl) adamantane, 6.13 pounds (0.050 mol)

5.00 g (0.060 mo

209815/1743

ORIGINAL

Ethyl chloroacetate, 5, _00 g (0.06OMol) sodium bicarbonate and

B / 1

■ "ί

20 cm "of methanol is added. The insoluble material becomes filtered off and the filtrate evaporated to dryness. The residue is dissolved in 60 cm of 1N hydrochloric acid and mixed with 10 cur 70% strength perchloric acid. The precipitated one The perchlorate salt is filtered off, washed with cold water and dried. The free base will regenerated with 10big sodium hydroxide and removed distilled from unchanged starting material, the higher-boiling fraction is the ethyl ester of N- (1 -Adamantylmethy]) glycine.

Example 15

In one equipped with a magnetic stirrer and reflux condenser 100 cm "flasks become 0.050 moles of 1- (N-methylaminomethyl) adamantane (see Example 2), 0.050 mol of freshly prepared 2-diethylaminoethyl chloride (from 2-diethylaminoethyl chloride hydrochloride by neutralization and extraction with ether), 5.0 g (0.060 mol) sodium bicarbonate and given 20 cm of methanol. The mixture becomes overnight heated on reflux condenser and then in 50 cm cold water poured. The mixture is extracted with ether. The ether extract is dried with anhydrous magnesium sulfate and concentrated under reduced pressure, with 1- ^ fT-2-diethylaminoethyl) -IT-methylaminomethyl / adamantane obtained will c

Example 16

0.10 mol of 3- (aminomethyl) tricyclo- ^ i3 | 1, 1 ⁵ 'j7tind.ecan (see Example 2), 15, 4 g (0.10 mol) of freshly distilled benzaldehyde and 50 cm '' of toluene, -j-ef'eben. The Lonuru., \ .Ira >] <} hours aiii reflux condenser heated. The toluene is evaporated and the residue is unikristallirvi'sr-l, v: ol; ei Ji - (- l-'i'ricyclo / i, 2, 1, 1 "'* ^ 7 ^u r -``-" l- ß ^ iyl ^ enzaldimirj orii ^ lten v / ird.

2 0 9 8 1 5/1 7 A 3

ORIGINAL

Example 17

A solution of 0.5 mol of 1- (aminomethyl) adamantane in 120 cnr tetrahydrofuran and 30 cur water is placed in a 400 cm autoclave made of stainless steel, whereupon 5 »0 g (0.11 mol) ethylene oxide are blown into it. The autoclave is ^{kept at 70 °} C. for 24 hours and then cooled and carefully relaxed. The solvent is removed under reduced pressure and the residue extracted with ether. The ether extract is dried with anhydrous potassium carbonate. The solvent is removed under reduced pressure and the residue at 100 ° C / 20 mm Hg sublimated ν, unreacted 1 ~ (aminomethyl) to remove adamantan. The sublimation residue is distilled off under reduced pressure, 1- / ΙΪ- (2-hydroxy ethyl) aminome thy l / adamantan being obtained.

Example 18

A solution of 0.10 mol of 1- (aminomethyl) adamantane in 75 cm 98% formic acid is left to stand for 48 hours at room temperature. After removing the formic acid by evaporation under reduced pressure, 1_ (Formamidomethy1) adamantane remains as the residue.

This compound can also be prepared as follows: 0.05 mol of i- (aminomethyl) adamantane are ^{refluxed in 25 cm 5 of} butyl formate for 19 hours. The excess butyl formate is removed by evaporation under reduced pressure, the residue 1- (formamido-

tv> methyl) adamantane remains.

co

oo

Example 19

cn

A suspension of 0.1 mole 3- (aminomethyl) tricyclo- / 4 "> 3.1.1 * _7undecan in 100 cm ice water turns into a 500 cm flask fitted with a mechanical stirrer and thermometer. The flask is placed in an IJIsbad chilled. 142 g of 5.25% sodium hypochlorite solution; -

• V: ·

(Trade name "Chlorox") is running at such a rate admitted that the temperature does not exceed 10 C.

After the addition has taken place, the ice bath is removed and the mixture is stirred for 30 minutes. It is then extracted three times with 50 cm ether each time. The combined ether extracts are dried over calcium chloride. The solution is filtered and the solvent removed under reduced pressure to give 3- (1T-chloraminomethyl) tricyclo ^, 3 | 111 JJ- undecane.

Example 20

A mixture of 0.10 moles of 3- (N-methylaminomethyl) tricyclo - / ?, 3.1.1 '_7undecane and 0.05 mol of succinic acid in 100 cirr Water is concentrated at 60 ° C. under reduced pressure. The succinate obtained is at reduced pressure 60 0 dried.

