SI8211571A8 - Process for obtaining 3,7 - diazabicyclo (3,3,1) nonane derivatives - Google Patents

Description

RICHTER GEDEON VEGYESZETI GYAR RT. Budapest, Hungary

PROCEDURE FOR THE PREPARATION OF 3,7-DIAZABICYCLO (3,3,1) NONANE DERIVATIVES

Technical field

The invention relates to the field of synthesis of heterocyclic compounds.

Technical problem

The invention solves the technical problem of the process for the preparation of new bicycle compounds of the general formula:

where:

2

R and R, brother-Independent, predstvaljaju C ₁ _galkil smaller group, a ·. 4

R is an esterified hydroxy group of formula -GR, where

R 4 is a benzhydryl group or phenyl group containing, if necessary, a phenyl or trihalomethyl substituent or one or more halogen substituents, or

5

R represents an esterified hydroxy group of the formula, -OCO-R, which represents

- 2 - (Ο _χ _, «aiKil) -carbonylokei jrup,

- a cynomoyl group which optionally has one halogen 111 and one lil of alcohol substituents,

- a benzoyloxy moiety which, if desired, is optionally substituted with an alkyl, phenyl or trhalomethyl substituent 111 one 111 v. 8e ¢ 3.4 alkoxy substituents, strong 111 v. 8e halo-oupetituents 1/111 ntro aupstltuont,

- a benzllollok3l group,

- xanthene-9-carbonylokel group,

- optionally substituted naphtholloxyl group, 111 • aolloalkyl group derived from a fifth- or Seeto-ring heterocyclic carboxylic acid which optionally contains a halo substituent on the ring, such as 1 stereoisomers 1 pharmaceutically acceptable ksele adlolone aoll of these compounds procedure for these new compounds, the hunting of the compounds of formula (1) are biologically active

crying eatlrital facts. The new compounds are derivatives of 3,7-dlasobiocyclo (3 »3, 1) nonana (blspldlna), which is aupatltulaan at position 9 ·

Synthesis of single compounds with the blspldnlIda skeleton, anger of the substituents, lil with the keto group at position 9, described js by L.J.Anet et al, in Austral, J, boi, Res ,, 3A. 330 (1950) 1

S.Chievarelli et al, in Gaez.Chlm.ltal ,, 8? »109 (1957)» see Chem »Abotr ,, 52» 15519d. boz a note on the biological facts of the obtained iodine.

The conformations of 3-raethyl-7-alkyl-3,7-diazabicyclo (3 '3p.) Nonane 1 of the corresponding 9-one derivatives were analyzed on the basis of BMB. of the apectors 1 dlpolnlh oomenato of trio J.E.Douglas 1 dr «, J.Org.Chom»,

- 3 33355 (1968) · aa on the basis of the mass spectrum by · P.C.fiuenits 1 dr ,, J, Uoterooyollc Chem., 14 * 423 (1977). The rotational configuration of the carbon atom in position 9 was glued by P.Schelber 1 dr »,

Acta Chim.Acad.Sci.Hung., 102 (3) .297 (1979). on 9th and 9th hydrolts The only ions that have been asymmetrically substituted in positions 3 17 · However, in these publications, it is excrucible for hourly etching.

Blapidine Compounds, Which Is Substituted? in position 9, they were disclosed in DE-05 27 49,584 as agents for CN5 stimulation and against Parkinson's disease, and in DE-OS 27 26,571 as antiarrhythmic eupetanoes. bespidine, with one having anti-potassium antioxidant agents, described by eu in DB-OS 27 44,248.

9-keto and 9-unsubstituted free compounds were also published in the Belgian patent Bo · 830,153 (see also DB-03 2 <28,792) · Of these compounds 9-unsubstituted derivatives repented to possess entiaryltmid effects, together with therapeutic iiria double know lldoeal care ·

The derivatives of 9-substituted 3,7-dlaeabloalklo (3 »3, 1) nonaaa or compounds containing such halves are described and in the following

Smiessan 1 Dr. ·, J.Ked.Chen, 12 (1), 186 (1976)> see Chem «Abetx £ 4» 43995e, describe netil ether 1 ethyl ester 9 ^ ol compounds «as oupataaoe having aaalgeslSaa actions · Derivatives which have a cycloalkylene group or a methyl 1 phenyl group in position 9, described eu in DB-OS 26 58,550 ka ^ agents aa CBS stimulation 1 soalgeside agents, · '\ ώζ?

Belgl strong patent Bo. $ 667.08 (see also DE-03 26 21.056) discloses fs derivatives of ch-ampnoylpilicone klaellne aa antlvlralnlm 1 antibacterial actions, which may contain, but among others: l «-forr <.ll-biepidine as aupatituont in the 6th position the aforementioned united blapidlnecl acolet has no eupotituent in position 9 ·

It is, moreover, novel that compounds of the general formula (I) may be obtained by the compounds of the general formula (11)

/

B ¹ - »

Λ

HH ² /

(U)

2 in which the E and E deflniaanl above are well known for the etherification of 111 eaterlflcaeia, and are especially favored by 'fashionable aatiarithmic agents, This stain is not surprising since such an effect has been observed earlier in the already known 9-supetituidanil compounds.

The biological effects of the new compounds are lapitated as follows

During the initiation of antlarltml cells, he was first treated intravenously aa 1 mg / kg acontal to induce «heart rhythm disturbance (Ked, Exp. (Boael) 10.93 (1964)) *, and the compounds were given by the tatic. Yes, intravenously 1 dose was determined to return the ae ritaa to 50% (ΒΒ ^ θ mg / kg) ·

Acute toxicities of the eu-glued compounds on the nuts at lntravenoan administration and determined in doses that cause emrtnoet in 50% (^ 50 mg / kg) · In both tests, the ref lrental lamb was smoked lidocal.

