2-ADAMANTIL HYDRAZINE AND COMPOSITIONS CONTAINING THEM.

Description

TITLE TEVA*PHARMACEUTICAL INDUSTRIES LTD HAR HOTZVIM JERUSALEM ISRAEL 2-ADAMANTIL HYDRAZINE AND COMPOSITIONS CONTAINING THEM. INV. DES. WEIMER BEN ZION S'JC-Il RAUL STERLIMG JEFFREY YELLIN HAIM PRIORITY ISRAEL PATENT DOM.-N. 53440 OF 22 NOVEMBER 1977 September 8, 1985 Rome, there______________....____________..._____ 60304-ab Register A Protocol No. 30071 A 78 MINISTRY OF INDUSTRY, COMMERCE AND CRAFTS Provincial Office of Industry, Commerce and Crafts of Milan CIPU OF THE MINUTES OF DEPOSIT FOR BRAND-.TYO OF INDIVIDUAL INVENTIONS In the year 1978, the twenty-second day of the month of November, at eleven and forty-one o'clock, the company TEVA PHARliACEUTICAL INDUSTRIES LTD. based in Hotzvim, Jerusalem (Israel) of Israeli nationality Via jQSUtemoxx ' MODIANO & ASSOCIATI Sas di dr.ine. G. MODIANO & C. through an agent (Italian Patent and Trademark Agency) and electively domiciled for legal purposes in Milan - Via Meravigli 16 at the office of the agent has presented to me, the undersigned: - Application in bo io for the granting of a PATENT FOR an industrial invention having as TITLE. 2-Hydrazines and Cholepoiesis containing them PRINCIPAL Kfixrwnxàx Inventors designated as WEINER Ben-Zlon, SUGHI Raul, STERLMG Jeffrey, and YELLIN Haim. Patent application priority is granted in: eraei e u. 53440 of November 22, 1977. Supplementary to patent no., (application no. ... dep. the granted accompanied by: - Description of a duplicate of 60 pages of writing. - Drawings, plates no. 2 in duplo. - Priority document and Italian translation (with reservation) - u maratimiBrtwjmmrr - Declaration of consent of the inventor to be mentioned in the patent. - Proof of payment on postal account no. 0066B004 in the name of the Tax and Concession Registry Office Rome of L.203· 500® sent by the Post Office of Milan 15 21.11.1978 n. 326 - Revenue stamp of L tWW 2,000. The application, descriptions and drawings listed above have been signed by the applicant and countersigned by me and stamped with the office stamp THE / DEPOSITOR JfwLh-. For copy with original 68304-ab I ) t 'ιυ O λ; O 071 A / 7β Hon.le tójJI STERO INDUSTRIA COMMERCIO ED . Ufficio - R Ο MA— The Company - r ... J3j jbUliiKBa wBeji TOTA PHARMACEOTICAL INDUSTRIES LTD. -30G71, 22XI78 of Israeli nationality With registered office in Hotzvim, τη Jerusalem (Israel) through Representative MODIANO A ASSOfìTATT dL Dr.IagaG JEBIAHQ. and _@1 et tivamente domiciled for legal purposes in Milan, ...Via Mera Vàgli 16, rìntnAnfìa_la conoeHaiowe of a patent Main title: » 2-AJUMANTIL Designated Inventors. : rtltUSR Ben—Zlon, SU uni Raul, STgRUNP____________ Jeffrey, and YEI.LTN fiaim ._______u Priorit à de Z the patent application in: ____Israel__ ;_______________________ _________ N. 53440 of 22 November 1977,-____________________ ____________ _Documentation attached; _ ___ _ a) Description in duplicate of n ft 60 pages of writing__ ' *» ___b) Difficulties of 2____tables in duplicate_____... „______ _ s) Letter of appointment - RjiteB'Ìin4jsi ni«SMrrtWMigsLnx________________ , ___d) Priority document with Italian translation (with reservation)___- -____ __r h isti» irtMMWir· re e* M ta ni j *** »(«»» ,____________.____________ ____ f) Declaration of inventor_____________________________________ ___ g) Certificate of payment (c^CcPo N t, OO668OQ4) of LP 203*500,-_____________________________ issued by the Post Office of Milan 15 on _h) Brand from bubbles of L l. Date 2 2 NOV. ,a78 'Uncial Rogante 68304 / CEL / lm (51608-Case 4) 2-ADALIANTIL IPRAZINE AND COMPOSITIONS CONTAINING THEM TEVA PHARLiACEUTICAL INDUSTRIES LTD., , a Har Hotzvim, Jerusalem (Israel) Designated Inventors: WEINER Ben-Zion, SUCHI Baul, STERLING Jeffrey and YELLIN Haim. Filed on 2 2 NOV. 1978 at No. ® 0 0 71 * / 71 The present invention relates to new derivatives of 2-adamantyl hydrazine, their accetigijàli acid addition salts .·· • 4 · Jt < from the pharmaceutical point of view and procedures for preparing them.. • · 4 · · · • 4 4 · · of new compounds and their salts. ; •4444 4*4 • *4*4* Specifically, the present invention forWi'Sfce*··. .··· .·· *···, * : new derivatives of 2-adarcantil hydrazine of the formula genqrojLeÌΛI • · 4 4 4 • Mi where R^ is hydrogen or a lower alkyl group of 1-4 carbon atoms, Rg and are the same or different and are each hydrogen, an unsubstituted or substituted radical which is a lower alkyl of 1-4 carbon atoms, a lower alkanoic acid radical of 2-4 carbon atoms or its lower alkyl ester, adamantyl, aryl, aralkyl in which the alkyl moiety has 1 to 4 carbon atoms or an unsubstituted or substituted heterocyclic radical of aromatic character; or R^ and R^ together with the nitrogen atom to which e9 are bonded form a non-aromatic cyclic radical. co unsubstituted or substituted; and their pharmaceutically acceptable acid addition salts. The term lower alkanoic acid radical herein refers to a radical which is bonded to the hydrazine nitrogen atom by one of its non-carboxylic carbon atoms, i.e., to a carbon atom forming part of the lower alkyl backbone of said radical. ·· ·· • * ·· · · When R or and / or R, it is a lower alkyl ester d. J ···♦·** * ··· * • * « ···· of a radical of an alkanoic acid with 2-4 carBójiiJo atoms, • · · · · * · · · · and Λ ····♦» · the ester-forming lower alkyl radical can, adv^sen^-.· ♦ · ·· · • ζ · Pius, be methyl, propyl, butyl. ί* . * '! · · · . .····· Examples of heterocyclic radicals of character *.&sb-*··..· • · · · · · ····... matic for which they can be both, Rg and R^, J5hno;.'.l • · · · and pyridinyl, quinolinyl. ....· Examples of cyclic radicals formed with Rg, R^ and the nitrogen atom to which they are bonded are piperazino, piperidino, homopiperidino, pyrrolidino, morpholino, thiomorpholino, hydantoin, heptamethyleneimino radicals, each of which can be substituted. Compounds of formula A in which R^ is H may be prepared in accordance with the present invention by reacting 2-adamantanone with a hydrazine compound in which one nitrogen is unsubstituted, of the general formula B. NN where Rg and R^ have the same meanings as in the formula t A, and reducing the resulting hydrazone. The reduction can be carried out in any conventional manner, such as with sodium cyanoborohydride, lithium aluminum hydride, or by catalytic hydrogenation, for example, using any suitable conventional hydrogenation catalyst, such as the Adam catalyst. w .· ·· « · • · · · This reaction is schematized in the following diagram. - ··· · • · · · · * of Reaction I in which R« and R^ have the same meanings**doi> £ j · ·· · me in formula A: Reaction Scheme I • · « « » :· • · · « * • · ·· • . • * ·. · · NH-N This general process was applied in accordance with the present invention in the preparation of the following novel 2-adamantyl hydrazine derivatives: 1-(2'-adamantyl)-2,2-dimethylhydrazine 1-(2'-adamantyl)-2-^ 1*-(2*-hydroxyethyl)__7hydrazine 1-(2'-adamantyl)-2-butyl drazine 1-(2 *-adamants1)-2-(adamant-1-iImeti1)hydration 1-(2'-adamantyl)-2-phenethyl drazine 1—(2'-adamantyl)-2-phenylhydrazine » 1-(2'-adamants1)-2-(^-bromophenyl)hydrazine -42-(2'-adamantyl)-1-benzyl-1-phenylhydrazine 1-(2 1-(2 1-(2 1-(2 1-(2 1-{2 1—(2 1-(2 1-(2 4-(2 4-(2 4-(2 1-(2 1-(2 1-(2 1-(2 1-(2 ·· · • · · · « ·· ·· « -adamntil)-2,2-diphenylicrazine ' -adamanti1)-2-(m-trifluoromethylphenyl)hydrazine -adamanti1)-2-(o-carboxyphenyl)hydrazine -adamatni1)-2-(2”-pyri di1)hydra zine -adamantiì)-2-^ 4-(7' ,-chloroquinolinyl)_7hydrazine -adamantylamino)pyrrolidine -adamanti lamino)pipers of na -adamantylamino)homopipers of na -adamanti laminino)eptame tylene imine -adamanti laminino)morphine -adamantylamino)thiomorpholine -adamantylamino)thiomorpholine-1,1-di oasis do -adamantylamino)piperazine ·'··Ζ • · · · · -adamantylamino)4-methylpiperazine -adamantylamino)-4-benzylpiperazine -adamantylamino )-4-(m_trifluoromethylphen±l)piperazine -adamantylamino)i dantoin In another embodiment for the preparation of compounds of formula A in which R^ is H, 2-adamantanone is condensed with a protected hydrazine compound in which one nitrogen atom is unsubstituted, the resulting protected hydrazone compound is reduced with an appropriate reducing agent, and the protecting group is removed. This embodiment will be referred to hereinafter as the - 5 IS( ' (TV Jk.7 protected hydrazone execution. The protection can for example< be by means of an acyl group such as, for example, acetyl, benzoyl or t-butyl carbonyl. If the protecting group is an acyl group, it can be detached by acid hydrolysis, for example, with hydrochloric acid or with gaseous HCl in the presence of nitromethane. This embodiment of the preparation of the compounds according to the present invention is represented in part (a) of the Scheme of Λ'.*.. ···· .··· Reaction II below. In this reaction scheme, "the" The protecting group is assumed to be acetyl which is bXftί· • · · · · is usually just one example. In this reaction scheme T^fia. ** ·· the same meaning as in formula A: ·* *. (See diagram on next page) - 6 / 9 / !O \ωλ Reaction Scheme II partial reduction partial reduction · ·..