When this example is repeated using 0.10 moles of 3- (aminomethyl) tricyclo ^ 4,3,111 ^ * f / tm-decane. and 0.10 mol of lactic acid gives the corresponding lactate.

In the above examples, equivalent amounts of other suitable starting materials can be used for the preparation further compounds falling under the invention, including those listed above, can be used.

The compounds prepared according to the invention can in antiviral treatment, administered in any way in which the active substance is similar to that of the viral infection infested area in the body. This of course includes the areas before the start of the infection as well as after. For example, the treatment can be parenteral,

209815/1743 " ³ ° ~

■;> ■■: ·.: ■. : BAD · ORIGINAL

i.e., subcutaneously, intravenously, intramuscularly, or intraperitoneally. As an alternative or at the same time, treatment can be used be done orally.

The dosage depends on the virus to be controlled, the age, health status and weight of the patient, the extent of the infection, the nature of any concurrent treatment, the frequency of treatment and the desired effect. In general, the daily dose is of active ingredient between about 1 and 50 mg / kg body weight, but lower amounts, for example 0.5 mg / kg, or higher amounts can also be used. Usually in amounts of 1-20 mg, preferably 1-10 mg / kg / day, the given all at once or over the day will give the desired results.

The active ingredient prepared according to the invention can be used in aromatic agents such as tablets, capsules, powders or liquid solutions, suspensions or elixirs for oral administration or in liquid solutions for parenteral use and in certain cases in suspensions for parenteral use (except intravenous). These preparations contain the active ingredient usually in an amount of at least 0.5 wt -. $> And at most 90 wt .- ^, based on the total weight of the preparation.

In addition to the active ingredient prepared according to the invention, the antiviral agent contains a solid or liquid, non-toxic pharmaceutical carrier or auxiliary agent for the Active ingredient.

In one embodiment of one made according to the invention In the drug, the solid carrier consists of a capsule, which can consist of ordinary gelatin. The capsule contains about 30-60% by weight of a compound made in accordance with the invention and 70-40% of a carrier fabric. In another embodiment, the active ingredient is

2098 15 / 17A3 - 31 -

Tableted with or without excipients. It is also possible to incorporate the active ingredient into a powder and as Powder to apply. These capsules, tablets, and powders usually make up about 5-95%, preferably 25-90% by weight the end. They preferably contain 5-500 mg of active ingredient, about 25-250 mg being particularly preferred.

Suitable pharmaceutical auxiliaries and carriers are sterile liquids such as water and oils obtained from petroleum or animal, vegetable or synthetic Are of origin, e.g. peanut oil, soybean oil, mineral oil, sesame oil and the like. and aqueous dextrose solutions (glucose) and like sugar solutions and glycols, such as propylene glycols or polyethylene glycols, are preferred as liquid carriers, in particular for injectable solutions. The sterile injectable solutions usually contain about $ 0.5 to $ 25, preferably 1 - 10 wt .- ^, of the active ingredient.

Oral administration can take place in suspensions or syrups, in which the active ingredient is usually about 0.5 to 10? Pounds, preferably 2-5% by weight. As a pharmaceutical Excipients in these forms can be aqueous carriers, e.g. aromatic water, syrups or pharmaceutical Slimes are used. Suitable pharmaceutical excipients are provided by E.W. Martin and E.P. Cook in "Remington's Practice of Pharmacy ". The following examples are given for further explanation.

Example 21

Standard capsules are produced by filling conventional two-part hard gelatine capsules, each weighing about 50 mg, with 50 mg of powdered hydrochloride of the adamantane compound according to the invention, 125 mg of lactose and 1 _{ml of} "Cab-o-sil".

- 32 209815 / 17A3

/ SAD ORIGINAL

Example 22

Instead of the hard gelatin capsules mentioned in Example 21, soft gelatin capsules are used. In addition, the powdery adamantane compound previously dissolved in mineral oil.

Example 23

Example 21 is repeated with the exception that the dosage unit is 50 mg of active ingredient, 4 mg of gelatine, 1.5 mg of magnesium stearate and 100 mg lactose ordered and is pressed after mixing with a conventional tableting machine into tablets ₀ may provided also with a suitable coating pills or tablets are used that release the active ingredient slowly over a longer period of time. A sugar coating can be applied to improve the taste.

Example 24

A parenteral, injectable preparation is made adding 5% by weight of the active ingredient in sterile, aqueous 0.9% Saline solution can be stirred.

The compounds prepared according to the invention are antiviral agents for pets. For example, they are effective against swine influenza. An important application of the compounds prepared according to the invention is thus the control of this infection by adding an active ingredient sum feed of the infected animals. For most purposes, the active ingredient will be in an amount of around 0.0001 to 0.1% by weight, preferably from 0.001 to 0.02% by weight, based on the total weight of the ingested feed, used »'...