The pharmacological benefits of the above mentioned euu Table le it * · ¹ · Table 1 and also give the therapeutics index of kte 1 of one index (t «repentek the index of the new unilateral | terkpetttek index of Lidocain)"

T.hela 1

The compound

therapist.

index index ratio

3,7-direotyl-9-benaoilokai-3,7diasobicyclo (3.3, l) nonone 0.08

3-methyl-7-oul-9 / - (4 '-chlorobenzyloxy) -3,7-dlazabicyclo (3,3,1) nonone dihydrochlore 0,6

9.0 C, 0w9

26.0 0.023

3,7-diotyl-9- (4'-chlorobonzoyloxy) -3,7-diazobicyclo (3,3, 1) nonane dihydrochloyl hydrate 0.4

11.0 0.036

3 »7-di-n-butyl-9- (4 '-chlorobenzoylloxy) -3,7-diazabicyclo (3,3, 1) noncn phthunarate 0.25

3.7-dinethyl-9-enoxy-3 »7-diazabicyclo (3.3, 1) noncn fumarate 1.15

3.7- dimethyl-9- (4 * -chlorofenckai)

3.7-diazabicyclo (3.3, 1) nonon fumarate 0.9

5.0 0.050

39.0 0.029

52.0 0.017

3.7-dir.ctyl-S-benzhydryloxy ·

3.7- diczibic fang (3,3,1) ncnun fucarat

3-Octyl-7-ethyl-9 $ - (4 * -chloroquinol3l) -3,7-diazabicyclo (3> 3, 1) n-dihydrochloronic

3-phenyl-7-ethyl-9 &apos; - (2'-h arophenoxy) -3,7-diacabicyclo (3,3,1) non-dihydrochloronic

3-N-ethyl-7-ethyl-9tf- (2 ', 4'-dichlorobenzyloxy) -3,7-diasabicyclo (3,3, 1) nonane dihydrolyl d

1.2 21.0 0.057

1.25 41.0 0.030

1.15 28.0 0.041

1.1 20.0 0.055

of compounds ^ed 50 «50 therapist · index relationship index 3-methyl-7-ethyl-9 * - C 4 * -f «nyl- i benzoUoksl) -3 »7« & l & zabiclklo- (3,3, l) n.onaa i, 2 19.5 • 0.061 6 3,7-Diethyl-9- (xantea-9 carbonylloca) -3,7-di-sabicyclo (3,3, 1) nononaa u, 27 14,0 0.019 16 3,7-dimethyl-9- (2'-naphthoyloxy) 3 "7-diazabiolclo (3" 311) nonan bia (methanesulfonate) 0.11 17,0 0.006 58 3,7-dimethyl-9- (3 * ^? Methoxy-4'e toxi-benzoyloxy) -3,7-diazabiocyclo (3,3 * 1) nonaa 1.0 13.5 0,074 5 Lidooain lu, 0 28.5 0.351 1

Data from the table below show: that new compounds have 5 to 53 times more therapeutic effect than Lidooain · street-based good results were observed 1 when the disorders of the removal of the disorder were tested for guinea pigs previously treated with ea 1 mg / kg of oubain to cause erratic rhythm disorders "new compounds in accordance with the present invention have no beta-receptor blocking effects, while their local anaathetical effects approach the same with Lidocuin" anti-calcium effects, Antagonistic effect of calcium (p ^) 3-methyl-7-ethyl-93 ^ (4 * -chlorobeazoyloxy) -3,7diacabicyclo (3,3 'l) noahl dihydrochloride, about the same as Terapramil. compounds that are initially apparent in therapy (4,3> 4,6 &apos; a ρτχα substance, and 4,58-4,7 &apos; and another).

Iran's adhesive is also how crazy compounds affect the electrophysiological parameters ar ca. Smokers have crazy compounds that have an irritant effect and increase the threshold of stimuli, time prophecy .; a Impulse 1 refraction period, so that they affect the developing system. '' • '•• j ·· * «· · ·' 'the stimulation and conduction of the pulse of the heart in the following manner: which is particular to no1 · · S. /. .; · Koda ea staaovihti eliminating rhythm disturbance.

Γ · '·.

The possible torapeutic dose of insane compounds when administered in clinical treatment is about 0.5 * 1 mg / kg, with intravenous administration and about 10 g / kg when taken orally. This amount of active agent can be taken either in single dose or in multiple doses throughout the day, regardless of the type of disorder it will treat.

3-Methyl-7-ethyl-9 * - (4 * -chlorobenzoyloxy) -3 »7 * diazabicyclo (3.3, l) noaic dihydrochloride, eupatance ea ρ.ο. / Εβ ^ θί.ν, 16, 7 * It seems especially year after year for oral administration.

%

The sludge compounds of the general formula (i) can be obtained by the present invention by having the hydrocoyl group at the 9-position of the compound of the general formula (II), in which ΐΛ and as defined above are esterified or oterfluoro. More clearly,

a) when a compound of general formula (I) is to be obtained, in which iP is a hydrocarbon group of formula -OR ⁴ , but the compound of general formula (II) is reacted, or the corresponding 9-alkyloxy meth alcoholate with the compound of general formula (III )

R ⁴ - X (111) where it is ⁴ defined mountains, and also halogen, or

b) when the compound of general formula (1) is to be obtained, in which the hydroxy moiety of formula -O-CU-R ^ is ϊΡ eterified, the compound of general formula (XI) is reacted with the carboxyl kioel of the crazy general formula (IV) ( IV)

R ⁵ - CCvli. to the Jo-O-CG-K ^ group is a definioann foro, or t? n nc <: in, a non-reactive active agent, optionally, in the presence of an acid-binding agent such as j & ial.metal or other substance which it catalyzes the »runooetherification, and, if desired, the separate isomers ee are separated from the resulting isomer resinous substance, 1 (111 the compound of the formula (I) obtained as a circumferential base is converted into a mucous hear d an acceptable acid addition salt, 111 is liberated from the salt of formula (1) from its salt ·

Of the empty substances of general formula (11), the new derivatives in which R ¹ and R ^{2 are the} same and represent the ethyl 111 n-butyl group »This new iodine moiety can be obtained by the catalytic hydrogeacyl corresponds to Judas derivatives 9-one.