·' h Col ··1 / J ,. · • · ····! .·· and ♦ Concentrated HCl By means of a modification of the embodiment of the protected hydrazone, the protected hydrazone obtained as above is subjected to a substitution reaction whereby the substituent Rg having the same meaning as in formula A is introduced, and the resulting substitution product is subjected to total reduction. For example- For example, in the case where R^ is a lower alkyl, the substitution reaction can be carried out, for example, by treating with sodium hydride ITaH followed by alkyl iodide R^I. The total reduction in this embodiment can be carried out with known strong reducing reagents such as lithium aluminum hydride. The above modification of the protected hydrazone embodiment is described in part (b) of the above-mentioned reaction Scheme II. / .*.*.*. ···· Examples of compounds that were prepared in ^cp.oi;d&· with the above modification are 1-(2 ,-adamantyl)-2^4*M3i? ; • · · · · · ·♦··· ·· methyl hydrazine; 1-(2'-adamantyl)-2-ethyl-2-methyl hydrazine .!· 1-(2'-adamantyl)-2,2-diethyl hydrazine. .· ·. ....... • · · · · Furthermore, by means of another modification • · · · · · the protected hydrazone embodiment, the protected hydrazone obtained as in the previous modification is substituted, subjected to partial reduction, e.g., catalytic hydrogenation, and the protecting group is separated from the resulting product. If the protecting group is an acyl, it can be separated by acid hydrolysis, e.g., with aqueous hydrochloric acid. This modification of the protected hydrazone embodiment is described in part (c) of Reaction Scheme II above. Again, by means of another modification of the protected hydrazone process which serves for the preparation of particular compounds according to the present invention in which ί there R is a lower alkyl radical (e.g., methyl), and R^ is as in formula A, 2-adamantone is reacted with a protected hydrazine in which one nitrogen atom is nonsubstituted. to give a corresponding protected hydrazone, the latter is partially reduced and the reduction product is subjected to a substitution reaction to introduce the R^ radical. ···· The reduction in this modification is also conventional, for example, by means of cyanoborohydride of .«ejìJiS.». 4 Similarly, any suitable procedure may be used. 4 4 4 4 4 * for the introduction of an alkyl group R. in the position ·! *· • · 4 N . With a particular procedure for the introduction of a methyl group, the melting agent is methyl fluorosulf οήδΤφ 4 in methyl acetate. ··.··' • 4 4 · * This modification is described in Reaction Scheme III where the hydrazine bears a protecting group R^, such as ethyl or phenyl. From the resulting substitution product, the protecting group can be cleaved, for example, with concentrated hydrochloric acid as indicated in part (a) of Reaction Scheme III. This process results in a 1-alkyl substituted 1-adamantylhydrazine. · 4· 4 · · .· 4· ·** 4 (See diagram on next page) replacement In this way, for example, (adamantyl)-1-methylhydrazine was synthesized, the protecting group R^ being, for example, phenyl. By means of a further variation of this embodiment modification of the protected hydrazone the protected substituted adamanti hydrazine of the previous modification is further replaced. For example, in the case that be a lower alkyl the substitution reaction can be carried out by treating with NaH followed by alkyl iodide, Rgl· E. From the resulting substitution product, the protecting group can be cleaved off, for example, with concentrated HCl as indicated in part (b) of Reaction Scheme III. This procedure results in an adamantylhydrazine, 1,2-biso. established. In this way, for example, 1,2-dime was synthesized. ·· · · « « tyl-1-(2'-adamantyl)hydrazine. where R. and R« are methyl intermolecules. :**' • · » · · • · · · · « Again, by means of a further variasiοη<ΐζζίχ <me£ • · · · · · ····· ·. e sta modifica della forma di esecuzione dell’idrazone prot^te,·* ····· : . : · · · · la adamantilidrazina bisostituita protetta della precedefità .... • · · · · variation is subjected to reduction with a known strong r£dtfc$ftTￂﾷ agent such as lithium aluminum hydride as in part (c) of Reaction Scheme III. In this way, for example, 1,2-dimethyl-2-ethyl-1-(2'-adamantyl)hydrazine was synthesized, where R^, R 2 and R^ are all methyl. 1,2-Di-(2'-adamantyl)hydrazine is produced according to the present invention by reaction of hydrazine with 2-adamantanone to produce di-(2-adamantyl)azine which is converted to the corresponding hydrazine by catalytic hydrogenation. This specific embodiment of the present invention is described in the following Reaction Scheme IV: Reaction Scheme IV * » The analogous 1-(1'-adamantyl)-2-(2-adamantyl)i4tóei• · · · · · · « » · e 1 • · · * * na can be prepared in an analogous manner by the rbazidU'* « · • * · · • · < u · ne of 1-adamantyl hydrazine with 2-adamantanone and subsequent hydrogenation of the resulting hydrazone according to the Sqlaè-k.·* ·' » . . • > « - · · • ί Λ Ϊ ma of Reaction I described above. .* ·, V.*! *< « · « >· • * · « · • « «4 · φ Still by means of another embodiment · • · · ♦ · · for the preparation of compounds according to the present invention wherein R^ is hydrogen and each of the two Rg and R^ is an alkanoic acid or ester, a modified process according to the above-mentioned Reaction Scheme I is used in which one of the nitrogen atoms of the hydrazine is replaced with an esterified alkanoyl group. Examples of esters according to the present invention thus prepared are the following: Ethyl ^”2-(2'-adamantyl)hydrazino_7acetate Ethyl / ”2-(2'-adamantyl)-1-methylhydrazine^ / acetate Ethyl alpha- / ^ 2-(2'-adamantyljihydrazino^propionate Ethyl alpha-^ 2-(2'-adamanti1)hydrazino_ / butanoate If desired, such compounds can also be isolated as HCl salts. Again, if desired, such an ester can be hydrolyzed under mild conditions to yield a free alkanoic acid. Hydrolysis, for example, can be by ion exchange, using any suitable ion exchanger such as that known by the trade name Amberiite. 120. This specific embodiment is described in the following Reaction Scheme V where R₁ and R₂ indicate radixU₂. ..·· ···:. alkyl compounds, where part (a) illustrates the formation of an ester, part (b) an HCl salt, and part (c) the formation of a free acid. And • · • " Reaction Scheme V *··*. • · · tee • · and • · ·· +h 2nn *4 zCHCO 2R 5 R4 ' (a) CHOO • · ♦ · « • * · · * ion exchange (c) Examples of ^2-(2'-adamantyl)hydrazino_y^alkanoic acids according to the present invention prepared in this manner are: / _ 2-(2'-adamantyl)hydrazino_7acetic acid 2-(2'-adamantyl)-1-methylhydrazino^acetic acid 7 ίθ Γ A alpha- / 2-{2'-adanantyl)hydrazino / propionic acid \ <n\ A fififi φ Alpha-^ / 2-(2'-adamantyl Jidi'azinoJ^butanoic acid. Attempts to use free hydrazino acids as starting materials in the previous embodiment were unsuccessful in many cases, presumably due to the amphoteric nature of these acids, which destroys the nucleophilic character of the hydrazine. However, this stripping does not occur when a hydrazino acid is οοηφ^ρ^.... · · · · a phenyl moiety and in this case a free acid can be: • · · · · · ****«· · sato as starting material. For example, the acid al / àl£ 1-Λ! * '*!· -(2'-adam.antyl)-2-methylhydrazine_ / -alpha-phenylacetic was pre^a. .* · ··· • · · · · rat according to the previous form of execution by the iara$ri??ioi. ***** free acid.   If in any compound according to the present invention obtained in accordance with any of the preceding processes a free hydrogen atom of the hydrazine structure is to be replaced, such substitution may be carried out in accordance with known processes, for example, alkylation with suitable alkylating agents such as treatment with a mixture of sodium hydride and alkyl iodide. For example, 1-(2--adamantyl)-2-(m-trifluoromethylphenyl)hydrazine obtained, for example, according to Reaction Scheme I gives upon treatment with sodium hydride and methyl iodide the corresponding 1-(2'-adamantyl)-2-methyl-2-(m-trifluoromethylphenyl)hydrazine. In this particular case the aryl group exists Ο / 'λ ο,Ο ;Ο > 8 OV te is responsible for directing 1 further substitution on the aryl-bearing nitrogen atom. Furthermore, the alkylation of any compound according to the present invention in which a hydrazine nitrogen is unsubstituted can also be accomplished by condensing said adamanylhydrasine with a suitable aldehyde or ketone. The resulting hydrazone can be reduced by any of the conventional reduction processes used in Reaction Scheme I. For example, 2-adaraantylhydrazine obtained, e.g.JtH. • · ... god, the corresponding 1-(2'-adamantyl)-2-isopropylhydride;..·.·. ***** ·.·· • · · · · · This embodiment is illustrated in the scheme of R^fCgìcr-··* • «·· Φ ne VI where R^ has the same meaning as in formula A and R 2 can be H or alkyl and R^ can be alkyl. ·· ·· Λ*?