'■■■;' . ■ ■ - 33 -

20981 5/1743> 8AD ORIGINAL

The invention "also relates to the manufacture of Animal feedstuffs, by mixing a finely divided animal feedstuff with one produced according to the invention Active ingredient.

Suitable feeds are in the book "Feeds and Feeding" by Frank B. Morrison (Morrison Publishing Company of Ithaca, Hew York 1948, 21st edition). The choice of the respective feed is of course left to the expert and depends on the animals, the economy, the available natural materials, the local conditions and the desired effect. Particularly important under this aspect of the invention is a concentrate that suitable for manufacture and sale to farmers or ranchers for addition to cattle feed. These Concentrates usually contain about 0.5 to about 95 wt. £ of the active ingredient together with a finely divided solid, preferably flour such as wheat, soybean and cottonseed flour. Depending on the animal to be treated, as solid additives ground grain, charcoal, fuller's earth, ground oyster shells and the like are used. Fine-particle attapulgite and bentonite are also suitable, which at the same time act as solid dispersants.

l'ie feed and the concentrates described above can of course contain other components of feed concentrates or cattle feed. As special important additives are proteins, carbohydrates, fats, vitamins, minerals, antibiotics, etc.

209815/1743

Claims (1)

Claims 1. New tricyclic compounds of the general formula where A
to the -C-R and B is hydrogen or if between C, - and C-carbon atom a CH ₂ group is inserted, Y
A is hydrogen and B -CR and the substituents R, X and Y X had the following meanings: X and Y can be identical or different and are hydrogen, methyl or ethyl
and R is 1 ·) - Ν ^ 3 ^ (° ^Η 2) ^{n iet 1} » ² » 3> 4 »5 or 6 2.) -NR ₁ R ₂ 209816/1743 original; _ 7c; in which again R. has one of the following meanings: Hydrogen, alkyl with 1 "to 6 carbon atoms, monosubstituted Alkyl with 1 to 6 carbon atoms and the following substituents: OH, alkoxy, with 1 to 2 carbon atoms, -MI ₀ , -NHR, or
-LRJi _n , where R, and IV can be the same or different and ^ edes an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cyclopropyl, cyclobutyl, cyclopropy! is methyl or cyclobutylmethyl and further R _OT R ₁ , chlorine, bromine, FormyVCH ₂ COOH ₁ -CH ₂ COOCH ₅ or -CH ₀ COOC ₀ Hp means with the proviso that when R _{1 is} alkenyl or alkynyl with a double or
3-bond in position 1, R _{0 is} an alkyl or monosubstituted alkyl as defined above, and that in the case of the adamantane _{compounds, when R 1 is} an unsubstituted alkyl radical having 1 to 6 carbon atoms or hydrogen, Rp is neither an ΐ / hydrogen atom nor a may be unsubstituted alkyl, and further R- an aliphatic radical, a monosubstituted one aliphatic radical with aromatic or heterocyclic substituent, is an aromatic radical or a heterocyclic radical with not more than 12 carbon atoms. and their non-toxic salts _c Process for the preparation of compounds according to Claim 1, characterized in that one a) a corresponding carboxamide or reduced b) a corresponding alkyl ketoxire :! r ^o rn.; adorns or 209815/1743 0AOORiGiNAL c) Appropriately substituted methanols from the Hitter reaction subjected and then hydrolyzed or d) reacts a corresponding amine with ethylene oxide or e) a corresponding amine with suitable aminoalkyl halides alkylated or f) a corresponding amine is reacted with ethylene halohydrins or g) a corresponding amine is reacted with aldehydes and the compounds obtained are optionally converted into the corresponding non-toxic salts. 3. A pharmaceutical preparation containing one or more compounds according to claim 1 and a suitable pharmaceutical Carrier. 4. orally ingestible capsules containing about 30 to 60 weight - / contain ° o of a compound according to claim 1 and 70 to 40 weight ^ of a non-toxic pharmaceutical carrier substance, 5. Orally ingestible tablet containing 25 to 90 weight- ^ one A compound according to claim 1 and containing 75-10% by weight of a non-toxic pharmaceutical carrier. 6. Orally ingestible syrup, which is approximately $ 2 to 5 weight a compound of claim 1 and the remainder of which consists essentially of a non-toxic liquid pharmaceutical Carrier consists. 7. A preparation containing about 1 to 10 weight percentages of a compound according to claim 1 dissolved in sterile saline solution. 8. Animal feed containing a feed material and a compound according to claim 1. 2098 1 5/17 A3 - 37 - 9. Animal feed concentrate, the 50 TdIs 95 weight ^ one A compound according to claim 1 and an edible, finely divided solid in admixture with "said compound contains. 10. Method of introducing 0.0001 to 0.1% by weight a compound according to claim 1 based on the total weight of the animal feed in a dietary animal feed. 209815/1743