Considering the starting point of the experimental fornaile (11), a new preparation of> methyl-7-ethyl-3,7-dl &apos; s (3,3, l) nonon-9-ol was also obtained, as well as the separation of 9-alpha-ol and 9- beta-ol isomers »

According to the process a) of the present invention, the compound of the general formula (II) is etherified with the compound of the experimental formula (Ill) on the hydroxy group at position 9, although the age is the same as the ether of the general formula (I). Preferably, prior to the formation of the ether, the 9-hydroxy group has converted the sub-substance to the corresponding alkali metal alcohol, in order to avoid the 3ir. Quaternization of the nitrogen atoms at positions 317.

Alkali metals or their hydrides 111 amides, such as potassium, sodium or the corresponding hydrides 111 amides, can be used as alcohols for the formation of alcohols »Hattrium hydride is a yellow reactant» Uva reaction oe may lead in an aprotic.pot 'refractory, Wao slo is dimethyl formamide. The reaction flows * 9 easily, and can be brought to an end by light emsSe warming.

It is desirable that the resulting alcohols react the base of the two reactions directly in the reaction of the nuclei in which the resultant η · / 1ίιά: .-. ~ General formula (XIX) · These last reactants are usually used in small excess. He wished to use a fluoride derivative as an etherification agent, since it is more difficult to react with other halo treatments of opSts formula (XXX) ·

Alcoholates react readily with fluoro compounds of opioid formula (XXI) "Reakoi abundantly poured over 1-6 hours at 60-110 ° C"

The reaction mixture is treated by adding, after decomposition of the alcohol with alcohol, "an aqueous solution of acid to the mixture to convert the base substance to the aqueous phase, and to remove the non-basic substance, such as an excess of an etherification agent of the general formula (XXX ) »Are extracted by extraction from a non-aqueous solvent. The aqueous phase is then treated with bass to release the diazabicyclic compound of SpSte formula (X) and its salts, and this free base is extracted into a suitable solvent. Evaporate the extract "and the product obtained" if liquid

- · ι is purified by distillation in vacuo, or if solid by crystallization. Usually, the salt is given a high purity base so that it can be converted into its acidic adduct without any special purification. The bases can be converted into their acid addition salts, preferably in dihydrochloride, di-idrobromides or fumarates, by some means well known.

In accordance with process b) of the present invention, the general formula (II) is acylated on the hydroxy group at position 9 to give the salt • ester generally for: zero (I). · X; ·

When it will be used as an acylation agent.

., ····

Other kioelin of formula (IV), the reaction is carried out, is fatal. " · '../-. - .. ^ 1 ii /.

in the presence of a dehydration agent and / or in the presence of a means for activating the turboxy group.

In the meantime, it is preferable to cc m, at as an anhydride, k or d or C, - but * eui a functional derivative of a »conjunction fusion, a compound of general formula (IV), as an acylating agent»

When using '.ulide' as the coupling agent, it is desirable that the acid chloride of the general formula (IV) is desirable, the reaction being carried out in the presence of an acid suspension.

e

If ras tv ar a5 in koae ^ eka rakoya base substance »as Sto

- · · · »

Is the pyridine base of ^ viSak.a knife-opener also plays the role of ^ acid binding agent,. In addition, an inert'orjuncible solvent which is suitable for dissolving and semi-supatanoui can be used as the reaction medium; product »in coabinaoia with any known binding agent such as triothio saline, unless acid is used to bind acid in this reaction, it is recommended to select an aprotic organic solvent as the reaction medium and starting substance and product well soluble, This solution · ':! cu chlorinated hydrocarbons »primarily chloroform. Preferably, the reaction is carried out at room temperature or with low cooling, to J-10 ° C.

When used as an acylating agent, the 0 ^^ allphatic ester of the general formula (IV) "it is desirable that the aoylating agent be used / high, and that the reaction be carried out in the presence of alkaline g · ·. * -» · metal or / some other cat ol from transesterification.

iiao kafeSlizcori aogu- sc to use alkali ^ gtali or their alcoholic *, hydrides or amides. It appeared that the e ^ oferočito ^good:? Is '.' -Z.

catalieato ^^ ^na ^ ^r AJ ^U31 * ethically oe used in the reaction of 0.01 to C, 1 mole of catalyst »counted per mole of diazabicyclic Iodine» '- which is with water in vacuo, at about 80-100 ° C. Under these

* · * Ualovlma reaction exactly 1-24 hours ·

The reaction amccha screams are treated as follows: The vaporizer vapor is evaporated in vacuo, so, if the hydrogen is roccoia in the presence of a catalyst, the aa treatment is treated to decompose the catalyst traces, with the remainder of the invention with an aqueous acidic solution, -basic substances are removed by mixture extraction · and the aqueous acidic phase is alkalinized 1 allobode base of general formula (Z) Is separated Ib aqueous mixture of extracellulose «The extract is treated in an already well-known manner, the free bases of general formula (I) are clouded with a high thickness. pure odor, so there is no need for purification before the formation of salts. · The bases are usually crystalline gott Solid solids, which can be purified, if desired, recrystallized. · If desired, free bases can be coated? adiolono salts, especially in dihydrochloride, dihydrobromides, dloethanesulfonates, etc., by methods known in the art.

