CA1259998A - 2,4,6,8-tetra-oxo-3,7-diaza bicyclo-(3,3,1)-nonane compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A compound corresponding to the formula:

(Vb)

Description

~12~ 3~

BAC~CGROUND OF THE INVENTION
1. FIELD OF THE INVENTION

~ The present invention relates to novel and valuable diaza bicyclo-(3,3,1)-nonane compounds, to processes of producing such compounds, to pharma-ceutical compositions containing diaza bicyclo-(3,3,1)-nonane compounds and their pharmaceutically acceptable acid addition salts, to processes of making such pharmaceutical compositions, and to methods of using said compositions in therapy.

2. THE PRIOR ART

3,7-Diaza bicyclo (3 ! 3,1)-nonane compounds have become of considerable interest in chemical as well as in pharmacological respect. The chemistry of said compounds is described, for instance, in the following publications:

... . ..... , ~, . .. . .... .

125~ 9~

Russian, Chem. Rev. vol. 34, page 439 (1965);
.~nm. Ist. Super Sanita, vol. 4, page 157 (1968~;
J. Org. Chem~ vol. 33, page 355 (1968);
Russian, Chem. Rev. vol. 42, page 190 (1973);
; Chem. Ber. vol. 110, page 3894;
~usLral. J. Chem. vol. 13, page i29 (1960);
J. Chem. Soc. vol. 115, page 686 (1919);
Pharmacological studies of said compounds have been described, for instance, in the following publication:
Eur. J. med. chem. 1977, pages 301-305.
The pharmacological properties of the known compounds extend from a relatively low local anesthetic activity as described in J. Chem. Soc. 1951, page 1706;
and an effect on the central nervous system as descrlbed in Published German Applications No. 26 58 558 and No. 27 49 584, up to a noteworthy antiarrhy~hmic activity as described in Published German Applications No. 24 28 792; No. 27 26 571, and ~o. 27 44 248.

SU~SI~RY OF ~E INVENTION
It is one object of the present invention to provide novel and valuable diaza bicyclo-t3,3,1)-nonane compounds which are characterized by a pharmacological profile of activity differing from that of the known compounds of Q1milar structure.
Ano~her object of the present in~ention is to provide simple and effective processes of producing such novel diaza bicyclo-(3,3,1)-nonàne compounds.
Another object of the present invention is to provide ~aluable intermediate products which can advantageously be used in preparing the novel and pharmacologically highly efEective diaza bicyclo-(3,3,1)-nonane compounds.

3 1~59~,~98 ~ further object of the presen~ invention is to provide novel anà efEective pharmaceutical compositions con~aining said novel diaza bicyclo-(3,3,1)-nonane compounds~
Still another object of the present invention i5 to ; provide a highly ef~ective method of using such pharmaceutical com-positions in therapy.
Other objects of the present invention and advantageous features thereof will become apparent as the descripcion proceeds.
The present invention is directed to novel dia~a bicvclo-(3,3,1)-nonane compounds of the following formula I
Z~

R~ 3--~4 / ~2 Z~ ~ 2 ~ ~ 2 In formula I
Zl and Z~ each denotes hydrogen, or both together form an axygen while Rl and R2 denote hydrogen, alkyl, alkenyl, or alkinyl, and R3 and R4 each denote an alkyl group, or both together form an alkylene group.
However, the designation of the above given substituents is characterized and limited by the following provisos:

3~3~

- 4 -~la) l~hen both substituen~s Rl and R2 are hydrogen and ~l ~nd Z2 together form oxygen, then ~he substituents R3 and/or R4 are alkyl with at least 2 carbon atoms and not methyl, or R3 and R4 together torm an alkylene group other than tetramethylene or pentamethylene,

5 i.e., R3 and R4 together for~ an alkylene group with less than 4 or more than 5 carbon atoms in the alkylene group.
(lb) l~en both substituents Rl and R2 are hydrogen and Zl and Z2 -re also both hvdrogen, then R3 and R4 are not both methyl, i~e., they are alkyl with at least 2 carbon atoms or one of them can be methyl and the other one al~yl with at least 2 carbon atomsq (~) When only one of the substituents Rl and R2 is hydrogen and the other one is methyl or ethyl, then R3 and R4 cannot both be methyl, nor can they together form tetramethylene or pentamethylene, i.e~, then R3 and R4 both are alkyl with at least 2 carbon atoms or together they form alkylene ~ith less than 4 or more than 5 carbon atoms.
(3) When both substituents Rl and R2 are not hydrogen but are alkyl, alkenyl, or alkinyl, then the substituents Rl, R2, R3 and R4 together must contain at least 5 carbon atoms.
According to a preferred variant of the present invention each of the substituents Rl and/or R2 of the diaza bicyclo-(3,3,1)-` nonane compound contains up to 12 carbon atoms and advantageously up to ;' carbon atoms.
As far as the substituents Rl and R2 indicate alkyl, such alkyl substituents can be branched alkyl groups as well as straight-chain alkyl groups. Straight-chain alkyl substituents are methyl, e~hyl, n-propyl, n butyl, n-pentyl, n-hexyl, or n-heptyl groupsO
Suitable branched alkyl substituents are iso-propyl, secondary butyl, 2-methyl propyl, 3-methyl butyl, 2,2-dimethyl propyl, 2-methyl pentyl, or 3,3-dimethyl butyl groups.

If the substituents Rl and/or R2 indicate alkenyl, such al~envl substituents can also be branched as well as straight-chain alkenyl groups. Straight-chain alkenyl groups are the pre-ferred substituents, such as the allyl, 2 propenyl, 2-butenyl, 5 3-butenyl, 2-pentenyl. 3-pentenyl, or 4-pentenyl groups. A .suit-able branched allcenyl substituent is, for instance. the 2-~ethyl-2-propenyl group.
According to another variant of the present invention the substituents Rl and R2 can also be cyc].o-alkyl ~roups and preferably cyclo-alkyl groups with 3 to 6 carbon atoms. Such cyclo-alkyl substituents are either directly attached to the respective nitrogen atom or bv interposition of an alkylene group with 1 to 3 carbon atoms and preferably of a methylene group. Examples of such cyclo-alkyl substituents are the cyclopropyl, cyclobutyl, cyclo-pentyl, and cyclohexyl groups. If these cyclo-alkyl groups are attached to the respective nitrogen atoms by means of an alkylene group, the preferred intermediate alkylene group is the methylene group.
As already mentioned above, the substituents Rl and R2 can indicate the same or different substituents. The preferred compounds are those in which the substituents Rl and R2 are the same groups, more particularly if the substituents R3 and R4 are different.
In so far as, according to a preferred embodiment of the present invention, the substituents R3 and R4 are alkyl, and more particularly straight-chain alkyl, the statements made hereinabove with respec~ to the substituents Rl and R2 apply accordingly to the substituents R3 and R4~ Preferably each of the substituents R3 and R4 contains 1 to 7 carbon atoms and more particularly 1 to 4 carbon atoms.