·* ···· .·*:* ···· • · * · Reaction Scheme VI h NNH 2 or A further modification of the previously mentioned alkylation-reduction process employs an alpha,α-dicarbonyl compound, e.g., a dialdehyde, to perform a reductive dialkylation to form a new ring comprising the previously unsubstituted nitrogen of an adamanylhydrazine. According to this process, the dialkylation is performed in the presence of a reducing agent, e.g., sodium cyanoborohydride. This modification is illustrated in Reaction Scheme VII. For example, a solution of 1-(2'-adamanyl)-1-methylhydrazine hydrochloride, e.g., in acetonitrile, was treated with an aqueous solution of glutaraldehyde in the presence of sodium cyanoborohydride to afford ι-Γ(2') 7A,da. • and • · « · mantil )-me ti lamino_7pi peri dina. (See Scheme VII, R=CIÌ»y* n^3)# • ··· * * · « · · · · Reaction Scheme VII • · · * • · • · » ?.· * • · « · · t* • · * · '· · « · · Very generally, compounds according to the present invention in which the hydrazine backbone is monosubstituted can be converted into disubstituted compounds where the substitution is on the same nitrogen atom or on different nitrogen atoms and any compound according to the present invention in which the hydrazine backbone is disubstituted can be converted by further substitution into the corresponding compound in which the hydrazine backbone is trisubstituted. In the preparation processes described above, the compounds of the present invention are obtained in the form of the free base or as acid addition salts. If a free base is obtained, it can be converted to c / 4* ♦ 4 « 4 ·· « · • « · · · • ·* • 4 · 4 · - · · · converted into an acid addition salt by reaction with a pharmaceutically acceptable acid as known per se and vice versa, if the first product obtained is an acid addition salt and the free base is desired, the salt is converted into the free base by reaction with a base, again as known per se. Furthermore, it is possible to convert an acid addition salt of a compound of formula A into a different acid addition salt. Particular compounds according to this invention having the general formula A possess valuable properties... fungicidal (for humans and plants), antiviral, antibacterial. · · · . ,*···· ​​zoic and antimicrobial. Compounds according to this • 4 · < 4 ** * *4* ζ tion are also active against infections caused by qtfei ··'. ΐ 4 4 4 4 *·· 4 viruses such as cowpox, herpes simplex or influenza from protozoan parasites such as Leishmania and Trypanosoma, or from microorganisms such as Leptospira, and also have activity on the central nervous system (CNS). For administration to patients, the novel compounds according to the present invention are compounded with pharmaceutically acceptable carriers, and if desired, with other pharmaceutically active substances, and / or conventional pharmaceutical adjuvants. The present invention also provides compositions each containing as an active ingredient a compound of formula A together with an acceptable carrier. Where such com17 - If the positions are pharmaceutical, the vehicle must be pharmaceutically acceptable. In the case of veterinary compositions or compositions for agricultural use, the vehicles are chosen accordingly. The present invention is further illustrated by means of the following examples to which -it is not limited, all temperatures are in degrees Celsius. / '''· ·*·*·* * * · · · Example 1 '.ζ.· · 1 11 · · 4 · · · * * ·· · • · 1-(2'-Adamantyl)-2,2-dinethylhydrazin hydrochloride ····· Ϊ”* ί' ·ίκ W ι M ι H p il. ι -fc -rfi— «II·· | * ••••4 · « « ······ An ethanolic solution of 2.0 g (13 millimM-fJ ··.. ,··· 4·* *···* * * of 2-adananthanone and 2.0 g (43 nimol) of 1,1-dimethyl^drasSAÌ • · · · · · ··· · .· na was kept at reflux for 2.5 hours. The solvent was removed '.*.*.* • ♦ · 4 4 4 « a · · · · under vacuum and the resulting hydrazone was reduced with 340 nimol) of lithium aluminum hydride in 100 nimol of tetrahydrofuran at reflux for 16 hours. After cooling to room temperature, the reaction was quenched with water and the medium was extracted twice with diethyl ether. The combined organic layers were dried over magnesium sulfate, and the title compound, isolated as the hydrochloride salt (1.1 g, 33% yield), was recrystallized from methanol / ether. mp 296-8° (d) nmr (DgO) ^3.13 (s, 6H) Calculated analysis for C^H^CIÌ^: C, 62.47; H, 9.98; N, 12.14; Cl, 15.40 .Found: C, 62.59; H, 10.22; N, 11.80; 15.54 - 18 The compounds described in the following Examples 2-17, and 41-48 were prepared by the same procedure as in Example 1, except that equimolar amounts of the appropriate hydrazine derivatives were used. Example 2 1-(2'-Adamantil)-2-fepetylhydrazin hydrochloride The title compound was obtained in yield of 20% using phenylhydrazine instead of 1.1-dimethylhydrazine c οιτΑ*·»β P- · · J .··* · Example 1. mp 248-250° (d), (isopropanol)· nmr (TEA) ^3.4$ - 3.90 (t, 2H); 2.96-3.33 (t, 2H) Analysis calculated for C^Hg^ClNg: C, 70.47; H, 8.80 01, 11,58 ». A'.'. 1? • 4 4 4* 4 4 4 4 44# , Found: C, 70.14; H, 8.74; N, 9J'13; 01, 11.88 Example 3 1-(2'-Adamantil)-2-phenylhydre.zin - hydrochloride The title compound was obtained with a yield of 56% using phenylhydrazine instead of 1,1-dimethylhydrazine as in Example 1, mp 230-234° (d), (isopropanol) Calculated analysis for Ο^^Η^^ΟΙΝ^: N, 10.05; Cl, ​​12.74 Found: N, 10.00: 01, 13.22 Example 4 2-(2'-Adamantil )-1-benzyl-1-phenylhydrazin dori hydrate ? / ao The title compound was obtained in 42% yield using 1-benzyl-1-phenylhydrazine instead of 1,1-dimethylhydrazine as in Example 1. mp 208-9° (d), (isopropanol) nnr (CEC1 3)& 7.16-8.00 (n, 10H); 5.20 Analysis calculated per Cg^Kg^CHÌ,,: C, N, Found : C, Example 5 • · • · · • · ···♦ • * ** #· The title compound was obtained with yield ··*·· . ···· • · · · · · 65% using 1,1-diphenylhydrazine instead of 1,1-dine tilidrard·»®. ..... • · · · as in Example 1. (s, 2H) 74.89; H, 7.86; 7.56; 01, 9.60 74.90; H, 8.00; 7.61; 01, 10.07 ·· ·· *··*·* · • « · * · ···· ···· 1-(2'-Adamantil)-2 t 2-diphenyl krazine hydrochloride mp 148-150° (d), (isopropanol) nnr (THU) £> 6.80 - 7.60 (m, 10H) Analysis calculated for G22^27^^2 : θ' 74.47: E, 7.61; N, 7.81; Cl, 10.01 Found: C, 74.66; E, 7.82; E, 7.89; 01, 9,59 Example 6 1-(2 t-Adamantil)-2-(m-trifluoromethylphenyl)hydrazine hydrochloride XI compound of the title was obtained with surrender of the 61% using (n-trifluoromethylphenyl)hydrazine instead of 1,1-dinethylhydrazine as in Example 1. .o σ, mp 246-7 6 ¢(3), (diethyl ether) nmr (Γ.ΈΟ-ά g,) £>7.23 - 7.63 (m, 4Η) Analysis calculated for θ^ΟΙ?^} C» 5δ» δγ* H» 5»37ϊ N, 8.07; F, 16.45; Gl, 10.24 Found: C, 59.06; H, 6.65; N, 7.73; F, 16.59; Gl, 10.67 • · • · · · · · »· · • · · · *··· Example 7 1- (2 lA(ìamantyl)-2-(o-carbosoiphenyl· ) hydrazine The title compound was obtained with yield, d.el *·**** · · · 66# using N-aminoanthranilic acid instead of 1,1-dimethylazine as in Example 1, except that the resulting hydrazone was reduced with sodium cyanoborohydride. “*· ··*·. ***** ···· ·· * i. · The title compound was isolated as basell?ieera'.' • · · · · mp 217-218° (d), (isopropanol) nmr (TEA) £8.16-8.46 (m, 2H); 7.13-7.50 (m, 2H) Calculated analysis for c-,y H22 ?T2°2 ì 71.32; H» 7.69; N, 9.79 Found: C, 70.95; H, 7.86; N, 9.77 Example 8 1-£2'-Adamanti!)-2-(2-pyridi)hydrazin hydrochloride The title compound was obtained with a yield of 75# using (2-pyridyl)hydrazine instead of 1,1-dimethylhydrazine as in Example 1. mp 248-250° (d), (ethyl acetate / methanol) nmr (CLCl^ 10.34 (s broad 1H) ; 6.59-8.07 (m, 4H) Calculated analysis for C^H^CIH : C, 64.40; H, 7.87; N, 15.02; CI, 12.70 ,e>S>0( Found: C, 64.14; H, 7.94; ' N, 15.01; Cl, ​​12.98 Examples or 9 1-(2'-Adamanti laminino) pyrroli din hydrochloride The title compound was obtained in 58% yield using 1-aminopyrrolidine instead of 1,1-dimethylhydrazine as in Example 1. ·'”*· · · a · mp 275-278° (d), (isopropanol) ***** *···· ​​nmr (CDCl / TEA) 3.46- 3.96 (m, 4H) ...J ** * a* 4 · · Calculated analysis for C^H^N^Cl: N, 10.91; Cl, ​​13.84 *: Found: N, 10.85; Cl, ​​13.59 ***· ♦ 4 *44* Example 10 »...Ì .. · 4 1-(2'-Adamantilamino)pÌPeridin hydrochloride ····; I 1 I II ΙΙΙ·Ι W ———4 4 4 4 e 4 4 4 * The title compound was obtained in 51% yield using 1-aminopiperidine instead of 1,1-dimethylhydrazine as in Example 1. r* 4 4 > · 4 4 · '· 4 4 4 4 mp 275-7° (d), (isopropanol) nmr (CDC1^ / TFA)2 3.10 - 3.45 (m, 4H) Calculated analysis for C^^H^CIN^: C, 66.54; H, 9.98; N, 10.35; Cl, 13,12 Found: C, 66.39; H, 10.18; IT, 10.51; Cl, ​​13.05 Example 11 1-(2'-Ad amantilamino)homopiperidine hydrochloride The title compound was obtained with a yield of 40%. using 1-aminooriopiperidine instead of 1,1-dimethylhydrazine as in Example 1 mp 268-271° (d), (isopropanol) nmr (ODCl^ / TEA) E 3.23 - 3.63 (m, 5H) Analysis calculated for C^6^29^^2 1 67.48; H, 10.19; N, 9.84; Cl, 12,47 Found: C, 67.54; H, 10.26; N, / 7$94; Cl, 12,65 :* Example 12 4-(2-Adamantilamino)morpholine hydrochloride The title compound was obtained in 3el yield; • * • * ·» · · 51% using 4-aminomorpholine instead of 1,1-dimethylhydrazide. Ic© 1 · · · • · * · me in Example 1. '** * “ * * Λ mp 272-5° (8), (isopropanol) nmr (CEGl^ / TFA) 3.70 - 4.06 (m, 4H) ; 3.36 - 3.70 (m, 4H) Analysis calculated for Ο^Η^Ν,,ΟΙΟ: C, 61.65; H, 9.17; N, 10.27; Cl, 13,02 Found: C, 61.92; H, 9.09; n, 10.18; Cl, ​​13.42 Example 13 4-(2,-Adamantilamino)-typmorpholine-1,1-dioxide hydrochloride hemihydrate The title compound was obtained in 6% yield using 4-amino-thiomorpholine-1,1-dios3ido instead of 1,1-dime. tylhydrazine as in Example 1. - 23 / 9·' q. '.