The compounds of the present invention can be converted into pharmaceutical preparations by methods well known in the art using conventional pharmaceutical carriers, diluents, and / or other additives.

Finding more detail in the details with the help of sweet and chirar that should not be captured by the limited.

Example 1

Add 1.08 g of sodium hydride to a solution of 5.0 g of 3.7 ^ dimethyl3,7-dihydrocyclo3,3,1 l) nouon-9-ol in 5v acre diraethylformSCOide under a nitrogen atmosphere. When the spontaneous separation of VodOhlk has been given, the mixture is stirred for 3 minutes at 60 C and then added to the slurry ?, or even to the outlet, Slurry slides a few tins ^r '' ·· When the reaction is complete and the mixture is diluted ea 10 ml EataaoJi ^ Sd .v »?, V · '. ·. A 'I aim to break up the high-sodium sodium hydride, so cc c mo 5 a the stock oa 7 xal hydrochloric acid j evaporate in vacuo, ttstate »c dissolve in 5 ^ ml of water, so the solution, ekAtraSau is two ways aa 50 ether each, with the aim of removing the knife. To each lye oo is added potassium carbonate, ave while uc is extracting the oil -aa pat gg ca, which is extracted three times with 50 nd diotlether each. combined with ether extracts oauSe above nagnesium snlfat, filtered, the filtrate evaporates ₉ and the free base »which, when debuted as a residue, converts the salt to its funarate * and> o salt ages at a yield of $ 71.9, considered bass ·

The obtained 3t7 * dinethyl-9-pheoxy-3t7-dia «abiocyclo (3i3, l) nonane fumsrat melts at 1 $$ - 197 ° C, after recrystallization from the ethanol 1 diisopropylether's solvent. 121-122 ° C / 10 ° a, | ° »1.5472.

Anino alcohol, used as a starting substance, obtains ee from 3 _t 7 * dln0til »3f7« diazablcyclo (3,3, l) nonan-9-one, a known substituent, by catalytic hydrogenation * Compound 9-ol melts at 130- 131 ^ 0, after recrystallization from hexane,

Brlmer 2

The equivalent of 1 mole of 3,7-dimethyl-3,7-diazabicyclo (3,3 l) nonan9-ol is reacted with the equivalent of 1.5 mol of the corresponding aryl fluoride, as described in Example 1, at which age I brought it, compounds:

a) 3,7-dimethyl-9- (4 * -chlorophenoxy) -3,7-diazabicyclo (3,3 | l) nonane fucarate Yield: 51 ° C: 211 ° C (after recrystallization from methanol and diisopropylether),

b) 3,7 * diBotyl-9 "(3 *" trifluoroirrotyl-phonocyclo) -3,7-cLiC1bicyclo "(3,3 <1) nonone dihydrochloride. Irritation 75 »5 #, m.p.:196°C (after

- f. · ??

ro crystallization is. n-butunol).

Example 3

It would react 10 g of 3,7-dichloromethyl-3-7-di-z bicyclo (3.3 _T l) nonun-9-ol and 24.7 Z benzbidryl bromide, as is generally the case in Example 1 · Convert the product to fumarate, dissolve the salts in methanol, and narrow the soil with a motile til codon. 3,7-Diiaethyl-9-beazhydrilok3i-3,7-diaanbicyclo (3,3, 1) nonane fumarate is obtained in 50% yield and with t: 200-201 ^ 0.

Primor 4

3.7 * ·

Let 18.3 3 3.7 "dira®til-diazabicyclo (3.3 _r l)" nonan-9-ol 13.5 s benzyl chloride react for 4 hours on a regular teaper a ture, as opiate ou Example 1 are given the 9 g (32.3%) of 3 »7-dimotil-9-bonziloksi-3,7-diasabiciklo (3,3, l) _noaana> m.p. * _t; 137 · 140 ° 0/10 Pa »Freedom Base Quickly CrystallizedAfter the Jan I, mp» 7O-75 ° O.

The base is converted to fumarate in a well-known manner », So ee melts at 145 ~ 146 ° C, after crystallization from ethanol»

Example 5

Allow 10 g of 3-oethyl-7-ethyl-3,7-diazabicyclo (3,3, 1) nonon-9-alpha-ol to settle in a solution obtained from 50 ml of dry dimethyl formamide 1 8.93 G fluorobonsole as described in Example 1 »The product will purify the vacuum of deotilation * 3-tyl-7-yl-9-slf af en ocel-3,7-dia zc bicycle is obtained (3,3,1 ) nonaa, in a yield of 69.3%, 3a m.p. : 132-134 ° C / 18 Pa, n | ° - 1.5412,

The dichldroclorld of the upper base melts at 230-231 ° C, after recrystallization from cmeSe isoprop: r.la and methylethyl ketoaa, -.

The active substance in the hot reaction, 3-n »til-7" StlX * 3,7 · diazabicyclo (3,3, l) nonan-9-ol, will be obtained in the following ways' • 7- ^? · » ^; ·· ···

First oe at prem 3-n »til-7-otil ~ 3» 7-diti2abicyclo (3, '$ fl) nonan * · ^x \ ·· -.Hi'

9-οη from l-Ethyl-4-iiporidone, paraforaaldehyde 1 ethyluenes., Prooa procedure suggested by J.E.Uou ^ IclSS d 61., P-g ^ .ChOin. , 31,355 (1966

The compound ee is obtained in a yield of. 92,3.5 / »with m.p.:96~97°C/3 Well, n | ° - 1,4971.