~2S9~99~3 In principle the substi~uents R3 and R4 rnay indica~e the same or different groups. Preferred compounds according to th~
present invention are compounds in which the substituents R3 and R4 indicate ~he same groups, especially if the substituen~s Rl and R2 are different groups.
.~ccording to a special embodiment of the present in-vention in which the substituent R3 is che same as the substituene R" said substituents R3 and R4 jointly may form an alkylene chain of the Formula -(CH2)n-. In this case, the preferred values Eor n are be~ween 3 and 6 and more particularly between 3 and 5.
! ~ subgroup according to the cosnpounds of the above given Formula I is characterized by the feature that the substitu-ents Zl and Z2 together ~or~ an oxygen group.
Said sub-group of compounds represents valuable inter-mediate products for the preparation of pharmacologically highlyeEfective diaza bicyclo-(3,3,1)-nonane compou~ds Said sub-group c~nprises compounds of Formula I in which both substituents Rl and R2 indica~e hydrogen. Especially selected representatives of this group of compounds are 2,4,6,8-tetra-oxo-3,7-diaza bicyclo-(3,3,1)-nonane compounds of the following Formula II in which the substituent R5 is hydrogen:
.

O O
~ ' R5~ H II

//~
O ~ \\O

- 7 - ~ ~ 9 ~9 ~
Furthermore, this sub group of compounds comprises compounds of Formula I, in which only one of the substituents Rl and R2 is hydrogen. Represent-atives of this group of compounds are 2,4,6,8-tetra-oxo 3,7-diaza bicyclo-(3,3,1)-nonane compounds of Formula II in which the substituent R5 indicates the same group as given for the substituent Rl, or such nonane compounds of the following Formula Va ~< ,, '.

H-~ 3~~ -R2 Va h7~ . .
O

where R2 is as previously defined, excluding hydrogen.

Compounds of Formula I in which both sub-stituents Rl and R2 are not hydrogen, are also included in said sub-group of compounds. Such compounds correspond to the following Formula Vb . .~ .

R~ 2 ,~ ' .
o ~L2S~9~

Other co~pounds corresponding to the following For~ula Vc R6- -R6 vc in which the substituents R6 correspond either to the substituent Rl or to the substituent R2, are comprised also be the aforesaid sub-group of compounds. Compounds of the type of Formula Vc are designated as symmetrically substi~uted compounds, because the sa~e substituent is attached to both nitrogen atoms.
The second subgroup of compounds of Formula I is charac-. teriæed by the feature that each of the substituents Zl and Z2 o indicates hydrogen.
This sub-gro~p of compounds comprises compounds of the following Formula YIa H 'fI a \\ ~

In said Formula both substituents Rl and R, have already ~een denoted as hydrogen.

~s9~

Said sub-group of compou~ds also comprises compounds of the following Formulas VIb or VIc in which only one of the substituents Rl or R2 is hydrogen-R1~ ~\N-H VIb \

R2 ~Z~ -H y Said compounds of Formula VIa, YIb, and VIc represent also useful intermediate products for the preparation of pharmacologically especially effective diaza bicyclo-(3,3,1)-nonane compounds according to the present invention.
Furthermore, the present invention co~prises also com-pounds in which the substituents Zl and Z2 indicate hydrogen while the su~stituents Rl and R2 do not indicate hydrogen, but rather one or ~he other of the substituents mentioned hereinabove. These com-pounds correspond to the For~ula VlIa .

~25~ 3~

R~ -R2 VI

or of the Formula VIIb .

~>-R6 VlIb) The compounds of Formula VlIb are sym~etrically substituted whereby the substituents R6 correspond either to the substituent Rl or to the substituent R2 as given for the compounds of Formula I herein-above. The compounds of Formulas VlIa and VIIb possess ~aluable phar~acological properties.
Especially useful representatives of compounds selected from the group characte~ized by For~ula VIIa are, -or instance, 3,7-dia2a bicyclo-(3,3,1)-nonane compounds which are substituted by the following substituents:

~259~

N-Isopropyl-N'-(2-methyl propyl)-9,9-pentamethylene-, N-Isopropyl-N'-(cyclohexyl)-methyl-9,9-di-n-butyl-, N-n-~utyl-N'-(2-methyl propyl)-9,9-dimethyl-, N-n-Butyl-N'-(cyclohexyl)-methyl-9,9-dimethyl-, ; N-n-Hexyl-N'-methyl-9,9-diethyl-, N-(2-~ethyl propyl)-N'-(3-butenyl)-9,9-di-n-propyl-, N-n-butyl-N'-(3-butenyl)-9,9-dimethyl-.
Selected representatives of the group o~ compounds charac-terized by Formula VIIb are 3,7-diaza bicyclo-(3,3,1)-nonane compounds with the ~ollowing substituents:
N,N'-Diethyl-9,9-dimethyl-, N,N'-Di-n-propyl-9,9-diethyl-, N,N'-Di-isopropyl-9,9-dimethyl-, N,N'-Di-isopropyl-9,9-di-n-propyl-, N,N'-Di-n-butyl-9,9-dimethyl-, N,N',9,9-Tetra-n-butyl-, N,N'-Di-n-butyl-9-methyl-9-ethyl-, N,N'-Di-(cyclopropyl)-methyl-9,9-tetramethylene-, N,N'-Di-n-hexyl-9,9-dimethyl-, N,~ -Di-n-hexy~9-ethyl-9-n-butyl-, N,N'-Di-n-hexyl-9,9-tetramethylene-, N,N'-Di-(cyclohexyl~-methyl-9-methyl-9-ethyl-, N,N'-Di-(cyclohexyl)-methyl-9,9-pentamethylene-, N,N'-Di-n-decyl-9,9-dimethyl-, N,N'-Di-isopropyl-9-methyl-9-n-propyl-, N,N'-Di-n-butyl-9~9-trimethylene-~N,N'-Di-~2-propenyl)-9,9-dimethyl-, N,N'-Di-(3-butenyl)-9,9-pentamethylene-, N,N'-Di-(3-butenyl)-9,9-dimethyl-, ~l,N'-Di-(3-butenyl)-9-methyl-9-n-propyl-.

Furthermore, the present invention is concerned with pharmaceutical co~positions which contain at least one compound oî the Formulas VIIa or VIIb or their pharmaceutically acceptable acid addition salts.
SuitaDle ?ha maceutically acceptable acid addition sal~s are, for instance, wacer soluble as well as wacer insoluble salts with inorganic or organic acids, such as, for instance, the hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, perchlorates, acetates, propionates, butyrates, citra~es, gluconates, benzoates, salicylates, sulfosalicvlates, ~aleinates, laurates, fumarates, succinates, tartrates, oxalates, stearates, tosylates (p-toluyl sulfonates), 2-hydroxy-3-naphthoates, 3-hydroxy-2-naphthoates, mesylates C~eth~ne sulfonates), naphthalene sulfonate;, and the like.
The present invention is also concerned with providing simple and effective processes of produ~ng 3,7-diaza bicyclo-(3,3,1)-nonane co~pounds of the Formula I as gîven hereinabove. Said process is characterized bv the feature that (a) in order to produce compounds of Formula II, correspondingly ~0 substituted dinitriles of For~ula III
~_<,C'I~

R5-N >~ III
-~ \ .
~ CN

- 13 - ~ ~5~9~

or mononitriles of Formula IV

~ /
R5- ~ ~ IY

~

in which Formulas the substituent , R indicates hydrogen or the substituent Rl, while the sub-S stituents Rl, R3, and R4 indicate the subs~ituents given hereinabove, are hydrolyzed under acidic conditions to the bi-- cyclic compounds of Formula II

o 9 R5 ~ ~-X (Il) ~\0 (b) In order to produce compounds of Formula V, the resulting, cor-respondingly substituted compourds of Formula II
(bl) in which the substituent R5 is nydrogen or the substituent ~1 are mono-alkylated ~i~h a compound of Formula R~, in wnich X
is a reacti~e group, ~o compounas ol For~ulas Va or ~b i2S'~

H-N/~3 N-R2 Ya o P~2 Vb O
.