σ> \ rJ w-- Jy of 5% as pf 285-250° (d), (dinethylfornamide / water) mass spectrum ( n / e )Ii +=284. Example 14 1-(2,-Adanantilamm.ino)-piperazin hydrochloride The title compound was obtained in yield using 1-aminopiperazine instead of 1,1-dimethylhydrazine in Example 1. mp 312-314° (d), (isopropanol) nmr (CUCI / TEA)à 3.3 - 4.0 (m, 8H) Calculated analysis for C^Hg^N^Cl: C, 61.65; H, 9.91» N, Cl, 13,07 Found: Ό, 61.58.; Il, 9.88; N, Cl, 13,66 Examples or 15 1-(2-Adamantilamino)-4-methylriverazine hydrochloride The title compound was obtained in 22% yield using 1-amino-4*-methylpiperazine instead of 1,1-dimethylhydrazine as in Example 1. mp 279-284° (d), (isopropanol) nmr (CLOl^ / TPA) is > 3.9^ - 4.06 (m, 6lì); 2, 26 (s, 3H) Calculated analysis for Cg^Hg^GlgN^: C, 55.90; H, 9.00; N, 13.04; Found: C, 55.63; H, 9.27; N, 13.19 Examples or 16 1-(2 l-Adamantilaminc)-4-benzylpiperazine dori hydrate-monoi hydrate The title compound was obtained in 15% yield using 1-amino-4-benzylpiperazine instead of 1,1-dimethylhydrazide as in Example 1. mp 269-273° (d)j (isopropanol / methanol) nmr (C3X31 / TPA) (a, 5H) ; 4.00-4.36 (d, 2H) Analysis calculated for R, 10.09; Cl, ​​17.06 Found: R, 9.72; Cl, ​​17.35 Example 17 .··. I Ai I · · ···* 1- (2-Adamantilamino)-4-(m-trifluorom ylphenyl)piperazin.*^lorf.·-** .·*· ···· • · ·. · hydrate ϊ ·· · · · · · · · ..... · · *··· ... The title compound was obtained with a res^\dpl··· · .»j· ·· 30% using 1-amino-4-(m-trifluoromethylphenyl)piperazine Vavecje ; . .· · ·*· · * *.··*·* of 1,1-diinethylhydrazine as in Example 1. '··'. ΪΛ. ***** ,,··* mp 254-7° (d), (isopropanol) ϊ.ί.· ••••Z nmr (CDCl / TPA) is 7.26 - 8.00 (m, 4H) ; 3.53 - 4.23 (m, Analysis calculated for θ21^29^3^3^1 : C, 60.64; H, 6.97; R, 10.10; P, 13.71; Cl, ​​8.54 Found: C, 60.93; H, 7.27; R, 10.24; P, 13.42; Cl, ​​8.91 Example 18 2- Adamantilyhydrazin hydrochloride An ethanolic solution of 34 g (450 millimoles) of acetylhydrazine and 68 g (450 millimoles) of 2-adamantanone was refluxed for two hours, allowed to cool, and the white precipitate was collected by filtration to yield 83 g of acetyl-2-adamantanone; mp 204-206°. Reduction of this hydrazone was accomplished by refluxing 30 g (140 mmol) of the crude product in 400 ml of dry tetrahydrofuran, with 5.5 g (140 mmol) of lithium aluminum hydride for 16 hours. After cooling, the reaction was quenched with water and the reaction medium was extracted twice with dimethylene chloride. The combined organic layers were dissolved in magnesium sulfate. Removal of the solvent under vacuum yielded 27 g of a white solid with spectra consistent with 1-ac and 1-ίί- - (2'-adamantyl)hydrazine; hp 177-9th. *.***' ···' The acetyl group was separated by refluxing.1Qg; . .····· • 4 · · # · of this product in 70 ml of concentrated HCl for two hours*.*. / &*.. ···** ..·· •. · . · · On cooling the precipitate was collected by filtration..(7,9 and 2-adamantylhydrazine was recrystallized from isopropanolbóóme HCl salt in 63% yield. pf 295-8° (d) nmr (DMSO-dg) is 7.00 (m, 4H, exchangeable); 3.30 (broad s, 1H), 1.66 (m, 14H) Calculated analysis for C^H^Cll^x C, 59.26; H, 9.38; N, 13.82; Cl, 17,52 Found: C, 59.08; H, 9.54; N, 13.72; Cl, 17,72 Example 19 2-Adamantylhydrazine hydrochloride The title compound was prepared alternatively □ ....·Λ / in 48% yield using bensohydrasine instead of acetylhydrasine following the procedure of Example 18. Example 20 2-Adamantylhydrazine hydrochloride The title compound was alternatively prepared in 17% yield using t-butylcarbonate instead of acetylhydrazine following the procedure of Example 18. .... * The t-butylcarbonate group was finally eliminated.·&&. • * · · nitromethane with hydrochloric acid. ϊ Example 21 . . ··* 1-(2'-Adamantyl)-2,2-dimethyhydrazin hydrochloride *·· 1. To a suspension of 360 mg (9 millimoles) of sodium iGìV ***** ···* • · · · · · of sodium in 75 ml of tetrahydrofuran was added 2.0:^.^7.'5' • · · · millimoles) of the hydrazone resulting from the UT*' condensation 1.4 g (9 mmol) of adamantanone and 5.4 g (27 mmol) of tert-butylcarbazate. After refluxing for 1 hour, the reaction medium was cooled and 1.06 g (7.5 mmol) of methyl iodide was added and reflux was continued for another two hours, and after the reaction medium was cooled, the reaction was quenched with water and the medium was extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo leaving 1.9 g of product with spectra consistent with the expected methylated hydrazone. Reduction of the carbazate as well as hydrazone structures was accomplished by treating 850 mg (3 mmol) - 21 ~ 110 mg (3 nillimoles) of lithium hydride tetrahydrofuran refluxed for 16 hours. reaction was tempered with acid solution of this product with -aluminum in 20 ni of After cooling, the ammonium chloride solution and the medium were extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate, and removal of the solvent under vacuum afforded 450 mg of oil, which was dissolved in diethyl ether and treated with gaseous hydrochloric acid to yield the... compound of the title (50% yield) with identical properties to those described in Example 1. Example 22 1-(2'-Adamantil)-2-ethyl-2-methylhydrazine hydrochloride The title compound was obtained with a yield of 49$ using ethyl iodide instead of methyl iodide following the procedure of Example 21. mp 281-4° (d), (isopropanol) nmr (CDCl^ / TEA) £3.43 (q, 2H) ; 3.06 (s, 3H)i 1.45 (t, 3H) Analysis calculated for C^Hg^NgCl: C, 63.80; H, 10.22; N, 11.45; Cl, 14,51 Found: C, 63.72; H, 10.29; N, 11.01; Cl, 14,37 Example 23 1-(2 1-Adamanti!)-2-ethyl1-2-methylhydrasine hydrochloride To 2.3 g (60 millimoles) of sodium hydride in 100 ml of refluxing tetrahydrofuran add 10 g (48 millimoles) of 28 Ο Ο moles) of acetyladanantylhydrasone (compare Example 18). After an hour, the reaction medium was cooled and 6.8 g (47 mmol) of methyl iodide. After a further 2 hours of reflux, the reaction medium was cooled, the reaction medium was quenched with water, and the medium was extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate, and removal of the solvent under vacuum afforded 1-(2'-adamantyl)-2-acetyl-2-methylhydrazone. Treatment of 1.7 g (7.9 mmol) of this iodide was carried out at 100°C. Μ · I · 4 4 4 termed with 360 mg (9.4 millimoles) of lithium-Alunff hydride· ' • . · .··· .·* 4 nio in 75 ml of tetrahydrofuran under reflux for 16 hours reduced. I ..···· * * * 4* both the hydrazone and the amide to give the compound of ** ···· * * · * · in 70% yield with properties identical to those described; 44 4 # in Example 22. Example 24 1-(2 1-Adamantil)-2,2-diethylhydrazine hydrochloride The title compound was obtained in 44% yield using ethyl iodide instead of methyl iodide following the procedure of Example 23. mp 270-2° (d), (isopropanol) nmr (CDCl^) 5 3.20 - 3.62 (q, 4H), 1.33 - 1.66 (t, 6H) Calculated analysis for C^H^ClNg: C, 64.99; H, 10.46; N, 10.85; Cl, 13.75 Found: C, 64.95; H, 10.42; N, 11.20; Cl, 13,82 Example 25 %iQ 1-(2'-Adamantium)-2-methylhydrazine hydrochloride To 2.3 g (60 mmol) of sodium hydride in refluxing tetrahydrofuran was added 10 g (48 mmol) of adamantylacetylhydrazine (cf. Example 18). After 1 hour the reaction medium was cooled, 6.8 g (47 mmol) of methyl iodide was added and reflux was continued for another 2 hours, after which the aqueous preparation was prepared. 