Dissolve about 18.2 g of 3-fluoro-7-ethyl-3,7-diazabicyclo (3,3, 1) nonon-9-one and 190 al ethanol, so that the solution is hydrogenated for about 4 hours at half pressure from 4 Mva, in the presence of 1 g of allysin of platinum (I7) oxide, the Reaction mixture contains two possible <5 a isomers in a ratio of 90 (50, the ionomer in which the hydroxy group at position 9 aa of the ethereal B * ethyl group is designated as alpha-isoaer, while the one in which the hydrokai group is in position 9 on the side of the R-aetyl group is designated as beta-isoaer. "

The isoether mixture is treated with an alcoholic solution of hydrochloric acid in isopropanol as modium. The alpha-isoether, which is soluble as dihydrohlorld, is separated by double recrystallization from isopropsnol * Salt, mass 7> 7 e *, obtained in a yield of 60%, with t * t «(250 ° C (decomposition) ·

The base liberated from this salt is a colorless crystalline solution, which melts at 8O-89 ° C. · The data from the Li & R spectrum is evidenced by the structure of the isoers reported by P.echeihor and K.IiSndor in Act3 Ckim.Acad.oci. uung., 102,297 (1979). When subjected to thin-layer chromatography on silica gel 60 as an adsorbent, the crust was swollen with an ethanol mixture of 29% aqueous ammonia in a 9: 1 yield as a solvent, the compound was shown to be uniform.

iCOČnoat that reversed upon alr-isomer recrystallization; is collected, evaporated, and the resulting 18 g is formed in 50 al water. »The solution is saturated with potassium carbonate, and the ounce is extracted and the base is extracted a pot of 6 a ml of hi or of or ma. the combined chlorophyllic solutions, dried over magnesium sulfate, were filtered and the filtrate was evaporated. - <iiazabicyclo (3,3, 1) nonan-9-bota-ol, as a colorless crystalline opiate, soluble at 9S-99 ° C · Yield 30% (2.7 g) after three phases of crystallization .

The purity of the beta-isomers was demonstrated by thin layer chromatography, and the resulting position of the 9-beta-hydrokai was group-confirmed by HMH φ octroscopy, as described above, in relation to the alpharisomer.

Example 6

As described in Example 3, it yields 3-methyl-7-ethyl-3,7-diasabicyclo (3,3, 1) aonen-9-alpha-ol, and then converts it to the following 9-alpha-aryloxy derivatives , according to the procedure in Primor le

a) 3-methyl til-7-e til-9-alpha- (3 ^r -trifluoromethyl-t-yl-enoxy) -3,7-diaBabylcyclo (3, 3, 1) nonaa dihydrochloride, mp ·: 16O- 161 ° C (from ethanol, acetone and ether), yield: 62.55 ".

b) 3-Aethyl-7-otyl-9-alpha- (4'-allorophenocai) -3,7-diazabicyclo (3.3.1) nonane dihydrochloride, mp: 139-141 ° C (from isopropanol and otra), yield: 51 »5 /» ·

o) 3-methyl-7-otyl-9-apha- (3 * -chloro-enokoyl) -3,7-diazabiocyclo (3.3.1) nona dihydrochloride, mp: 209-210 ° G (from otaool, acetone and ether ), yield: 76.9Λ.

d) 3-methyl-7-otyl-9-or N- (2 * -chlorophonoyl.si) -3,7-diazabicyclo (3.3.1) nonone dihydrochloride, mp: 241-242 ° 0 (from ethanol, acetone and otra), yield and 4ϋ> ό.

e) 3-Methyl-7-otyl-9-apha- (4'-phenylunocolo) -3 '7-diazabicyclo (3.3.1) nonane, mp: 91-92 ° C (after recrystallization of JB ^ B n-hecaane) , prino3: 3 5 / λ ·> '·. ··' · · * ^^ »7>.» ·· »«> * t? '' 'Z * ·· !? /'.·. ·

·. 'R - <^ Λ ·. '·

Example 7

Prepare ee 3-tyl-7-ethyl'3,7-diazabicyclo (3,3, 1) aonan-9betarol, as in Example 5, and then fall to react with 3-irifluoro • methyl-fluorobeazole. as described in Example 1, at the age of 3-methyl-7-ethyl-9-beta- (3'-trifluoromethyl-phenoxy) -3,7-diazabiocyclo (3,3-l) aonane base, in yield 34.5 *, mp .: 121-122 ° C / 9 Pa, η | θ a 1,3605 · bo, dihydrochloride is a colorless crystalline substance, which melts at 163 * 164 ° C, after crystallization from isopropaol. £ TlW-Q

Hase forms 10 g of 3.7 ~ dimethyl-3.7 "diazablolklo (3.3, 1) nonan9-ol in 50 ml of dry pyridine, and a solution of 11.24 g of benzoyl chloride in 50 ml of dry pyridine is added. for 30 minutes and the solution was “cooled down and its temperature was maintained at 5-10 ° C.” After that, the mixture was stirred for 3 hours at ambient temperature, and most of the pyridines were removed in vacuo. The mixture is treated with 50 ml of water, mixed with acidic with 20 ml of concentrated aqueous hydrochloric acid, and the mixture is extracted three times with 50 ml of ether each, in order to remove any non-existent uptake. The water moose was saturated with potassium carbonate and extracted three times with 50 ml of chloroform. j of in o so chloro formula rac, forms, Q3u5o above the stains of yum-aulphate a, filtered and filtrate up the hour. The residue was crystallized from n-hexane. 3,7-diaeyl-9-benzoyloxy-3,7-diazabicyclo (3,3, 1) nonane is preferred, in a yield of 42.5z and aa _; -t »ts 100-102 ° C.