(b2) According to another embodiment of the present invention the compounds of For~ula II in which the substituent R5 is hydrogen~
are dialkvlated wit:~ a compound of For~ula R6~ in ~hich X is a reactive group9 to yield symme~ricallv substituted compounds of Formula Vc ï2~

O D
~~~ .

R6~ R6 ( vc ) in which the substituents R6 correspond either to the sub-stituent Rl or to the substituent R2 as given hereinabove.
(b3) According to another embodiment of the alkylating process step (b) of the present invention, the compounds of Formula II
in which the substituent R5 is hydrogen, are successively mono-alkylated with compounds of the Formulas RlX and with compounds of the Formula R2X to yield the dialkylated co~pounds of Formula Vb as given hereinabove. 0 (c) In order to produce compounds of Formula VI, the resulting, correspondingly substituted compounds of Formulas II or Va are reduced to compounds of Formulas VIa, VIb, or VIc ~, }~ R~5 ~4 ~-H VI ~
\

3L259'~98 R1~ H VIb \\ \/

F~2 \~>-h ~Ic (d) Compounds of Formula VII are produced (dl) ~y reducing the resulting, correspondingly substituted com-pounds of For~ula Vb to compounds of Formula VIIa R î \ ~'-~2 (VII

125~99~3 (d2) ~ccording to another variant of the present invention com-pounds of Formula ~'c are reduced to sy~etrically substituted compounds of Form~l~ VIIb _~-R6 ( VIIO) (d3) By proceedi~g according to step Cd3) compounds of Formula VIa are dialkylated by .eaction with compounds of For~ula R6X to yield sym~etricallv substituted compounds of the above given Formula YIIb.
(d4) Or according to ste? d4 compounds of Formula VIa are succes-sively ~ono-alkylat2d by reaction with compounds of Formula RlX and with compou~ds of Formula R2X to yield compounds of Formula YIIa.
(d5) According to step d; compounds o Formulas VIb or, respectively, VIc are mono-alkylar~d by reaction with compounds of the Formulas Rl~ or, respectively, R2X to compounds of Formula VIIa.
(.d6) ~ccording to step d6 compounds of For~ula VIb are mono-alkyl-ated by reaction ~ith compounds of ForDula Rl~, while com-pounds of Formula Vlc are mono-alkylated with compounds or Formula R2~ so as to yield sym~etrically substituted com?ounds ~O of Formula VIIb.

` 18 - 12~9~ 8 DET.~ILED DESCRIPTION OF PREFERRED EMBODIMENTS

In all these reaction steps the substituent X indicates a gruup or atom which is capable to react with the hydrogen atom of the starting materials of Formulas V or VI so as to attach the group Rl or the group R2 to the compound of Formulas V or VI, j wnereby ehe subs~ituent X aots as a so-called "v2n-shing group".

The preferred sequence of reaction steps for producing the final products of Formula VIIa are the steps a, bl, or, re-spectively, b3, and dl. The final products of Formula VIlb are preferably produced by following the reaction steps a, b2, and d2.
The intermediate products obtained by carrying out said interme-diate reaction steps represent espec.ally valuable and ?referred inter~ediate products according to the present invention.
The 2,4,6,8-tetra-oxo-3,7-diaza bicyclo-(3,3,1)-nonane compounds of For~ula II can also be prepared in an analogous manner as described in J. Am. Chem. Soc. vol. 80, page 3915 ~1958) by re-acting the dinitriles of For~ula III

~ ~ N

R5-N ~ (III) ~ \
~ C~' or the ~ononitriles of Formula IV

-19- ~.2S~t~
o~ c~

R5 ~ ~ (IV) `R
> = 4 with mixtures of acid and water of a high acid content, for instance, with highly concentrated sulfuric acid or phosphoric acid. The dinitriles of Formula III
are known from the literature or they can be syn-thetically produced in an analogous manner inaccordance with known processes by condensing alkylidene acetic acid esters with cyano acetic acid amides as described in Org. Syn. vol. 39, page 52, or by reacting cyano acetic acid esters with ketones in ammoniacal alcohol solution in accordance with the process described in Org. Syn. vol. 36, page 28.
The mononitriles of Formula IV which are partly known from the literature, are obtained by condensation of the respective ketones with cyano acetamide in an alkaline medium as described in J. Chem. Soc. vol. 99, page 422 (1911).
The reduction of the 2,4,6,8-tetra-oxo-3,7-diaza bicyclo-(3,3,1)-nonane compounds of Formula II or, respectively, that of their N-mono-alkyl derivatives of Formula Va or, respectively, o~ their N-N -dialkylation product of Formulas Vb or Vc can also be carried out in a known manner, for instance, as described in J. Am. Chem. Soc. vol. 78, page 2582 (1956; or in Israel. J. Chem. vol. 4, page 39 (1966).
Complex metal hydrides such as, for instance, ~.~

~2S~ 3~3 -- ZO --lithium aluminum hydride or sodium boron hydride in the presence of Lewis acids have proved to be especially advantageous reducing a~ents for the reduction of the oxo groups.
Preferably lithium aluminum hydride is used in a mix-cure of 70 parts of cetrahydrofurane and 30 parts of toluene. In contrast to the above mentioned methods or to the procedure de-scribed in Europ. J. Med. Chem.,vol. 12, page 301 (1977) there is achieved complete reaction in said solvent mixture already af~er a relatively short reaction time of about 2 hours to 4 hours. If access and act.ion of the reducing agent are being hindered for steric reasons, for instance, when reducing N-isopropyl substituted starting compounds, more prolonged.reaction times are required. It has proved to be of advantage to use an excess of the reduci.ng agent amounting to Z00 % to 400 % thereof.
If the tetra-oxo compounds are substituted by unsatura-ted groups ~ and/or R2, for instance, by alkene or alkine groups, sodium bis-(2-methoxy ethoxy) dihydro aluminate is used as the pre-ferred reducing agent.
The alkylation of the tetra-oxo compounds of Formulas II
` 20 or Va or that of the diaza bicyclo-(3,3,1)-nonane compounds of Formulas VIa, VIb, or VIc obtained by reduction of the tetra~oxo compounds is carried out under basic conditions, for instance, with sodium hydride in dimethyl formamide, with alkali metal carbonate in dimethyl formamide, with sodium methylate in methanol, with sodium propylate in propanol, with sodium isopropylate in iso-propanol, or with sodium amlde in toluene or xylene, in accordance with the known principle of phase transfer catalysis, among others.
The alkylation, especially that of the eetra-oxo compounds of Formulas II, Va, or Vb in which the substituent Rl is hydrogen, is most advantageously effected with sodium hydride or an alkali metal carbonate in dimethyl formamide a~ increased temperature.

. . . . .. . _ . . ..

9~9~

The starting materials used in the above described processes are preferably employed in stoichiometric amounts. For the alkylation of the compounds of Formulas II or, respectlvely, VI there is preferably employed an excess of alkylating or depro-tonising agent in an amount of 25 ~ t:o 70 ~.
As alkylating agents there are used compounds of theFormulas ~ ~, R2X, or, respectively, R6~ in which the substituent X
indicates a reactive or "vanishing" group, as it is known.