10 g of crude 1-(2'-adamantyl)-2-methyl-2-acetylhydrazone was added. This hydrazone (6.5 g, 29 millimoles) was reduced with.. 200 mg of FtO-.HgO (Adams Catalyst) in 200 ml of ethanediol. · - · · · · « * · · · · absolute under the pressure of 60 psi (4.92 kg / cm ) pér*j2 Filtration and evaporation afforded 6.2 g of material, which was immediately refluxed to concentrate for 2 hours. Collection of the precipitate afforded 4.3 g of the title compound (Yield after cooling 64%). mp 305-307° (d) nmr (TFA)£3.33 (s, 3H) Analysis Calculated for C^H^dN^: C, 60.96; H, 9.69; N, 12.93; Cl, 16,39 Found: C, 60.91; H, 9.58; N, 12.64; Cl, ​​16.81 Example 26 1-(2 1-Adamantiì)-2-ethylhydrazin hydrochloride The title compound was obtained with a yield of - 30 7oo 62% using ethyl iodide instead of methyl iodide according to the procedure of Example 25. mp 283-292° nmr (TPA)S 3.53 (q, 2H)j 1.49 (t, 3H) Calculated analysis for Ci2 H23 ClIÌ2 i 62.47; H, 9.98; N, 12.14; Cl, 15,40 Found: C, 62.33; H, 9.37; N, 11.96; * · · · 01> 15- 83· .... • · ·· * • « · · * · Further crystallization raised the puntini; z melting above 300°. Example 27 1-(2-Adamantil)-1-methylhydrazine hydrochloride To a solution of 1.35 g (5 mmol) mantyl)-1-benzoylhydrazine (see Example 19) in methyl acetate at 0° was added dropwise 1 mg (5.5 mmol) of methyl fluoroisofonate. After 15 minutes the volatile components were removed in vacuo and the resulting oil was taken up in 50 ml of methylene chloride, washed with equal volumes of 2ΓΓ sodium hydroxide and water, respectively, and dried to afford 1 g of 1-{2'-adamantyl)-2-benzoyl-1-methylhydrazine, a white solid. The bensoyl group was separated by refluxing 1 g of the above-mentioned intermediate in 50 ml of concentrated HCl for 24 hours. After cooling and extraction with benzene / ether, 1:1 the aqueous layer was evaporated to dryness giving in 30'in drop 570 Ì7a_o 580 mg of the title compound (50% yield). mp 159-202° (d), (isopropanol) nmr (CECl ) E 3.00 (s, 3H) Calculated analysis for C Hg ClTTgt C, 60.97; H, 9.70; N, 12.93; Cl, 16,39; Found: C, 60.68; H, 9.48; N, 12.62; Cl, 16,00 .... • * Example 28 -- .-.7.. ···· • ··· “ 1-( 2 ' - Ac.amam til )-2-moft 1-2-(r-tri flnoromo ti 1 ber / , 1 )hydrazi*>s» tJLjfrìp _ • · · · · • · · · · · drate ϊ . Z ······ ···♦··Φ A mixture of 3 g (10 millimoles) of 1-(2'-adamityl)*···. · · * c ·*· : —2-(n-trifluoromethylphenyl)hydrazine (compare Example ¢6) '.e .. • · · · · e (25 millimoles) of sodium hydride in 100 ml of benzoic acid and kept at reflux for 16 hours. After cooling the reaction medium to room temperature, 7.1 g (50 millimoles) of methyl iodide were added and the reaction medium was kept at reflux for another 16 hours. After cooling, the reaction was quenched with water, and the medium was extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate, and removal of the solvent in vacuo afforded 3.3 g of crude material, which was purified by preparative silica layer chromatography (cyclohexane:ethyl acetate, T1), isolating 1.1 g of oil, which was converted to the title compound by treatment with hydrochloric acid (30% yield). - 32 pf 139-144° (d) , (ether) nmr (CDCl )&7.40-8.50 (m, 4H) ; 3.60'(s, 3K) Calculated analysis for C^H^I^ClP^: C, 59.92; H, 6.65; Π, 7.76; P, 15.81; Cl, ​​9.84 Found: C,59.77; H, 6.56; R, 7.58; P, 15.71; Cl, ​​9.83 Example 29 ···· • · 1- ( 2 r -Adama nt il ) -2-me ti 1- 2- ( mtri fluoromethyl phen i 1 ) hydra ziiià\cl o . * 9 · ·*. hydroxide hemihydrate ... « . · < , ··· · • j . ···· • · ·« · The title compound was prepared in yield 3^ using 1-methyl-1-(m-trifluoromethylphenyl)hydrazine hydrochloride instead of 1,1-dimethylhydrazine as in Example 1, excellent. The resulting hydrazone was reduced with cyanoborohydride of j^odid·.**. 9 «999 mp 165-70° (d), (ethyl acetate) ····· 9 9 9* nmr (CDCl )5.7,40 - 850 (m, 4H) ; 3.60 (s, 3H) Analysis calculated for -j 8^25^ 2^ Ρ?3θ 1 / 2 : G* 58.45; H, 6.76; R, 7.58; P, 15.42; Cl, ​​9.85 Found: G, 58.84; H, 6.44; R, 7.58; P, 14.93; 01, 9.83 Example 30 1,2-di-(2'-Adamanti!)hydrazine 1.1 g (3.8 mmol) of di-(2-adamantyl)azine was reduced with 60 mg of PtO 2.H2° (Adams Catalyst) in ml of methanol under a pressure of 60 psi (4.92 kg / cm ) of H_ for 16 hours to afford 790 mg of the title compound (72% rt). pf 326-9° (methanol / methylene chloride) Analysis calculated for ^0^32^2 1 θ* 79Ì94; H, 10.66; li, Found: 0, 79.77; H, 10.49; K, Example 31 1-(1-Adamanti!)-2-(2-adamantyl)hydrazine hydrochloride 7qo 9.32 9.31 An ethanolic solution of 1.5 g (10 millimoles) of 2-adamantanone and 2.3 g (10 millimoles) of 1-adamantylhydrazine hydrochloride were refluxed for 3 hours. After cooling, the solution was dissolved in water. • · · · · of hydrazone which ίϊι·.γίάο»τ^· « mi of absolute ethanol pet* ···. of H, •ea · aqueous base to deliver 2.5 g to with 250 mg of PtOg.HgO in 200 3 hours under 60 psi (4.92 kg / cm ) • ·· * After removal of the solvent under vacuum, the re^tàucf / .l * was suspended in ether, filtered, and the filtrate was treated with HCl. The title compound was obtained in 45% yield. mp > 300° (methylene chloride / ether) nmr (CDCl / TEA) & 3.2 (m, 1H); 1.6-2.5 (m, 29H) Analysis Calculated for C^H-^NgCl: C, 71.28; H, 9.88; N, 8.32 Found: C, 70.84; H, 9.12; K, 8.21 Example 32 Ethyl ^ _2-(2-adarantyl)hydrazino_7acetate hydrochloride An ethanolic solution of 1 g (6.6 mmol) of adamantanone and 1 g (6.6 mmol) of ethyl hydrazinoacetate hydrochloride was refluxed for 2 hours. After cooling, the solvent was removed under vacuum and the resulting white solid was neutralized with aqueous sodium carbonate and extracted f twice with methylene chloride. The combined organic layers were dried over magnesium sulfate and removal of the solvent afforded 1.2 g of oil with spectra consistent with the expected hydrazone, which was immediately reduced with 200 mg of PtO^.H^O (Adams catalyst) in 50 ml of absolute ethanol at 60 psi (4.92 kg / cm ) of H- for 16 hours. After filtration and removal of the solvent in vacuo, the resulting oil was dissolved.TJM AA « · · ether and treated with gaseous hydrochloric acid to give^·; TO 800 mg (50%) of the title compound, mp 201° (d), (isopropanol) nmr (CDC1 ) δ 4.3 (q, 2H), 4.2 (s, 2H), 1.3 (t, 3H) *· ·· A AA AA • · A* A « A A · Calculated analysis for C^H^CIN^: C, 58.23; H, 8.68; TO Cl, 12,32 Found: C, 58.07; H, 8.57; N, 9.71; Cl, ​​12.70 The compounds described in the following Examples 33-35 were prepared by the same procedure as in Example 32, with the exceptions noted and using the appropriate hydrazine derivatives. Example 33 Ethyl / “2 -(2'-adanantyl)-1-methylhydrazino^ / acetate hydrochloride The title compound was obtained with a yield of 65% using ethyl 1-methylhydrazinoacetate instead of ethyl hydrazinoacetate hydrochloride and reducing for 48 hours instead of 16 hours TgO, as in Example 32. mp 164-5° (d), (ethyl acetate) Analysis calculated for C, 59.50; H, 8.92; N, 9.26; Cl, 11,73 Found: C, 59.41; Η, 8.7β; N, 9.02; Cl, 11,41 Example 34 1 ' 1 ···· * 4 · · · · * Ethyl alpha- / 2-(2'-adamantyl Jihydrazine / nropionate chlorhydrsftA** The title compound was obtained with a yield of *!· « using ethyl hydrazino-2-propionate hydrochloride instead of e'iiL· hydrazinoacetate hydrochloride as in Example 33. mp 215-217° (d), (isopropanol) • « · ·· Calculated analysis for C .^H^CII^O^ 59.50; H, 8.92; IJ·, ci, 11.73 Found: C, 59.57; H, 8.95; N, 9.21; Cl, ​​12.13 Example 35 Ethyl alpha / -2-(2'-adamantine)hydrazino_ / butanoate hydrochloride The title compound was obtained in 65% yield using ethyl hydrazinoate-2-butanoate hydrochloride instead of ethyl hydrazinoate hydrochloride. mp 194-7° (d), (ethyl acetate / ether) Calculated analysis for CgHggClN^O^: C, 60.66; H, 9.16; N, 8.84; Cl, 11,21 Found: C, 60.88; H, 9.38; N, 9.05; Cl, ​​11.35. - 36 Example 36 / 2-(2'-Adamantyl)hydrazino 7' acetic acid hydrochloride The hydrazine ester hydrochloride (1 g) of Example 32 was hydrolyzed with 4 g of Amberlite IR-120 (H) ion exchange resin in 50 ml of water under reflux for 16 hours to give the title compound in 47% yield after filtration and evaporation of the solvent. .·**·. ·· · · • · * · And mp 184-5° (d), (isopropanol) ···< nmr (TEA) ξ 4.20 (s, 2H) Analysis calculated for Ο^Η^Ν^Ο^ΟΙ: Found: C, 55.27; H, 8.06; Cl, 13.62 C, 55.65; H, 8.53; Cl. 1.51pm. ·♦*· • a · * · e · Example 37 72-(2'-Adamantil) — 1-methylhydrazipol acetic acid hydrochloride The hydrazine ester hydrochloride of Example 33 (6 g) was hydrolyzed with 3 g of Amberlite IR-120 (H) for 6 h in refluxing water to give the title compound in 57% yield after filtration and evaporation of the solvent, mp 190-3° (d), (isopropanol) nmr (TPA) £ 6.33 (S, 2H), 3.28 (s, 3H) Analysis Calculated for C^Η^^NO^OIO^: C, 56.83; H, 8.34; N, 10.16; Cl, 12.88 Found: C, 56.38; H, 8.47; K, 9.94; Cl, 13,02 TqO 4 • 4 *··♦ ,*· · Examples ο 38 alpha-2-(2-,-adamantyl)hydrazino- / rpropionic acid hydrochloride The idiazino ester hydrochloride of Example 34 (4.7 g) was hydrolyzed with 5 g of Amberlite IR-120 (H) for 10 hours in refluxing water to give the title compound with a 60% R2 after filtration and evaporation of the solvent. pf 183-6° (d), (isopropanol / ether) .·***. '···** Calculated analysis for C JLJL0.C1: C, 56.83; H, 8.38; Ky.'.iOjfiO; >4 jj .··;· ···· ci, 12.93 Jj • · · · · · 4 Found: C, 56.48; H, 8.77; Cl, 12,64 Example 39 Alpha- / 2-(2'-adamantyl)hydra3Ìno7 lbutfeitÌol acid hydrochloride* 444 * The hydrazine ester hydrochloride of Example 15 (5 g) was hydrolyzed with 2.5 g of Amberlite IR-120 (11) in refluxing water for 16 h to give the title compound in 20% yield after filtration and evaporation of the solvent, mp 205-8° (d), (isopropanol) Analysis Calculated for C^H^^N^O^Cl: C, 58.23; H, 8.66; N, 9.70; Cl, 12.30 Found: C, 58.27; H, 8.60; N, 9.46; Cl, ​​12.21. Example 40 Alpha- / 1-(2'-adamantyl)-2-rethylihydrazino_y,-alpha-phenylacetic acid The title compound was obtained with a yield of 58%. y(jo' using hydrazinophenylacetic acid hydrochloride instead of 1,1-dimethylhydrazine following the procedure of Example 1, except that the resulting hydrazone was reduced with sodium cyanoborohydride. pf 134_7<> (isopropanol) nmr (CUCI ) g 7.06-7.53 (m, 5H) ; 4.31 (S, 1H), 2.36 (S, 3H) Analysis calculated for C^HggNgOg: C, 72.61; H, 8.28; N, .8.9 1 • · · · Found: C, 72.74; H, 8.42; N,$ﾃ5l…. ﾷ-*.