·. ·. .The base is converted to uncle dihydrochloride in the usual way. The crystalline salt was dissolved at 26 ° C after recrystallization from isopropanol.

* 17

Example 9 lucfci cc to react 3,7-di'r.r.til-3,7-dluz.ibicllo (3,3, l): icnan9-ol oa the corresponding acll hal id has, as described in. Priraoru 8, so they get the following Compounds:

a) When oe uses 4-nitrobonsyl chloride as a reactant, they are obtained

3.7-DiCotyl-S- (4 * ^, -nitrobenzoyloxy) -3,7-diaeabiocyclo (3,3, 1) · nononaa, in 80.6% yield, The product is melted at 150 ° 0, after rocriotalysis from glycol. and til ether dire,

The hydrochloride of the above compound was isolated as a hoohydrate according to the "methanol crystallisation alloy, m.p." x 272 ° C.

b) when 4-chlorocinamoyl chloride is used as a reactant to obtain SO

3.7- dimethyl-9- (4'-chlorocycloinocyclo) -3,7-diazabiocyclo (3,3, 1) noanoic acid, in 75.3% yield »· The product melts at 111-112 ° C after recrystallization from dllzopropilotra.

c) When oe as a ro act ant uses 4- * xoetokoicinamoyl chloride / get 80 3 _t 7-difiethyl-9 ~ (4 ^z ~ aetokoi-cinaEioyloxy) -3 »7 ^w dia8abioyclo (3i5fl)« noaan, in 87 yield. 2 ^. Dense at all. The yellow oil is directly converted to the dihydrochloid. co oe melts at 230 ° C with decomposition after recrystallization from alcohol,

d) The reactant uses 3 »4,5-thiimiythoxy-oinamoyl chloride as the reactant, yielding 3» 7-diethyl-9- (3 ', 4' »5'-trimethoxy-ethyl-eloylcarbonyl) 3.7-diazabicyclo (3 > 3 »l) noaan, in a yield of 61.5 It is produced. melts at 130 ° C, after crystallization from dllzopropilotra, Kihi or id bazo oo melts at 248 ° C, decomposed, after recrystallisation with water aqueous alcohol.

Primor 10 'S.

By: ^Λ. · '****', "/ * ··

Allow to react 6 g 3 "Ciotyl-7" otyl-3,7 "dcAfcabioyclo (3" 3 "* / nonan-9-ulfa-ol about 9,16 g benzoyl chloride, as described in U

In Example β, ee was then obtained 3-alpha-7-ethyl-9-alpha-tenzoyloxy-3,7-diazabicyclo (3,3, 1) nona, in a yield of 6v, 7%. Oil key product at 175-178 ° C / 1.2 kPa, n * ⁰ »1.5275. The free base dihydrochloride ionic hydrate 'is melted at 236-237 ° C, and recrystallized from isopropanol.

Example 11

The following derivatives of 3-motil-7-otyl-9-alpha-aryloxyGi-3,7-dusabicyclo (3,3, 1) nonana ee to bi j a and with corresponding starting σι p stanzas in accordance with the post-tuples and the aisle are primordial

a)> aetyl-7 * ethyl-9-alpha2k- (2 *, 4 * “dichloro7benzyloxy) -3” 7-diaabiocyclo (3 »3 | l) aonane dihydrochloride, mp: 1O5-1O7 ° C (recrystallized from ethanol and ether mixtures), yield 48.1%.

b) J-Motyl-7-Otyl-9-alpha (4 * ^, -'-chloro-benzolloxy) -3,7-diazabicyclo (3.3.1) nonaa dihydrochloride, mp: 14O-142 ° C (after recrystallization from mixtures e ethanol and ether), yield 40.2%,

c) a3tyl-R7-ethyl-9-alia- (4'-phonyl-benzoyloxy) -3,7-diazabiocyclo (3.3.1) nonaa, mp: 91-92 ° C (after recrystallization from n-hexane) , 50% yield. The dihydrochloride oo melts at 163-185 ° C, recrystallizing from ethanol and ether,

Example 12

Allow 3-Rethyl-7-ethyl-3,7-diasabicyclo (3,3, 1) nonaa-9-beta-ol to react with 4-chloro-benzoyl chloride, such as 3 opioid in Example 8, to give is 3-a: otyl-7-ethyl-9-boto- (4 * -fluoro-benzoyl) / -3 * -ES) -3,7-diasabicyclo (3,3, 1) nonQn, in yield 70. · · SazG melts AS $ 6-67 ° C »after crystallization from petroleum ether (i.e., incl .: 12u ° C),

The upper base dihydrochloride, prepared in the usual way <x, is a 'colorless crystalline substance which melts at 175 ° C after the blade; of isopropanol.

Example 13

I

Let 9.9 S of 3,7-diethyl-3,7-diaza-bicyclo (3.3, 1) ¾ nonan-5-ol with 4-chlorobonzoyl chloride be reacted, as described in example 8, to give 3 , 7 "diotyl-S- (4 ^/ -chlorobcazoyloxy) -> 3.7 · diazabicyclo (3.3" l) nonaa dihydrolyl chloride monohydrate, in yield 53.65, aa mp: 116-12O ° C.

Paul knows how to pour ounces and can be prepared in the following ways

Let 1-otyl-4-piperidone aa paraformaldohido 1 otilamino react, yielding 3,7-diethyl-3,7-diazabiocylo (3,3, 1) agann-9-oa, in a yield of 68% 1 aa incl .: 87 ° C / 1.3 Pa, n | ° »1.4935« Barometers ae 49 e obtained substance in 300 µl of carbon · alcohol, add 0.6 'g of platinum (IV) oxide (Adams catalyst) ), and the arnesia is hydrogenated slowly for about 7 * hours, for about 7 hours, the catalyst is filtered off, the filtrate is evaporated, and the residue is recovered by heptane »They get 54 g of 3.7 ^w dietii-3.7- diazabioifclo (3.3 µL) aalb-9-ol yield 71%, and mp 6l, 5 ° C.