~ore particularly the most useful alkylating agents are the cor-responding alkyl halogenides, alkyl tosylates, alkyl brosylates, oralkyl mesylates. The most preferred alkylating agents are the alkyl halogenides and especially the alkyl chlorides or bromides.
It is also pos~ible to produce the alkylating agent in situ from the corresponding alcohols~ for instance, according to the method of Mitsunobu, a5 described in Synthesis 1931, page 11. When pro-ceeding accordi~g to said method,it is not necessary to add a de-protonising agene.
The reactions described hereinabove can be carried out at atmospheric pressue or also at increased pressure. Working at atmospheric pressure is the preferred procedure.
The reactions take place preferably in an inert organic solvent or in a mixture of such a solvent with water. Suitable inert organic solvents are, for instance, ethers, such as diethyl ether, dioxane, or tetrahydrofurane, halogenated hydrocarbons, such as methylene~dichloride, or carbon tetrachloride, dimethyl formamide, or acetone.
The reaction temperatures at which the aforesaid processes are carried out, can vary within a range between about 20C.
and about 200~ C. and preEerably between 40 C. and lS0~ C.

~25999~

Separation of ~ono- and di-alkylation products which might become necessary, can be effected in a manner known per se, for instance, by alkaline extraction or by chromatographic sepera-tion.
The above disclosed processes permit the preparaeion of compounds with the most varied pattern of substicu-tion. Thus it is possible to achieve symmetric or asymmetric substitution in 9-position of the resulting diaza bicyclo-(3,3,1)-nonane compounds, more particularly by selecting the desired sub-stituents R3 and R4 in thestarting materials of Formulas III and IV.
On the other hand it is also readily possible to produce N,N'-symmetrically or N,N'-asymmetrically substituted diaza bicyclo-3,3,1)-nonane compounds of Formulas II, Va, Vla, VIb, or VIc by selecting the respective alkylating agents of Formulas RlX or R2X.
If the substituent. Rl or, respectively, the sub-stituents R5 and Rl and also the substituents R3 and R4 are different from each other, there is obtained a mix~ure of stereoisomers in the various process steps. These stereoisomers can readily be ; 20 separated from each other by known methods, for instance, by fractional precipitation of suitable salts of the compounds, by fractional column chromatography9 or by fractional seperation by adjusting the aqueous solution to varying pH-values. If the sub-sti~uents R3 and R4 are different from each other, separation is preferably carried out with the tetra-oxo compounds of Formulas II, Va, or Vb or with the diaza bicyclo-(3,3,1)-nonane compounds of Formulas VIb or VIc obcained from the compounds of Formulas II, Va, or Vb by reduction.
The acid addition salts obtainable according to the present invention are produced in a known manner bv reacting the basic compounds of For~ula I with acids which form pharmaceuti-cally acceptable salts.
.

9~9~3 The compounds of Formulas VIIa and VIIb and their pharmaceutically acceptable acid addition salts are characterized and distinguished by interesting pharmacologlcal propercies. More particularly, they reduce oxygen consumption by the heart, affect heart rate, and normalize cardiac rhythm. The novel coMpounds according to the present invention thus have a noteworthy activity and a high physio~ogical compatibility.
As a result thereof, said novel compounds exhibit a satis-factory anti-arrhythmic activity in relatively small doses.
On the other hand, only a very minor ~mdesired negative i~-fluence on the contractile force of the heart has been observed.
Accordingly, the novel compounds are characterized by an especially favorable relation between anti-arrhythmic activity or prolonga-tion of the cardiac refractory period and negative inotropic side effects. Thus, they possess a satisfactory therapeutic index. Surprisingly, they show a positive inotropic activity when administered in small doses.
The influence of the active compounds according to the present invention on myocardial oxygen consumption has been investigated in animal models and determined according to the method of Neill as described by W.A. Neill, H.H. Levine, R.J. Wagman, and P. Gorlin in Circulation Research, Vol, 12, page 163 (1963). The blood circulation measurements which are required for these tests, namely, systolic blood pressure and heart rate, were determined accordin~ to the design of experimental procedure as described by G. ~ushmann, W. Schumacher, R. Budden, and U.G. Kuehl in J. Cadio-vasc. Pharmacol., Vol. 2, pages 777-792 (1960). As is evident from the ollowing Table l, the active compound reduces the product of heart rate and systolic blood pressure. Thus, the tested compound reduces the consumption of oxygen to be supplied to the heart. This effect is observed in intravenous administration ti.vo) as well as ,i9~98 on intraduodenal administration (i.d.) and is to be a~tributed to the action of the compound tested.
The anti-arrhythmic activity of the active compounds according to the present invention was demonstrated on the intact e~Yperimental animaL by means of experimeneally produced disturbances of the cardiac rhythm. When administering aconitine to rats by continuous intravenous infusion, there are observed in the eletro-cardiogram considerable disturbances in the heartbeat, such as, for instance, ventricular extrasystoles. l'he tested aniMals were male Wistar rats of the weight class between 250 g. and 350 g. The in-fluence of an active compound according to the present invention upon such rats af~er an aconitine infusion was determined according to the method of Raschak as described by M. Raschak in Arzneim.
Forsch. vol. 25, No.4, pages 639-641 (1975). The results of these tests are given hereinafter in Table 2. Said Table 2 shows the difference in time, in %, between a test with the active compo~nd and a control test at which ventricular extrasystoles were observed on administration of the active compound and a control solutionO
The active compound was admlnistered intravenously in the form of an isotonic sodium chloride solution, i.e. the vehicle, in a dose of 6.0 ~mole/kg. Th8 dose administered is one t~enthieth of the lethal dose (LD50) as determined on ~ice. The LD50 on peroral administration to mice of the tested compound amounts to 1038 ~mole/kg. The control test was carried out by intravenous administra~ion of the vehicle, i.e. of an isotonic sodium chloride solution. After intravenous administration of the active compound to be tested and of the control solution, the aconitine solution - was administered by infusion in an amount which was constant per time unit. The period of time was measured within which ventricular extrasystoles (ES) were observed. Said period of time, in minutes, is given in Table 2 as well as the difference in the period of time observed on administering the test compound and the control solution.