*:* : ﾷ Example 41 * * ; .    . 1-(2'-Adamantyl)-2- / 1-(2~hydroxyethyl) hydroxyl hydrazine. The title compound was obtained in yield of S%. ﾂ ﾟ  ﾷ  ྡྷ .�  · · using 2-hydrazinoethanol instead of 1,1-dimethyl··ll······1 example • · · · * except that the resulting hydrazone was reduced. ·*· * · with 50 psi (4.92 kg / cm) of Hg over 10% palladium on.coal. , mp 220° (d), (ethyl acetate / methanol) nmr (CLCl^) S 3.9 (m, 2H); 3.45 (m, 3H) Calculated analysis for C^gHg^ITgOCl: C, 58.41; H, 9.33; N, 11.35 Found: C, 58.07; H, 9.29; M, 11.52 Example 42 1-(2 t-Adamantyl)-2-butylhydrazine hydrochloride The title compound was obtained in 15% yield using butylhydrasine oxalate instead of 1,1-dimethylhydrazine as in Example 1, except that the resulting hydrazone was reduced to sodium cyanoborohydride. - 39 ou ,ω mp 230° (d), (isopropanol) nmr (CDCl ) 8 0.95 (t, 3H) Analysis calculated for 1θ»83 Found: N, 10.69 Example 43 1—(2 *—Adamantyl)— 2—(adamant—1—ylmethyl)hydrazin hydrochloride, the title compound, was obtained in 46% yield using adamant-1-ylmethylhydrasine instead of 1,1-dimethylethyl]trimethyl ... pf ^>300° (methanol) 9 9 9 4 :· ·· ·. • 9 « • · ·· • 9 9 ·«· 9 9 9 • » • 9 ·· · · nmr (CDCl^ / TEA): 8 3.4 (m, 1H) ; 2.7 (m, 2H) Calculated analysis for C^H^E^Cl: TT, 7.98 Found: TT, 7.87 ***** Example 44 1-(2,-Adamantil)-2-(p-bromophenyl)hydrazin hydrochloride The title compound was obtained in 17% yield using 3-bromophenylhydrazine instead of 1,1-dimethylhydrazine as in Example 1. mp 204-7° (d), (isopropanol) nmr (CDCl^ / TPA) 8 6.7-7.3 (m,4H), 4.5 (s broad 1H) Calculated analysis for ^^Η^ΤΤ^ΙΒτϊ C, 53.70; H, 6.15; TT, 7.83 Found: C, 52.41; H, 6.21; TT, 7.65 many was Example 45 1, (2'-Adamantil)-2-^ 4'*-(7'-chloroquinolinyl)_ / hydrazin hydrochloride hydrate The title compound was obtained in 40% yield using 7-chloro-4-hydrazinoquinoline instead of 1,1-dimethylhydrazine as in Example 1, except that the hydrazone was reduced with sodium cyanoborohydride, mp 286-288° (d), (isopropanol) nmr (CDCl / TPA) S 7.2-8.5 (m, 5H); 3.3 (m, 1H) Calculated analyses for C^Hg^E^ClgO: C, 59.69; H, 6.59; Cl, 18,58 Found: C, 59.95; H, 6.29; Cl, 18,99 Example 46 l-^'-Adanantilamino^ptamethyleneiramine hydrochloride The title compound was obtained in 24% yield using 1-aminoheptamethyleneimino instead of 1,1-dimethylhydrazine as in Example 1. mp 247-250° (d), (isopropanol / ethyl acetate) nmr (CECl^) 3.4 (broad s, 4H) Calculated analysis for C ^H^NgCl: C, 68.34; H, 10.38; N, 9.38; Cl, 11.89 Found: C, 68.09, H, 10.49; N, 9.49; Cl, ​​12.17 · * * e · »· · · > - « · « **>*.*.. · · · · ·**·' ·.·· ···. · • » · « · • · · a » · ..... ,, λ ; · : iCiVW • · · · · ·*♦*· . » · · · * « ♦ · · · ….. • · · · * Example 47 ϊ υ' 4-(2 l-Adamarythylamnino)thiomorpholine hydrochloride The title compound was prepared with yield of 35£ using 4-amninothiomorphdine instead of 1,1-dimethylhydrazine as in Example 1 pf 257–261° (d), (isopropanol) nmr (CDCl^ / TPA) £ 3.3–3.7 (m, 4H) ; 2.7–3.0 (m, 4H) Analysis calculated for ^−.4^25^2^ 1 S: ^8.23; H, 8.66; Κζ.£.70; .*·· Cl, 12.30; s, 11.08·.:: ···:. Found: C, 58.50; H, 8.62; » <;g, • » AAA Cl, 12.72; S, 10.96″··; Example 48 5V TO A · • ♦ A ··.:. A « * A •a A · A · A .AA 1_(2»_Adamantelamine)idanthone hydrochloride …. AAAA The title compound was obtained in 65% AAA yield using 1-aminohydantoin sulfate instead of 1,1-dimethylhydrazine as in Example 1 except that the resulting hydrazone was reduced with sodium cyanoborohydride. mp 210-213° (d), (isopropanol / methanol) nmr (CDCl^ / TFA) & 4.6 (s, 2H) Calculated analysis for C^H^qNjO^CI: C, 54.64; H, 7.00; N, 14.71; Cl, 12,43; Found: C, 54.37; H, 7.12; IT, 14.77; Cl, 12.15 - 42 Example 49 Γ 1..(2 '-Àiamant il )-1,2-djmethylhydrazin hydrochloride / χ*-; O' / • o '(P w, To a solution of 10 g (45 mmol) of 1-(2'-adamantyl)-2-acetyl-2-methylhydrazine (cf. Example 25) in 300 ml of methyl acetate (under nitrogen) was added 5.1 g (45 mmol) of methyl fluorosolione over half an hour. After 2 hours of stirring the volatile components were removed in vacuo and the residue partitioned between aqueous sodium bicarbonate / jee^u···· chloroform. The organic layer was dried and given as 9 g 1-(2'-adamantyl)-1,2-dimethyl-2-acetylhydrazine. The hydrolyzed solution was hydrolyzed in 60 ml of concentrated H01 for 2 hours. After removal of the volatile components under vacuum, the residue was crystallized from isopropanol, giving the compound of 'Jj^of·.··, ·*···· ​​with a yield of 15%· ····* • · * · · mp 159-191° (d)', (isopropanol) nmr (CECl^ / TPA)£ 2.9 (s, 3H), 2.7 (s, 3H) Analysis calculated for ^·]2^23^2θ^ : θ' ^2.47; Η, 9.27; E, 12.14; Cl, 15,40 Found: C, 62.52; H, 9.86; N, 11.89; Cl, ​​15.27 Example 50 1-(2'-Adamant!)-1,2-dimethyl-2-ethylhydrazine hydrochloride To 5.3 g (25 millimoles) of l-(2'-adamantyl)-2-acetylhydrazine (compare Example 18) in 50 ml of methyl acetate at 0° was added 3.1 g (25 millimoles) of methyl fluorosulfo- 43 - nate with stirring. For 1 hour the volatile components were removed in vacuo and the residue partitioned between 10% aOH and methylene chloride. The dried organic phase was concentrated to 5 g (22 mmol) of 1-(2'-adamantine)-1-methyl-2-acetylhydrazine which was reacted with 1.1 g of NaH (25 mmol, dispersion in 55% mineral oil) in 100 ml of dry tetrahydrofuran. After 2 hours of reflux, the suspension was allowed to cool to room temperature and was agglomerated. • · · « · 3.1 g (21 millimoles) of methyl iodide. After another 2 hours of reflux, the reaction medium was cooled and the reaction was carried out. Λ·... was quenched with water. The mixture was then partitioned between acetate and methylene chloride and the dried organic layer was treated to 4.4 g (19 mmol) of 1-(2'-adamantyl)-1,*24··φ.η^·ζ • · ethyl-2-acetylhydrazine which was treated with 1.3 g (34*auC• · · · * limoles) of lithium aluminum hydride in dry tetrahydrofuran. After 3 hours of refluxing the reaction medium was cooled to 0° and the reaction was quenched with an excess of sodium sulfate decahydrate. After filtration, the concentrated filtrate was dissolved in ether and treated with gaseous HG1 to give the title compound in an overall yield of 21%. mp 170° (d), (isopropanol) nmr (GDG1 ) $2.76 (m, 5H); 2.48 (s, JH) Analysis calculated for C ^Hg^NgCls N, 10.83 Found; li, 10.47 ￎﾷ*ￂﾷￂﾷ ￢ﾀﾢ ￂﾷ ο ,ο ω 'σ Example 51 1-(2 1-Adamanti!)-2-isopropylcresin hydrochloride A methanolic solution of 2.5 g (12.3 mmol) of 2-adamantylhydrazin hydrochloride and 2 g (34 mmol) of acetone was refluxed for 4 hours. The resulting hydrazone was reduced with sodium cyanoborohydride in ethanol. After 1 hour the suspension was neutralized with 10% NaOH, the volatile components were removed in vacuo, and the residue was partitioned into ether and water. The dried ether layer was treated with gas. The title compound obtained with mp 315° (isopropanol) nmr (CLCl^ / TFA) £3.1-3.7 (m, 2H); 1.4 (d, 2H) Analysis calculated for C^H^5^2^ : 11 »44; Cl, Found: N, 11.18; Cl, ​​yield of L.2jS# 14.51 14.21 • 44 4 444 4 . a 4 4 • 4 4 »·· Example 52 1-J2· -Adamantil)methylamino^piperidine hydrochloride hydrate To a solution of 1.1 g (5 mmol) of 1-(2-aphantyl)-1-methylhydrazine hydrochloride (see Example 27) in 15 ml of acetonitrile was added 3 g (7.5 mmol) of a 25% aqueous solution of glutaraldehyde followed by 200 mg (12.5 mmol) of sodium cyanoborohydride and a few drops of concentrated HCl to ensure acidity. After hours of stirring the volatile components were removed in vacuo and the residue was partitioned between 10% KOH and methylene chloride. The organic layer was dried (1gSO4) and the solvent was added. The solution was removed under vacuum and replaced with diethyl ether. The resulting solution was treated with HCl to form the title compound, which was isolated in 45% yield by filtration and washed with ethyl acetate. mp 195-201° (d), (washed with ethyl acetate) nmr (CDCl^) ¢3.8-2.8 (m, 4H), 2.9 (s, 3H) Calculated analysis for C^gH^NgClO: C, 63.47; H, 10.25; N, 9.26; Cl, 11,74 ;··· / ···« Found: C, 63,64; H, 10,45; * · · · » Cl, 11.96 The results are reported in the following test. *···· ​​;. demonstrate the antimicrobial, antiprotozoal CNS, fungicidal and antiviral activities of the compounds according to this invention. List of figures: • · · · · Fig. T - fungicidal activity on plants of the compound of Example 18; Fig. 2 - fungicidal activity on plants of the compound of Example 29. Antimicrobial activity was demonstrated against Leptospira hemicoplasma, antiprotozoan activity against Leishmania and Trypanosoma; CNS