Allow 10.10 g of 3,7-di-n-butyl-3,7-diazabicyclo [(3,3,1) nonan-9-ol to be reacted with 7.7 g of 4-chloro-benzoyl hi or Ida, as described in Primor Θ to give 3,7-dl-n-butyl-9- (4'-chlorophylls-benzyloxy) -3,7-diazabicyclo (3,3, 1) nonaa, which is then converts to fuuarat. Oo, when they are melted at 18v-16'i ⁰ C, they get in a yield of 57.55.

The starting uapstaacu oo obtained from 3,7-dl-n-butyl-3,7-diazabicyclo (3,3, 1) nonan-9-one (i.e.: 123 ° C / 7 Pa, η | θ «1 , 4863) by catalytic and 1'adduction, which is described in Prim. Lj., The obtained 3,7di-n-butyl "3,7" diuzabicyclo (3,3, 1) nonan-9-ol ee .. crystallizes from petroleum ether (t .klj,: 120 ° ΰ) and then feats · sublimation u

'^; . · Ί? : -'''- i'-o'- ·. ··· -'rt ”· ^ι z: <'- ζ ····. · * .. ' '' - - ~ ~ - vacuum. Pez will be jnn, the crystalline pouches are melted at 31-32 ° C

Let ββ react with 10 g of 3 »7-di2 * ethyl-3,7-diaz abiocylo (3, ^ 1) ·· nonsin-9-ol with 19.57 g of xanthene-9-carbonyl chloride, lao $ to jq opfc '·''with the axis of Example 8 to give 3.7' diraotyl-9- (kaanten-9 ^with -carbonyl-oxy) -3,7-diazabiocyclo (3,3,31) noane, in the yield of 58> X $ »The free base is dissolved at 108 ° C, after recrystallization from n-helsan, and the corresponding veneer from melting at 191-193%, then recrystallization from ethanol and ether smog« crlnre 16

13.3 8 2-Naphthoyl chloride was added to a solution containing 8.5 g

3,7-dimethyl-3,7-diazabiocyclo (3,3, 1) noaen-9-ol 1 100 ml chloroform, at a temperature below 20 ° C, and allow the roacoion omega to stand at room temperature for one hour the solution was evaporated in vacuo and the residue was triturated with 100 nl of water. The aqueous layer was quenched with 10 ml of hydrochloric acid, then extracted twice with 50 ml of ether, the aqueous phase was made with an alkaline addition of kalljurn carbonate, and the liberated base was extracted three times with 50 chloroforms each. above the cagnosium hydrate, filtered and the 00 filtrate evaporated, the soil residue was dissolved at 76-78%, after recryption and extracted from 2-butaao, irinos 99, j. Age Joni 3 »7-Diaethyl-9- (2 ^z- naphthoyloxy) -3,7-diazabicyclo (3,3, 1) -nonane salt is converted to its di (not® sulfonate) in the usual way ·

They are soluble at 212 ° C, after recrystallization from ethanol.

Example 17

The 3,7-direthyl-3,7-diazubicyclo (3,3, 1) -aonan9-ol is reacted with the corresponding acylation aromatics as described in Primo 16, so that the following compounds are obtained:

'··

g) 3,7-dimethyl-9- (4 * -methyl-benzoyloxy) -3,7-diazabicyclic (3,3 _> l) nonane, 63% yield, mp 5S-G- ° C (after sublimation in Dlhydrobraoid, which will attach to the usual process, soluble at 231-233 ° C, after rocrystallization from motanol,

b) 3-7-dimethyl-9- (4 * -ethyl-beneoyllocal) -3,7-diazabiocyclo (3,3 l) nonane, 90% yield, mp 62-63 ° C (vacuum sublimation) "The normal hydrobromide which is prepared in the usual way is soluble at 233-234 ° C, decomposed after recrystallization from ethanol,

s) 3 "7-dimethyl-9- (4'-chloro-beaxoilokai) -3,7-diax * bi $ iklo (3r3" l) · nonane, A 93% yield, mp "87-89 ° C ( post-sublimation in vacuum) · Dilhydrobromide, which is prepared as usual, will dissolve at 26G ° C, upon decomposition, after recrystallization with an aqueous acetone solution.

d) 3,7-dimethyl-9- (2 '-chloro-4 * -nitro-benzyloxy) * 3,7-diacabiocyclo (3,3, 1) nonane, in 73% yield, mp 116-H7 ° O (subtle recrystallization of la acetone). The dihydrobromide, which is prepared in the usual manner, melts at 237-238 ° C, upon decomposition, recovered from the acetone aqueous solution. "

e) 3,7-dimethyl-9- (3 * -methoxy-4 * -ethoxy-bonzoyloxy) -3,7-diazabicyclo (3,3,1) nonane, in 93% yield, mp 72 -73 ° C (sublimation in vacuum). The customary dlhydrobromide melts at 178-18 ° C with decomposition, after rcriotalization by ir. ethanol,

f) 3,7-Diraethyl-9- (2'-furoyloxy) -3,7-diazabicyclo (3,3> l) nonane, in 71.9% yield, mp 131-132 ° C (after recrystallization from aooton ). Dlhydrobromide, which undergoes the usual change of mode, dissolves at 239-241 ° C with decomposition after recrystallization from methiol.