One of the active compounds tested is the compound of Example 3, No. 302, i.e., N,N-di- n -butyl-9,9-dimethyl-3,7-diaza bicyclo-(3,3,1)-nonane as described hereinafter. There are also given the results obtained by testing an equitoxic amount of the drug known under the traderLark "Lidocain", i.e., 2-(diethylamino)-N-(2,6-dimethyl phenyl)-acetamide. Said compound is a known anti-arrhythmic agent which is used in human therapy and has proved to be highly effective. In addition, the test results, as hereinafter described, for three other compounds according to the present invention, are given in Table 3.

' 12~;~99~

,~ , I I , Ul ~ o ~ ~ , ~ ~ ~ ~ I
h C I ~ - O
C C~

~- `rl C I .
tJ ~ I I
-/ C I --' I , I
r l r~
' -- I I . I
~ --I 1` 1~ o aJ a~ I I I
~ _I I I

_ ~ Q e , o ~

1~ 5 E-~ O I ~ kl Z

~.~5~9~

. - 27 -T a b 1 e 2 Anti-arrhythmic activity determined by the aconitine test in rats ___________ _____________________________________________________ Test compound Dose Time to Change ~mole/kg.~ occur.rence [ % ]
of E', [min.]
_____________.______________________________________________________ Control test with vehicle 0 6.7 Example 3, No. 302 administered as '~_ 10 di-tartrate 6.0 8.2 ~ 23 Control test with vehicle 0 6.3 Lidocain lO 0 6.6 ~ 5 ______ ___ _____ ___ _____ ______________ .________________ __ __ __ ___ __ Furthermore the anti-arrhythmic activity of the novel active compound can be demonstrated and proved experimentally by 'i measuring the functional refractory period of the left atrium cordis of female albino Pirbrigh~-whlte guinea pigs of the weight class between 300 g. and 400 g. by means'of paired electrical stimulation in accordance with the,method of Govier as described in J. phar~a~nl~
Exp. Ther.,vol. 148, No. 1, pages 100-105 (1965). All anti arrhythmic drugs which at present are used in therapy and which differ in their chemical structure are distinguished by being able to prolong the functional refractory period. In addition thereto said method permits to detect the effects of compounds on the contractile force of the myocardium. Therefore, there are given in Table 3,as the functional refractory period FRP 125 ~O~ the values for those concen-trations in ~mole/l. which cause a prolongation of the functional ... ....

~5'9~398 refractory period to 125 % 18 ~inutes after administration of the compound co be tested, or, respectively, as contractile force F 75 %
the corresponding concentrations which cause a reduction of the con-tractile force to 75 % of the initial value. Furthermore, there is listed in Table 3 the quotient F 75 %/FRP 125 %, i.e. the quotient of the dose causing a decrease of the contractile force by the dose causing prolongation of the refractory period. Said quotient supplies information regarding the therapeutic index of the anti-arrhythmic action of a compound on the isolated organ. See P. Greef in Verhandlung der Deutschen Gesellschaft fuer Kreislaufforschung vol. 35, pages 88-97 (1969).
The direct effect of the active compound on the heart rate (FPQ) was tested on the spontaneously beating, isolated right atrium cordis of female albino Pirbright-white guinea pigs (GP) of 15 the weight class between 300 g. and 400 g. In Table 3 there ls given, as FPQ 75 %, the concentration in ~mole/l. by which a de-crease of the heart rate to 7~ % of the initial value is achieved 20 minutes after administration of the compound to be tested.
It follows from Table 3 that the novel active compound tested does not exhibit any noteworthy undesirable negative ino-tropic effects but that it displays an anti-arrhythmic and the heart rate reducing activity already at a very low concentration.

~2~ 398 T a b 1 e 3 Effect on the heart rate (FRQ) of the spontaneously _ __ ___ _ __ ~_ _ beating right atrium cordis of guinea pigs as well as on the contracti:Le force (F) and on the function-al refractory period (FRP) of the electrically stim-; ulated left atrium cordis of guinea pigs ____________________________________ _______________~_______________ Test compound Effective concentration in Quotient:of Formula I (~mole/:l.) . ~ FRQ 75 % F 75 % FRP lZ5 % F 75 %
~P 125 %
________________________________________ _______________ ___________ Example 3 No. 302 ad-ministered as di-tartrate 3 104 l 104 Comparative com-pound administered as di tartrateabout 215about 215122about 2 The results obtained in comparative tests which were carried ou~ with the known compound N,N',9,9-tetramethyl diaza bi-cyclo-(3,3,1)-nonane are also given in Table 3. Said comparative compound is very closely related in its structure to the compounds according to the present invention such as the N,N1-di-n-butyl-9,9-dimethyl-3,7-dia~a bicyclo-(3,3,1)-nonane compound of Example 3, No. 302. The comparative tests clearly show the outstanding superior therapeutic index of the compounds according to the present invention in contrast to the known compounds,although said known compounds 25 per se exhibit a therapeutic index of action which is superior over .

~259g~9~

that of recognized known agents, such as, for insLance, "LIDOCAIN", as follows from the expert opinion given in Table 1 of published German Patent Application No. 24 28 792.
The superior activity of the compounds according to the present invention i9 characteri~ed by ~he combination of the ~ollow-ing effects: ~he reduction of oxygen consumption by the heart, the normalization of the cardiac rhythm, a favorable influence on the heart rate, and a positive inotropic effect.
This profile of pharmacological activity renders possible the use of the new compounds in the treatment of the ischemic heart disease, of life threatening arrhythmias, and of heart failure.
The compounds according to the present invention produce the above mentioned pharmacological effects within a dosage range between about 0.1 mg./kg. and about 10 mg./kg. They can be ad-ministered enterally or parenterally.
The present invention is also concerned with a process of producing novel and valuable pharmaceutical compositions which `- contain at least one compound of Formulas VlIa or VIIb or their pharmaceutically useful and acceptable acid addition salts. Said process comprises mixing said active co~pounds with suitable inert pharmaceutically acceptable excipients and converting the re-sulting mixture in a known manner into the desired galenic preparations. Suitable galenic preparations may be, for instance, tablets, dragees, capsules, powders, granules, aqueous or oily sus-pensions, emulsions, syrups, or solutions for oral ad~inistration, suppositores for rectal application, or sterile injectable suspen-sions or solutions for parenteral administration.

.. . . .. . . . ... . .... .. .

9~:39~