activity against albino rats and albino mice; fungicidal activity against plant fungi; and antiviral activity against HSV-1 (Herpes Simplex) and influenza viruses. The results are as follows: ACTIVITIES AT THE LICENSE HOSPITAL Leptospira canicola Kipod 146 .5 The tests were performed under the following conditions: Leptospira: Inoculum: 1-10'' cells / ml Incubation time: 10 days, 28°C Evaluation: Direct counting with dark field microscope after 4, 7 and 10 days Means used: minimum minimum + 0.5% albumin (Pentex*%.':. Korthof environment rich in serum; • · and · * Korthof-rich environment with serumÀ2%. * *' * The results are summarized in the following Tables · · AMYLEPTOSPIAL ACTIVITY *“*· • · # Minimum inhibitor concentration ( / ug / ml) · — ' • · · « ♦ ··* • · and *·. of Example Mo. Minimum minimum solubility + Pentex Korthof + 8% Korthof + 2% 1 Water 12.5 12.5 12.5 10 Water 12.5 100 18 Water 3.125 6.25 125 12.5 27 Water 3.125 6.25 50 37 Water 25 25 12.5-25 12.5 3 ELISO 6.25 100 6 ELISO 12.5 50 29 ELISO 6.25 6.25 It can be seen from the above results that the tested compounds of Examples JT. 1, 3, 6, 10, 18, 27, 29 θ 37 are shown to be they were all active. ARTIAL ACTIVITIES - COPY IT YOURSELF Some compounds were tested against 4 mycoplasmas. The procedure used was as follows: The following bodies: 1. LT. gallisepticum 2. K. capricolum 3. II. hominis 4. A. laidlawii .... • A •aa· Analysis: 50% growth inhibition in liquid medium. ···· • ··· * *··* :* * * Results; The tested compounds of Examples TT. 2, 10, 16 furej».. • A * · · A • · · · · AA were found to present a 50% inhibition at 4·ί concentrations AA • AA ·· · · · between 5 and 30 yUg / ml, which are in the atf£i$iife range. ; * ￂﾷ ￂﾷ ￂﾷ￢ﾀﾙ* to antibiotic. TESTS ARTI LEISHI.TARIA AND ARTI TRYPATTOSORA * AAAA **”* A.** AA · · · ♦ AAAAA · AAAAA A. Evaluation of the activity of the medicinal product: ····· 1. I. tronica a. amastigotes in peritoneal extruded cells in Ile Coy medium in vitro at 37°C. +++ = clear all parasites within 24 hours ++ = clear all parasites within 48 hours + = clear all parasites within 72 hours + = partial clearance of parasites in 72 hours or more - = no activity against parasites. promastigotes in ITc Coy medium in vitro at +++ = no germinable parasites after 24 ++ = no germinable parasites after 48 + = no germinable parasites after 72 + = no germinable parasites after 96 - = Germinable parasites after 120 hours. °C. hours hours hours hours 11. Trypanosoma in vitro '\i θ' 7* Trypanosoma in medium 0.RPM1 in vitro at 37°C. Evaluation as in b. ΑΝΤΙ TESTS I 21 SH?'ANI AE ANTI trypanoso?.:a Result: She slams aia Try nanoscma Compound of- Ama sti gote Promastigote in vitro Example No. 1yug 100 / Ug 10yug 100 / Ug 1 0 yUg 100 / Ug • · · 4 3 + 8 .·· *· · + +++ + .+.W- 11 • · · · ji* + • · +++ 16 +++ • · · · • * ·· • · · 18 ++ + ++ - - • ···· 25 ++ — +++ ···*. • • • · • « « • · • · 27 + ++ - +++ ♦· · · • ·♦ • « · 36 — ++ — ++ ·. · • « · · · « · « * · 38 ++ ++ • • · · « · <ϊ • · · · * 49 - ++ 51 ·+ ++ - +++ Pentamidine Control +++ +++ ++ *« An effect was observed with this medicinal product after 1 hour at this concentration. No effect was observed with Pentamidine at this time point. Mild effect. Summary: The tested compounds of Examples 8, 16, 18, 25, 27, 36, 38, 51 were found active against Leishmania. The tested compounds of Examples 3, 8, 11, 49, 51 were found active against Trypanosoma A / 1 Έ À'> TrT* T^'r''>T AJ.AÌ / ΧΧΛ* 4k.·. -there Λ.~..'.. · —^.1 Male albino burps of the variety were used Charles River, weighing 200-250 g. Catalepsy was produced by haloperidol, 5 mg / kg ip. The animals were placed with their forepaws on a horizontal bar, about 10 cm above the ground, and the animals were deemed cataleptic if they did not change position for at least 30 seconds. The cataleptic animals were injected ip with one of the products, ··;· . · O / · · · drugs with a dose of 40-80 mg / kg. Catalepsy was again assessed at indicated intervals. Medicinal product: Symmetrel Control, IP cycle, Dose: 80 mg / kg • * · · 9 :· 99 9 « · • 99 • · 9i « 9 • 9 ♦··· Time rat 1 rat 2 rat 3 rat 4 .. · r£ fetus 9 9 9 9* 0 + + + + • 4 · · · 45 + - - - - 90 + - + + - 110 + + - - 180 + + - - + · anti-cataleptic effect 0 / 4 2 / 4 3 / 4 3 / 4 3 / 4 Maximum average effect 2.2 / 4 9 9 .·· Medicinal product: Compound of Example 27, Working Line ip Dose: 80 mg / kg Time rat 1 rat 2 rat 3 rat 4 rat 5 [.1 + + + + + 45 - + - + - 90 - + - - - 110 — + “ · » 180 + + + 4 · ». .· χί * Anti-cataleptic effect 3 / 4 1 / 4 2 / 4 3 / 4 4 4 4 4 4 « » » * · » « · · Date 1 / 3 / 1 <?8 Effetto mortale massimo 2,6 / 4 Medicinal product: Compound of Example 36, Working Line\· ip Dose 80 mg / kg • · * «· » ♦· • · · · « Time 110 18O Anti-cataleptic effect rat 1 rat 2 rat 3 rat 4 rat 1 5 • · > · · + + + + + - + - — + 2 / 4 1 / 4 443 / 4 2 / 4 0 / 4 Maximum average effect 1.6 / 4 Medicinal product: Compound of Example 10, Work line ro: ip Pose: 80 mg / kg Time rat 1 rat 2 rat j rat 4 rat 5 0 + + 4* + + 45 + - + - - 90 + + + + 110 + + + 7*·. • · 180 + + + + • ♦ a · Λ7.. ···· ···· 2... Anti-cataleptic effect 0 / 4 1 / 4 0 / 4 Effect 1 / 4 re dio massi] • · · · · · · · a · a * • aaaa irx: : . ♦.···· « · « * · * a · a ,6;xu;; ;. a ' · . . Summary: The tested compounds of Examples 10, 27 and 36 • · ». * · · · were all shown to be active. • · « a · aaa» e. aa·· aa · · · · STEREOTYPED C0I.T0RTAÌ.3NT0 ON MICE aaa « a , Male albino ICR types weighing 25-30 gaaa · * were placed in cages with a phallic mesh bottom, 4 in each cage. The drugs were injected intraperitoneally and stereotyped behavior (noisy nose sucking, biting, repetitive head movements) was assessed every 30 minutes. Medicinal Product Symmetrel Control, r Working Line ; p Dose 50 mg / kg Time (min) Bull 1 Bull 2 ​​Mouse 3 Mouse 4 0 0 0 0 0 30 1 1 1 1 45 1 1 1 1 60 2 2 1 1 90 1 1 2 1 ···· • · ···· 120 2 2 2 2 ··· • 4 4 4 · 4 4 4 135 2 2 2 2 ···· • 4 4 4 150 2 2 2 2 • 4 4 4 4 ♦ 4 4 4 4 4 · 180 2 2 2 2 !» 4 4 4 4 4 4 4 4 • 4 210 2 2 2 1 ···. 4 240 2 2 2 0 4 4 4 • · • · 4 4 4 4 · • 4 · .· Total value ·*· 17 17 17 13 .. · « 4 4 4 4 · 4 Average value 16 ····. • 44»* Medicinal product: Compound of Example 27, Work Line ro 1 .p. Dose 50 mg.kg Time (min ) Mouse 1 Mouse 2 Mouse 3 Tone 4 0 0 0 0 0 30 0 0 1 0 45 0 1 1 1 60 2 2 2 2 90 2 2 2 2 120 1 1 0 0 135 1 1 0 0 150 1 1 0 0 180 0 0 0 0 210 0 1 0 0 240 0 0 0 0 Total value 7 9 6 5 Average value 6.5 Medicinal Product: Compound of Example 10, Working Line— o ip Uose 50' mg / kg Time (min) Mouse 1 Mouse 2 Mouse Mouse 4 0 0 0 0 0 30 1 1 1 1 45 1 2 1 0 60 1 1 1 1 90 1 1 1 • · 120 0 0 0 / Ύ · * · * . · . ··· · * . . . · 135 0 0 0 A · · vaaaaa 150 0 0 0 rf · · · · · LA · · * aa * # · t · · · 18O 1 1 0 o · ' ; · , · · · . * 210 1 0 0 - · · · o : · · · . . · · · · 240 0 0 0 * · .. · o* · · · · · · *-·; ..·· • · · · · • · · · · Total value 6 6 4 : ee · · Average value 4.75** Summary: The tested compounds of Examples 10 and 27 are shown they were active. ACTIVITY* 7UMCICISA ON PLANTS The fungicidal activity on plants was tested as follows: Fungi: 1. Pythium S. rolfsii 3. Rhizoctonia 4. Sclerotinia Assessment: Growth inhibition on solid agar mixed with various concentrations of the tested compounds. V' * \ (Ι( 1 Concentration; 500 / Ug / ml, 250 / ug / ml, 100 yug / ml, 50 yUg / nl; 10 / Ug / ml. Results: The compounds of Examples IT. 18, 29 were tested and found to inhibit Pythium, Sclerotinia and S. rolfsii at a concentration of 50 µg / ml. The inhibitory activities against the 4 above-mentioned fungi are plotted in Fig. 1 for compound tQ • of Fig. 18 and in Fig. 2 for compound άθΙΙΈΞβηηΙ,ό·,*,^ / ··. ..... ·* · ··· · • · · · « In each case the control growth was 8.5 cm in 3 gijoinj,. • · · · · · PI INHIBITION TEST ON HSV ZI* REPLICATION · Z . Z ; · ... » Cells -BSC—1 (Green Monkey Kidney) ; **;· Virus -HSV-1 (Herpes Simplex) **': ·.·.· Inoculum -10 PPU / cell ····* Medium -BMEM + 10% CS ,··. · Herpes . ...^ J. Levitt & Y. Becker Virológy 3J. 129-134 (1967) jg Compound of the - Concent. TL aig / ml % Inhibition the Example No._ / Ug / ml_tonicity limit_»» Lover *** 50 50 93 Ex. 27 100 100 99.99 81 46 Ex. 36 200 200 98 100 0 0 Ex. 49 200 100 99.9 100 92 60 Ex. 10 50 50 96 40 50 #T,L. The highest concentration of the compound that complies 55 - or totally non-toxic. t ** % inhibition of control infected for a certain time and with the same PPV virus with no inhibition. ♦** Anantadine, used as a control. Results The tested compounds of Examples IT. 10, 27, 36 and 49 were found to inhibit HSV by 96-99% at a concentration of 50-200 µg / ml. ·· ·· .·· • · · · · • ··· *· ·· Effects on anti-flu viruses (results are rare); Proceedings: G. Appleyard and T'aber J. of Gen. Viroli 25 >· 351-357 (1974) • · • « ' The compounds of Examples No. 1 were tested (Τ, ζ7 . 31, 36, 42 and were found effective against influenza viruses '· · » « • · · « · • · ·. • · * ·· · • » · ··· » ♦ « « * za A at a concentration of 10-50 ^ug / ml.