· · '' •• 'v' * · '*''' · ',''' · c) 3,7-dimethyl-9- (2 * -chloro-nicotinoylokoi) -3,7-dii. ^, .abiocyclo (3.3, l) nor.sn, in 85% yield, mp: 123-125 ° C (after crystallization from methyl methylethyl ketone). The dihydrobromide, which is prepared in the usual manner, is dissolved at 2 $ 0 ° C, with decomposition, after recrystallization from aqueous methanol.

h) 3,7 * dlaethyl-9- (2'-techloyloxy) -3,7-diuzabicyclo (3,3, 1) -one, 83% yield, mp: 96-97 ° C. Dihydrobromide, which is normally prepared, dissolves at 26O-262 ° C, decomposing, after which recrystallization from methanol is desired. "

Example 18

0.3 grams of sodium cmcSi of 8 g of 3.7 * dimethyl * 3,7rdiazabiocyclo (3,3, 1) nonan-9-ol and 22 g (excess of 185%) of ethyl ether of phenylacetic acid are added to the raspberry chests. , a2 & »o hold on a water heater of a tulle, heated to 90 ° C, 6 Cacho να, under a vacuum of 2 kPa, The pressure is then adjusted in an atmospheric afferent, the reaction mixture is diluted with 50 ml of ether> and extracted from the base substance twice aa per 75 or 10% aqueous solution of hydrochloric acid, the aqueous phase is made alkaline by the addition of potassium carbonate, and the product, which is extracted as an oil, is extracted three times with 50 ml of chloroform. Only ec chloroform extracts, dried above nagneaium-culft, are pro / filtered, rc.:ivar- h evaporated. In vacuo, recovered in vacuo in the morning. "

3,7-Diethyl-9-phenyl, toi.si-3,7-diazabicyclo (3,3,1) nonone are obtained in 88.5% yield, t, mp: 168 ° C / 2O Pa, n ^ ° = 1.5310. Dihydrobromide, Keji cc preparation n- uubič-ROM: mode if no melting of 230 ° C _t transactions rekristaiizcci from ip.otunolu \ '^ r'>. ·. · ·. <£? ;

Primor 19

3 _r 7-DiNnetyl-3r7-diaiabicyclo.lo (3,3, 1) nonan9-ol was reacted with 100 l excess response of C3tra carbofacial kioeliro as described in Example. 10, and by the age of the following compounds:

a) 3,7-dimethyl-9 * benzoyloxy-3 »7-diazabiocyclo (3> 3« l) aonane, in a yield of $ 7i &lt; t &gt; t: 119 ° C (after crystallization from diisopropyl ether) · Fum &amp; melts at 205 ° C after recrystallization from saeSe of ethanol and ethanol ·

b) 3,7-din; otyl-9-aicothioylilocai-3,7-diazabiocyclo (3,3 | l) oxaaa with. incl. 103 ° C / 140 Pa and 7 ° C-75 ° C. 'irihydrobromide, which is prepared in the usual way, melts at 262 * 0, after recrystallization from methanol.'

No. Ρ-1571/82

24:

Claims (4)

The patent claims t A process for the preparation of 3,7-diazabicyclo (3,3, 1) nonane derivatives of the general formula: • in which: 1 2 R5R1 each independently represent a C1-6alkyl group; 3 4 R represents an esterified hydroxy group of the formula -OR, where R is a phenyl, chlorophenyl or benzhydryl group, or 3 5 R represents an esterified hydroxy group of formula -O-CO-R, wherein R ⁵ is fenil.-C ^ _ ₅ alkyl, 2-phenylvinyl optionally substituted by * with a halogen or with jednom or more C ^^^ alkoxy group; phenyl Koja men be supstituisanasa C ^ _ ^ alkyl: grupom, phenyl or trihalomethyl grupom, or jednom or more C ₁ _ ^ alkoxy group, a halogen and / or with nitro; diphenylhydroxymethyl; a xanthen-9-ylihaphthyl group optionally substituted or a heterocyclic ring such as pyridyl, furyl or thienyl, their stereoisomers or pharmaceutically acceptable salts with acids, in the first embodiment for the preparation of compounds of general formula (I) , where R is an esterified hydroxy group of formula -OR *, reacts a compound of general formula (II): 25: (II) 1 2 wherein R and R are as defined above or the corresponding alkali metal alcoholate having the compound of general formula (III): R ⁴ - X (III) where R is as defined above and X is halogen in polar ♦ an aprotic solvent, such as dimethyl formamide, in the presence of a strong base at a temperature between room temperature and 100 ° C, or in another embodiment, to obtain compounds of general formula (I), 3 5 where R-. is an esterified hydroxy group of general formula -O-CO-R, reacts a compound of general formula (II) with a carboxylic acid of the general formula (IV) R ⁵ - COOH (IV) V where R ^{5 is} as defined above or with its reactive derivative of the general formula (V): R ⁵ -CO-Z (V) wherein Z is a halogen or a C 1-4 alkoxy group in an organic solution such as chloroform or pyridine in the presence of an acid-binding agent such as pyridine, triethylamine or an excess of the starting compound of formula (II) and a catalyst such as an alkali metal or an alkali metal alcoholate, and if Selly separates the individual isomers and / or the resulting compound of general formula (I) which is the free base is converted to its pharmaceutically acceptable acid adiclone, or the base is generally of formula (I) is liberated from its salt. 26. A process according to the first variant of claim 1, wherein the compound of general formula (III) is used as the reactant, wherein X is a fluorine atom. 3. The process of the second embodiment of claim 1, wherein the reactive carboxylic acid derivative of general formula (IV) is an acid halide. A process according to the second variant of claim 1, characterized in that as a reactive carboxylic acid derivative of the general formula