The reaction summary on the following page illustrates the process of producing the compounds according to the present invention as described hereinabove. The synthesis illustrates the various reaction steps which are carried out in order to convert the compounds of Formulas III and IV by way of the intermediates of Formulas II, Va, Vb, Vc, VIa, VIb and VIc into the phar~acologically effective 3,7-diaza bicyclo-(3,3,1)-nonane compounds of Formulas VIIa and VIIbo The following examples serve to illustrate the present invention without, however, limiting the same thereto. They de-scribe more in detail the process of producing the novel compounds of Formula I and the preparation of pharmaceutical compositions containing active compounds of said Formula.

Example 1: General description of the procedure to be followed __________ in order to effect cyclization so as to produce 2,4,6,8-tetra-oxo-3,7-diaza bicyclo-(3,3,1)-nonane compounds of Formula II:
ZO g. of the dinitrile of Formula III which was prepared in an analogous manner according to the process described in Org. Syn.
vol. 39, page 52, or, respectively, 20 g. of the mononitrlle of Formula IV which was prepared in an analogous manner according to the process described in J. Chem. Soc. vol. 99, page 422 (1911), are heated in a~out 100 ml. of an acid of the composition and con-centration as given hereinafter in Tables 4a and 4b, between aboue 120 C. and about 140 C., while stirring, until they are comple-tely dissolved. Af ter about ~lO minutes to about 15 minutes the - 3 2 - ~1L2~j9~9~

. c~ \x \x ~xx ~. ~
~C

C: ~ .~ . ~ ~
~ X~ ~ ~ I
- ~' .

o ..

.~

_33~ ~X5~3~9~
entire reaction mixture is poured into ice water.
The precipi-tated tetra-oxo compound of Formula II is filtered off by suction, if required, is recrystall-ized, preferably from ethanol, and is dried. By S proceeding in this manner, there are obtained the compounds listed in Tables 4a and 4b.
able 4a: Production of tetra-oxo compounds of_ _ Formula II in which the substltuent R5 is hydrogen Compound R3 R4 Acid Melting No. Point [vol. ~] [ C.]
_______________________________ ______________________ 101 x) CH3 CH3 2 4 above 350 102 C2H5 C2H560 % H2S4 230 104n C4 9 4 92S4 195 - 199 105-(CH2)3- H2SO4 above 350 106 x)-(CH2)4 60 % H2S4above 350 107 x)-(CH2)5- H2SO4 310 108 x)CH3 C2H5 25 4/ 3PO4 3 4 109 x)CH3 n C3H7 2 4/ 3PO41 1 275 110C2H5 n-C4H9 70 ~ H2S4 140 x) Compounds not covered by the present invention.

-34- ~ S ~ ~g ~

Table 4b. Production of -tetra-oxo compounds of Formula II in which the substituent R5 corresponds to the substituent R

,Ço,m,-.
S' pound Melting No. Rl R3 R4 Acid Point [vol. ~] [ C.]
_______________________________________________________ 150 n-C4Hg CH3 CH3 H2SO4/H3PO4].:1 175-151 -CH2-CH(CH3)2 n-C3H7 n-C3H7 H2S4/H3 4 153 152 -CH2 ~ n-C4Hg n-C4H9 60 ~ H2S4 140 .. . .
153 n-C6H13 C2H5 C2H5 H2SO4/H3PO41:1 -oil 154 -CH2-CH(CH3)2 (CH2)5 H2SO4/H3PO41:1 182 Exam21e 2: General description of -the procedure ' to be followed in order to effect alkylation of the tetra-oxo compounds of Formula II

~ 35 ~ ~ 5 9 ~ g 8 Variant 2a Di-alkylation of the tetra-oxo compounds of Formula II in which the substituent R5 is hydrogen, by means of alkylating agents of Formula R6X in order to produce coMpounds of Formula Vc.
0.1 mole of the tetra-oxo compound of Formula II as obtained according to Example 1, is weighed into a preheated three-necked flask. 209 ml. of absolute dimethyl fornk~mide are added thereto. The mixture is heated to a temperature between about 60 C.
and about 70 C. Thereupon 0.25 mole of sodium hydride/ calculated as 100 % NaH, are added portion by portion to said mixture which is then boiled under reflux for about 1 hour. After cooling the re-action solution, there are added drop by drop, but relatively fast, 0.3 mole of the re~pective alkylating agent dlssolved in 50 ml. of absolute dimethyl formamide. The resulting alkylation mixture is then boiled under reflux for 3 more hours. Thereafter most of the solvent is distilled off in a vacuum. Methylene chloride is added to the residue and the ~ixture is washed with a 20 % sodiwm hydroxide solution. The aqueous phase is again extracted with methylene chloride. The organic solvent phases are combined, washed several times with water, and dried over magnesium sulfate. After distilling off the solvent, the remaining residue is recrystallized from a mixture of ether and hexane.
Alternatively the alkylation is carried out with the addition of an alkali metal carbonate as basic agent instead of sodium hydride, as it is described hereinafter:
. 0.1 mole of the tetra-oxo compound of Formula II, obtained according to Example 1, is weighed into a preheated three-necked flask. 0.25 mole of an alkali metal carbonate and 200 mlO of absolute dimethyl formamide are added thereto. The mi~ture is heated 3~ to 120 G. for one hour. After cooling the resulting reaction . .

_ 3~ S ~

solution, there are added drop by drop, but rather rapidly, 0.3 ~le of the alkylati~g agent dissolved in 50 ml. of absolute dimethyl formamide. The resulting reaction mixture is then boiled under reflux until complete reaction has taken place. After working up the reaction mixture as described hereinabove, the remaining residue is recrystallized from a mixture of ether and hexane.
Some of the compounds obtained according to the above described procedure are listed and characterized in Table 5a. "A"
in the column "Base" of said Table 5a indicates sodium hydride while "C" indicates an alkali metal carbonaee.

~ria~t 2b : General descriptibn of the procedure ~o be followed __________ in order to effect mono-alkylation of tha tetra-oxo compounds of Formula II in which the substituent R5 corresponds to the substituent Rl, by means of alkylating agents of Formula R2X in order to produce compounds ~f Formula Vb.
The procedure is the same as described hereinabove in Example 2a whereby, however~ in each case half the amount of sodium hydride or, respectively, of an alkali metal carbonate as well as of the al~ylating agent is used for carrying out the reaction.
By proceeding as described hereinabove in Example 2b there are obtained the compounds lis~ed in Table 5b.

- 37 - ~ 9~
Table 5a- Di-alkylation of the tetra~o~o compounds of Formula II in which the substituent R5 is hydrogen, by means of an alkylat-ing agent of Formula R6X in order to produce compounds of Formula Vc Com-pound Melting No. Rl ~ R2 R3 R4 X Base Point '' [ C- ]
__ ____________--_--_---------- ------------____________________________.

0 201 C2H5 C2H5 CH3 CH3 Br A 152-153 202 n-C4Hg n~C4H9 CH3 CH3 Br C 97 203 n-C6H13 n C6H13 CH3 CH3 Br A 68-69 204 CH2=CH CH =CH CH3 CH3 Br C 91 205 i 3H7 i_C3H7 CH3 CH3 Br A 99-101 206 10 21 n ClOH21 CH3 CH3 Br A 63 207 n-c3~l7 n 3H7 C2H5 C2H5 Cl A 94 208 3 7 i C3H7 n C3H7 n-C3H7 Br A 145-147 209 CH3 CH3 n~C4H9 n C4Hg J A 135-137 210 n-C4Hg n-c4H3 n~C4H9 n-C4Hg Br A 73-75 211 n C6H13 n C6H13 -(C82)4 - Br A 70 212 -CH ~ -CH2 ~ -(CFI2)4 - Cl A 160-161 ~.~

- 38 - 1~5~9~3 Table 5a continued:
