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Patent 1259998 Summary

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(12) Patent: (11) CA 1259998
(21) Application Number: 579322
(54) English Title: 2,4,6,8-TETRA-OXO-3,7-DIAZA BICYCLO-(3,3,1)-NONANE COMPOUNDS
(54) French Title: COMPOSES A BASE DE 2,4,6,8-TETRA-OXO-3,7-DIAZA- BICYCLO-(3,3,1)-NONANE
Status: Expired
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 260/273
(51) International Patent Classification (IPC):
  • C07D 471/18 (2006.01)
  • C07D 471/08 (2006.01)
  • C07D 471/10 (2006.01)
(72) Inventors :
  • SCHOEN, UWE (Germany)
  • HACHMEISTER, BERND (Germany)
  • KEHRBACH, WOLFGANG (Germany)
  • KUHL, ULRICH (Germany)
  • BUSCHMANN, GERD (Germany)
(73) Owners :
  • SOLVAY PHARMACEUTICALS GMBH (Germany)
(71) Applicants :
(74) Agent: NORTON ROSE FULBRIGHT CANADA LLP/S.E.N.C.R.L., S.R.L.
(74) Associate agent:
(45) Issued: 1989-09-26
(22) Filed Date: 1983-09-16
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
P 32 34 697.2 Germany 1982-09-18

Abstracts

English Abstract



ABSTRACT OF THE DISCLOSURE

A compound corresponding to the formula:

(Vb)
Image

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 alkinyl, 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 denotes 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 hydro-
gen, 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 penta-
methylene group, or if none of R1 and R2 is hydrogen
the substituents R1, R2, R3 and R4 together contain at
least 5 carbon atoms. The preparation of this compound

is also disclosed. This compound is useful for the
preparation of 3,7-diaza bicyclo-(3,3,1)-nonane
compounds which exert a favorable reaction between
anti-arythmic activity, or the prolongation of the
cardiac refractory period and negative inotropic side
effects.


Claims

Note: Claims are shown in the official language in which they were submitted.


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:


Image (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

47


Image
(Vb)


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



Image (III)


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



Image ( 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.

48

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.

49

11. A compound corresponding to
the formula:

Image (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.

51

Description

Note: Descriptions are shown in the official language in which they were submitted.


~12~ 3~
-- 1 --
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~

-- 10 --



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-.


- 12 -

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

~
NH2

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'~
-- 14 --




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~
- 15 -

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
-- 16 --




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

NH2
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~

- 21 -

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~

- 22 -

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
23 -

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

- 24 -

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,

- 25 -

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~


-- 26 --


,~ , 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

- 28 -

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

- 29 -

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~

- 30 -

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~
- 31 -

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
103 3 7 3 72 4 190
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
-CH2-CH2 -CH2-CH2
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
-CH - H 2 -CH -CH

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
2 2
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.]
_____________________ ___--____________________________________
301 C2H5 C2H5 CH3 CH3 160 - 170
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
2 2 -CH -CH
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 2 -CH -1H

~2~9~9~
- 44 -



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.

- 46 -
~,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.

Representative Drawing

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 1989-09-26
(22) Filed 1983-09-16
(45) Issued 1989-09-26
Expired 2006-09-26

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1988-10-04
Registration of a document - section 124 $0.00 1999-08-03
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
SOLVAY PHARMACEUTICALS GMBH
Past Owners on Record
KALI-CHEMIE PHARMA GMBH
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1993-10-06 1 12
Claims 1993-10-06 5 162
Abstract 1993-10-06 2 38
Cover Page 1993-10-06 1 22
Description 1993-10-06 46 1,208