Claims

1. CLAIMS ..... • · » · 1 1. Derivatives of 2-adamantyl-hydrazine of the general formula AR. wherein Rj is hydrogen or a lower alkyl group of 1-4 carbon atoms; R 2 and R^ are the same or different and are each hydrogen, an unsubstituted or substituted radical which is a lower alkyl of 1-4 carbon atoms, a lower alkanoic acid radical of 2-4 carbon atoms, 56 - • · · · · » * « « · ' · 9 · .··· • · · 9 · .* I · · .·· bonium or a lower alkyl, adamantyl, aryl, aralkyl ester thereof where the alkyl structure has from 1 to 4 carbon atoms or an unsubstituted or substituted heterocyclic radical of aromatic character; or Rg θ ^3 together with the nitrogen atom to which they are bonded form an unsubstituted or substituted non-aromatic cyclic radical; and their pharmaceutically acceptable acid addition salts. ···* 2. 1-(2'-Adamantyl)-2,2-dimethylhydrazine and su,tfT..sa·»· .··· ' ···. acid addition agents, pharmaceutically acceptable.

3. 1-(2'-Adamantyl)-2-phenethylhydrazine and its derivatives • · of acid addition, pharmaceutically acceptable. *··*. * * * 4. 1-(2*-Àdamantil)-2-phenylhydrazine and its acid addition compounds, pharmaceutically acceptable. ··.·· 5. 24(2'-Adamantiì)- 1-benzyl- 1-phenylhydrazine and its pharmaceutically acceptable acid addition salts.

6. 1-(2'-Adamantyl)-2,2-diphenylhydrazine and its pharmaceutically acceptable acid addition salts.

7. 1-(2 *-Adanantyl)-2-4n-trifluoromethylphenyl)-hydrazine and its pharmaceutically acceptable acid addition salts.

8. 1-(2'-Adamantil)-2-(o-carboxyphenyl)hydrazine and its acid addition salts, pharmaceutically acceptable. S. 1-(2*-Adamantil)-2-(2-pyridyl)hydrazine and its acid addition salts, pharmaceutically acceptable. Ο- 'Ο Ζ>' · σ Φ, A - 57 10. 1-(2'-Adamantilamino)pyrrolidine and its acid addition salts, pharmaceutically acceptable.

11. 1-(2*-A.camantilamino)piperidine and its acid addition salts, pharmaceutically acceptable.

12. 1-(2'-Adamantilamino)homopiperidine and its acid addition salts, pharmaceutically acceptable.

13. 4-(2-Adaaantilamino)morpholine and its acid addition salts, pharmaceutically acceptable. A 14. 4-(2-Adamantylamino)-thiomorpholine-1,1-dioxyl.. • · · A · AAAAAA do and its acid addition salts, pharmaceutically acceptable. AA AAA AAA AAA AAA ··. AAA AAA AAA 15. 1-(2'-Adamantylamino)piperasin and its acid addition salts, pharmaceutically acceptable. AA AA A * 10.1-(2'-Adamantilamino)-4-methylpiperazine and its acid addition salts, pharmaceutically acceptable.

17. 1-(2'-Adamantilamino)-4-benzylpiperazine and its acid addition salts, pharmaceutically acceptable.

18. 1-(2'-Adamantilamino)-4-(m-trifluoromethylphenyl)piperazine and its acid addition salts, pharmaceutically acceptable.

19. 2-Adamantylhydrazine and its acid addition salts, pharmaceutically acceptable.

20. 1-(2'-Adamantyl)-2-ethyl 1,2-methylhydrazine and its acid addition salts, pharmaceutically acceptable.

21. 1-(2'-Adamantyl)-2,2-diethylhydrazine and its acid addition salts, pharmaceutically acceptable.

22. 1-(2'-Adamantyl)-2-m.ethylhydrazine and its acid addition salts, pharmaceutically acceptable.

23. 1-(2'-Adamantyl)-2-ethylhydrazine and its acid addition salts, pharmaceutically acceptable.

24. 1-(2'-Adamantyl)-1-methylhydrazine and its acid addition salts, pharmaceutically acceptable. . 9 9 *9 9* 25. 1,2-Li-(2'-Adamantyl)hydrazine and its acid addition salts, pharmaceutically acceptable. ; • 9 999 · ••999 « 9 26. 1-(1'-Adamantyl)-2-(2'-adamantyl)hydrazine;*and* ··*·· '*.·· its acid addition salts, pharmaceutically acceptable, · · . · · · .. .····· 27. Ethyl 2-(2 '-adamantyl)hydrazino_ / acetate 'e'iupj.*. ***** ..·· · · · · · acid addition salts, pharmaceutically acceptable. **'* 9 9 9 9 * 28. Ethyl 2-(2-adamantyl)-1-methylhydrazine acetate and its acid addition salts, pharmaceutically acceptable.

29. Ethyl alpha-2-(2-adamantyl)hydrazine propionate and its acid addition salts, pharmaceutically acceptable.

30. Ethyl alpha-2-(2-adamantylhydrazine) butanoate and its acid addition salts, pharmaceutically acceptable.

31. 2-(2-adamantyl)hydrazine acetic acid and its acid addition salts, pharmaceutically acceptable. 32.2-(2'-Adamantyl)-1-methylhydrazino-acetic acid and its pharmaceutically acceptable acid addition salts.

33. Alpha-2-(2'-Adamantyl)-1-methylhydrazino-propionic acid and its pharmaceutically acceptable acid addition salts.

34. Alpha-2-(2'-Adamantyl)hydrazino-butanol acid and its pharmaceutically acceptable acid addition salts. ·· · » alpha- / ” 1-(2 '-adamantyl)-2-methylhyd^&jjo-J^. • ··· • * · · · · 35. -Alpha-phenylacetic acid and its pharmaceutically acceptable acid addition salts. • 4 i 36. 1-(2'-Adamantyl)-2-^ T-(2-hydroxyethyl)J^|j'aÌ* . .· ·*··*·· acid addition salts, na and its salts 1-(2'-Adamantyl)-butylhydrazine and its pharmaceutically acceptable acid addition salts. 1-(2'-Adamantyl )-2-(adamant-1 r'-ylmethyl) acid addition hydrazides, pharmaceutically acceptable. 39.1-(2'-Adamantyl)-2-(j>-bromophenyl)hydrazine and its pharmaceutically acceptable acid addition salts.

40. 1-(2'-Adamantyl)-2- / 4-(7-chloroquinyl)_ / hydrazine and its pharmaceutically acceptable acid addition salts.

41. 1-(2'-Adamantyllamino)heptamethyleneimine and its pharmaceutically acceptable acid addition salts.

60. 4-2. 4-{2'-Adamantylamine)thiomorpholine and its pharmaceutically acceptable acid addition salts.

43. 1-(2'-Adamantyllamino)hydantoin and its pharmaceutically acceptable acid addition salts.

44. 1-(2'-Adamantyl)-1,2-dimethylhydrazine and its acid addition salts, pharmaceutically acceptable.

45. 1-(2'-Adamantyl)-1,2-dimethyl-2-ethylhydrazine and its acid addition salts, pharmaceutically acceptable*. ***** 46. 1-(2'-Adamantyl)-2-isopropylhydrazine and its acid addition salts, pharmaceutically acceptable. ·.·.·*· • · 1 · 1 47.1_ / (2*-Adamantil)methylaramino_ / piperidine* * · its acid addition salts, pharmaceutically accepted* JJ,*48. Compositions containing as active ingredient a compound according to claim 1. .·· • * • · · ····, • · · · * pi TEVA PHARLACEUTICAL INDUSTRIES LTD. The Authorized Representative: *Ì£ b_-Iii^r&rModiaSo.