___________________ Com- l~lel~ing pounà Rl R2 R3 R4 X Base poin~

_________________________________________________________~____________ ~, 3 -C:i -O -C~2~ - (C~i2) g- 2~ ~ 1 40 2 I CH2 =fH - ( CH2) 5- Br C 120 C~3 2 ~ H 2 -CH 2 -CH 2 215 n-C H n-C H 3 2 5 Br A 82 216 -CH2{> -CH2{~CH3 C2H5 Br A1 12 115 217 3 7 3 7CH3 3 7 Br A 103 lO 218 CH2=CIH 2 ICH3 n-C H B~ A 57 ~CH 2 ~C~ 2 -CH 2 C~ 2 219 n--C6H13 n C6H13C2H5 4 9 Br A ~l 2 2 0 CH 2 =iCH 2 I CH 3 CH 3 Br A 1 2 ~ -1 3 0 221 4 9 4 9 - (CH2 ) 3- Br A1 10 - 3~ - 9 8 Table 5b : ~ono-alkyla~ion of ~he te~ra-oxo co~pounds of For~u-la II in ~hich the subs~ituent ~ corresponds to ~he substieuent Rl, by ~eans of alk.la~ ng agents of For-~ula R2X in order to produce co.pounds of For~ula Vb 5 Co~- Melting pNOund Rl R2 Base poin~

___________________________ _____ ____~_________________________________ ` 250 4 9 2 ( 3) 2 CH3 3r A 80 2 514 g 2 CH 3 3r A 8 0 - 8 3 -CH -CH

lù 252n-C4~9 -C~2- c~3 ~r A 100 253.CH3 6 ~3 C2H5 J A 93-96 254i--C3H7 CH2-0 rl-C4H9 3r A ~ 85 255 -CH2-CH (CH3) 2 2 ~ 3 7 3r A Ol 256 i-c33l7 -C~2 CH ~CH3) 2 ~ 2~ 4 A 101 ._ _ _ _ .j , .

~` - 40 - ~5~g~

Example 3- General description of the procedure to be followed in order to reduce the di-alkylated tetra-oxo compounds of Formulas Vb or Vc to the 3,7-diaza bicyclo-(3,3,1)-nonane compounds of Formulas VIIa or VIIb.
0.1 mole of lithium aluminum hydride are placed with a mixture of 100 ml. of a solution of 70 ml. of absolute tetrahydro~
furane and 30 ml. of absolute toluene into a preheated three-necked flask. There are slowly added thereto drop by drop 0.025 mole of the tetra-oxo compound of Formulas Vb or Vc in 100 ml. o~ a mixture of 70 ml. of tetrahydrofurane and 30 ml. of toluene at an oil bath temperature of 80 C. The reaction mixture is kept at a temperature of 120 C. for 2 to 4 hour~. Thereupon the reaction mixture is hydrolyzed under basic conditions. . The reaction mixture is then extracted with methylene chloride and the or~anic phase is dried over magnesium sulfate. The dried organic phase is then concen-trated by evaporation. The residue i5 subjected to fractional distillation under reduced pressure in a destillation flask provided with a bulb-tube fractionating column. By proceeding in this manner there are obtained, for ins~ance, the 3,7-diaza bicyclo-(3,3,1)-nonane compounds listed in Table 6a.
N,N'-disubstituted tetra-oxo compounds of Formulas Vb or Vc in which the substituents at the nitrogen atoms are alkenyl groups, are reduced in an analogous manner as described hereinabove by usingl as reducing agent, sodium bis-(2-methoxy ethoxy)-dihydro aluminate (sold under the trademark "Red-Al") in toluene. The reaction ~roducts obtained in this manner are listed hereinafter in Table 6b.

~ ~5~ 9~3 Table 6a: Reduction of the te-tra-oxo compounds of Formulas Bv or, respectively, Vc to the corresponding 3,7--diaza bicyclo-(3,3,1)-nonane compounds of Formulas VIIa or, respectively, VIIb.

Com- , -pound R . R R R 3Oiling No. 1 2 3 4 Point 0 0.1 ~orr.]
_____________________ ___--____________________________________ 302 n C4~9 n~C4H3 C~13 CH3 130 303 n-C6H13 n C6H13 CH3 CH3 210 - 220 304 i-C3H7 i C3H7 CH3CH3 100 - 120 305 n-ClOH21 n-ClOH21 CH3 CH3 230 306 n C3H7 C3H7 C2H5 C2H5 140 - 150 307 i-C3H7 i C3H7 n-C3H7 n~C3H7 150 - 160 308 n 6H13 n C6H13 -(CH2)4 - 250 309 -CH ~ -CH2 ~ -(CH2)4 - 230 310 n-C4Hg n C4Hg CH3 C2H5 180 - 200 311 6 13 n C6H13 C2H5 n-C4H9 230 312 n C6H13 CH3 2 5 C2H5 130 ~. ' 125i~5~9~
-- 4~ --Tab 1 e 6 a c on t inued .
Compound Rl R2 R3 R4 Boiling point ~o. [ C, at O . l Torr. ]
_________________________.___________.__________________._________________ 3 13-~H ~ ~0 ~ 2 -O ~ ( CH 2 ), 1 G 2 ~ ~

31 4_rH 2 -O -CH 2 ~0 3 2 5 3 6 * ) 31~i-C H l-C3H7 3 n C3. 7 1;~

316 3 7 CH;~ C~(('H3)2 -~CH2)5- 150.

317i-C H -CH2-O . 4 9 4 9 190-200 318n-C4Hg -C3i2-O CH3 c~3 160 319r.-CqHg -CH2-C~i(CH3)2 CH3 3 16C-1 /0 `~ 320n-C4Hg n-C4~9 - (CH2) 3- 170 321n-C4Hg n C~IH9 4 9 C4H9 ~10 *) - 2~elting point 43 - l~S9~

Table_6b _ Reduction or N-alkenyl substituted tetra-oxo compounds of For~ulas Vb or, respectiv~ly, Vc to the correspo~d-ing 3,7-diaza bicyclo-(3,3,1)-nonane co~pounds of For~ulas VIla or, respectively 7 VIIb 5 Com- Boiling point pound Rl R2 R3 R4 [C. at 0.1 Torr.]

_________________________________________~_________________ ________~
\ _..
3;O ~CH -CH=C;~CH2-C~=CH2CH3 CH3 1 6O

351 CH2=CH 2 1 - (CH2) 5- 1 7;
-CH -1H ~CH 2 ~CH 2 2 I CH 2 =CH CH 3 3 1 S

353 _CH2_CH (CH3) 2 _CH2 IH2 n_C3H7 n-C ~ 1 70 , . ~. CH2=CH

3 5 q n -C 4 H 9 -CH ~CH CH 3CH 3 16 5 CH2=C}I

2 1 2 C~ 3 3 7 1 3 O

~2~9~9~

The following Examples 4 to 6 describe pharmaceutical compositions ~-hich contain, as active agents, the pharmaceutically effective compounds according to the present invention, as well as methods of producing such pharmaceutlcal compositions.
Example 4: Tablets _____________________ Composition:
Active agent ( compound of Example 3, ~o.302 ~;: as ditartrate) 20 parts .
Corn starch 30 parts 10 Lactose 55 parts Polyvinyl pyrrolidone (known under the trademark "Kollidon 25") 5 parts Magnesium stearate 2 parts Hydrogenated castor oil 1 part .
Total 113 parts Descriptlon of production procedure.
The active compound is mixed with cornstarch and finely com~inuted lactose in a suitable mixing device. The resulting mix-ture is thoroughly moistened with a 20 % solution of polyvinyl pyrro-lidone ("Kollidon 25" sold by Badische Anilin- und Soda-Fabrik (BASF~) in isopropanol. If required, further amounts of isopropanol are added. The resulting moistened granulate is passed through a 2 mm.
mesh sieve. The sieved mixture is dried on latticed screens at 40C.
and is passed ehrough a sieve of a 1 mm. mesh width on a Frewit~
machine. The resulting granulate is mixed with magnesium stearate and hydrogenated castor oil and the mixture is pressed to tablets, each tablet ~eighing 113 mg. and containing 20 mg. of the active compound.

- ~5 ~ 1 ~ 5 9 ~ ~ 8 Example 5: Capsules _____________________ .
Composition:
Active agent (compound of Example 3, No. 302 as ditartrate) 20 parts Corn starch 20 parts 5 Lactose 45 parts Polyvinyl pyrrolidone ("Kollidon 25"~ 3 parts ~agnesium stearate 1.5 parts \~_ Silica gel (known under the trademark "Aerosil 200") 0.5 parts _ Total: 90 parts Description of production procedure:
____________________ _______________ - The active agent is mixed with the corn starch and the inely comminuted lactose in a suitable mixing device. The result-ing mixture is thoroughly moistened by means o a 20 Z solution of polyvinyl pyrrolidone ("Kollidon 25"3 in isopropanol. If requlred, more isopropanol is admixed. The resulting moist granulate is passed through a sieve of 1.6 mm. mesh width on a Frewitt machine. The sieved material is dried at 40 C. on a latticed screen. Thereupon the sieved and dried granulate is passed through a sieve of a mesh width of 1 mm., also of the Frewitt type. The resulting sieved granulate is then mixed with the magnesium stearate and the silica gel ("Aerosil 200" sold by the firm Degussa). Portions of 90 mg. each of the resulting mixture are then filled by means of an automatic encapsulating machine into capsules of size 4 consisting of hardened gelatin . When proceeding in this manner, each capsule contai~s 20 mg. of the active agent.

~,5~38 Example 6- Ampoules ______________~_______ Composition (per ampoule) Active agent(compound of Example 3, No. 302, as ditartrate) 5 mg.
; Sodium chloride 16 mg.
Water pro injectione ad 2.0 ml.

Description of production procedure:
_____________~_______________________ The sodium chloride is dissolved in the water pro injectione. T~e active compound is added thereto and is dissolved therein by stirring the mixture. Sufficient water pro in~ectione is added to the solution to adjust the same to its final volume.
The resulting solution is filtered through a membrane filter (0.25 ~).
2.15 ml. of the filtered solution are then filled in each ampo~le consisting of brown colored glass. The ampoules are then sealed 15 and are s~eam sterilized at 121 C. for 30 minutes. 2 ml. of the solution used for injection contains 5 mg. of the active compound.

'~ Of course, many changes and variations may be made in the process of producing the claimed compounds, in the starting maeerials, solvents, cyclization, alkylation, and reducing agents employed, in the methods of working up and purifying the r~esulting reaction products, and in the method of producing the pharmaceutical compositions containing the active agents, and the like, may be made by those skilled in the art in accordance with the principles set forth her~in and in the claims annexed hereto.

This application is a division of Canadian Application No. 436,831 filed September 15, 1983.

Claims (20)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound corresponding to the formula:

(Vb) wherein R1 and R2 independently from each other denote hydrogen, a substituent which contains up to 12 carbon atoms and which is selected from the group consisting of alkyl, alkenyl, and alkynyl, or a cycloalkyl group containing 3 to 6 carbon atoms which is attached to the nitrogen atom directly or by an alkylene group containing 1 to 3 carbon atoms, and.
R3 and R4 each denote an alkyl group containing 1 to 7 carbon atoms, or both together form an alkylene chain represented by the formula -(CH2)n- wherein n is an integer ranging between 3 and 6, with the proviso that when R1 and R2 each are hydrogen, R3 and R4 do not denote methyl and do not together form a tetramethylene or pentamethylene group and when one of R1 and R2 is hydrogen and the other is methyl or ethyl, only one of R3 and R4 may be methyl and R3 and R4 may not together form a tetramethylene or a pentamethylene group, or if none of R1 and R2 is hydrogen the substituents R1, R2, R3 and R4 together contain at least 5 carbon atoms, wherein for the preparation of a compound corresponding to the formula (Vb) wherein R1, R3 and R4 are as defined above, a compound corresponding to the formula:

(III) wherein R1, R3 and R4 are as defined above, or a compound corresponding to the formula:

( IV) wherein R1, R3 and R4 are as defined above, is hydrolyzed under acidic conditions, and for preparing a compound of formula Vb wherein R1 and R2 are not hydrogen the resulting compound of formula Vb' is subsequently alkylated with a compound R6-X wherein R6 has the meaning given above for R1 and R2 with the exception of hydrogen and X is a reactive leaving group.

2. A process according to claim 1, wherein each of said substituents R1 and R2 contains up to 7 carbon atoms.

3. A process according to claim 2, wherein R1 and R2 each denote an alkyl or alkenyl group containing up to 7 carbon atoms or a cycloalkyl substituent containing 3 to 6 carbon atoms which is attached to the nitrogen atom by a methylene group.

4. A process according to claim 1, wherein substituents R3 and R4 each denote alkyl containing up to carbon atoms.

5. A process according to claim 1, wherein substituents R3 and R4 are the same.

6. A process according to claim 1, wherein substituents R3 and R4 together form an alkylene chain of the formula -(CH2)n-, wherein n is an integer ranging between 3 and 5.

7. A process according to claim 1, wherein said substituents R1, R2, R3 and R4 together contain from 8 to 16 carbon atoms.

8. A process according to claim 7, wherein said substituents R1, R2, R3 and R4 together contain from 10 to 12 carbon atoms.

9. A process according to claim 1, wherein R1 and R2 each are n-butyl and R3 and R4 each are methyl.

10. A process according to claim 1, wherein R1 and R2 each are cyclopropylmethyl and R3 and R4 together form a tetramethylene group.

11. A compound corresponding to the formula:

(Vb) wherein R1 and R2 independently from each other denote hydrogen, a substituent which contains up to 12 carbon atoms and which is selected from the group consisting of alkyl, alkenyl, and alkynyl, or a cycloalkyl group containing 3 to 6 carbon atoms which is attached to the nitrogen atom directly or by an alkylene group containing 1 to 3 carbon atoms, and R3 and R4 each denote an alkyl group containing 1 to 7 carbon atoms, or both together form an alkylene chain represented by the formula -(CH2)n- wherein n is an integer ranging between 3 and 6, with the proviso that when R1 and R2 each are hydrogen, R3 and R4 do not denote methyl and do not together form a tetramethylene or pentamethylene group and when one of R1 and R2 is hydrogen and the other is methyl or ethyl, only one of R3 and R4 may be methyl and R3 and R4 may not together form a tetramethylene or a pentamethylene group, or if none of R1 and R2 is hydrogen the substituents R1, R2, R3 and R4 together contain at least 5 carbon atoms.

12. A compound corresponding to formula Vb as defined in claim 11, wherein each of said substituents R1 and R2 contains up to 7 carbon atoms.

13. A compound corresponding to formula Vb as defined in claim 12, wherein R1 and R2 each denote an alkyl or alkanyl group containing up to 7 carbon atoms or a cycloalkyl substituent containing 3 to 6 carbon atoms which is attached to the nitrogen atom by a methylene group.

14. A compound corresponding to formula Vb as defined in claim 11, wherein substituents R3 and R4 each denote alkyl containing up to 4 carbon atoms.

15. A compound corresponding to formula Vb as defined in claim 11, wherein substituents R3 and R4 are the same.

16. A compound corresponding to formula Vb as defined in claim 11, wherein substituents R3 and R4 together form an alkylene chain of the formula -(CH2)n-, wherein n is an integer ranging between 3 and 5.

17. A compound corresponding to formula Vb as defined in claim 11, wherein said substituents R1, R2, R3 and R4 together contain from 8 to 16 carbon atoms.

18. A compound corresponding to formula Vb as defined in claim 17, wherein said substituents R1, R2, R3 and R4 together contain from 10 to 12 carbon atoms.

19. A compound corresponding to formula Vb as defined in claim 11, wherein R1 and R2 each are n-butyl and R3 and R4 each are methyl.

20. A compound corresponding to formula Vb as defined in claim 11, wherein R1 and R2 each are cyclopropylmethyl and R3 and R4 together form a tetramethylene group.