Note: Descriptions are shown in the official language in which they were submitted.
227
The present invention relates to novel nor-tropane derivatives use-
ful as intermediates, particularly in the preparation of therapeutically
useful aroylamino-3 and heteroaroylamino-3 nor-tropanes, substituted
in position 8.
The present application is divided from Canadian parent application
343,219 filed January 8, 1980.
The parent application describes and claims compounds of the formula:
A ~ N ~ "~R
in which R represents:
- either a benzyl nucleus, in which case A-C0- designates:
. a 5-pyrimidinyl carbonyl nucleus of formula:
R2
N ~ C0 -
R 1~N ~
where the pair (Rl, R2) assumes any one of the followlng
values: (NH2, OCH3), tNH2, OC2 H5)~ (CH3 ~ N, OCH3)
CH3 ~ N, OC2H5), (CH3~ C2 5);
. an aroyl nucleus of formula:
2Z7
in which the pair (R3, R4) assumes any one of the following
values: (C2H5, H), (CH3, H), (CH3, Br), (CH3, Cl), (CH3, F),
(CH3, I), (CH3, N02), (CH3, NH2), (CH3, OH), (CH3, C6H5CH20),
(CH3, CH30), (CH3, CN), (CH3, CH3S02), (CH3, C2H5S02),
(CH3, H2NS02), (CH3, CHO), (CH3, CH3CO), (CH3, C3H7( )CO),
(CH3, CH3-CH), (CH3, C3H7(n)-C,H), (CH3, C3H7(iso) OH~
. an aroyl nucleus of formula:
OR3
,~ CO-
R5 R6
in which the set (R3, R5, R6) assumes any one of the following
values: (CH3, NH2, Cl), (CH3, NH2, Br), (CH3, CH3CONH, Br),
(CH3, CF3CONH, Br), (CH3, CH3CONH, Cl), (CH3, C~3CONH, Cl),
2~ (C2H5, NH2, Br), (CH3, CH3CONH, H), (CH3, NH2, H), (CH3, CH30,
CH30), (CH3, CH30, H);
. an aroyl nucleus monosubstituted or pd.lysubstituted by
the following groups or atoms: methoxy-3; methoxy-4; chloro-3;
chloro-4; fluoro-4; nitro~3; methyl-4; dimethoxy-2,3;
dimethoxy-2,6 dimethoxy-3,5; methylenedioxy-3,4; dinitro-3,5;
trimethoxy-2,3,4; trimethoxy-3,4,5; methoxy-2 nitro-3 bromo-5;
--2--
-' ~ ~3Z~
methoxy-2 dibromo-3,5 amino-4;
. a nicotinoyl nucleus of formula:
- or a benzyl nucleus monosubstituted in the ortho position of
formula:
~CH2--
in which R7 represents a chlorine atom or a methoxy or methyl
group, in which case A-C0- designates the 2-amino 4-methoxy
5- pyrimidinyl carbonyl nucleus of formula:
- or a benzyl nucleus monosubstituted in the meta position of
formula:
R8
~ CH2-
in which R8 represents:
. a methoxy group or a chlorine atome, in which case A-C0-
designates the 2-amino 4-methoxy 5- pyrimidinyl carbonyl
group, or
. a methyl or trifluoromethyl group or a halogen atom, in
2Z7
which case A-CO- designates the 2-methoxy 4-amino 5-bromo
benzoyl nucleus;
- or a benzyl nucleus monosubstituted in the para positions of for-
mula:
R9 ~ CH2 -
in which Rg represents:
. a methyl, methoxy or cyano group or an atom of bromine,
chlorine or fluorine, in which case A-CO- represents the
2-amino 4-methoxy 5 pyrimidinyl carbonyl nucleus,
. a lower alkyl, trifluoromethyl or cyano group or an atom of
chlorine, bromine or fluorine, in which case A-CO- represents
a 2-methoxy 4-amino 5-bromo benzoyl nucleusl or
. a fluorine atom, in which case A-CO- represents a 2-methyl
4-ethoxy 5-pyrimidinyl carbonyl nucleus of formula:
OC2H5
~CO -
CH3 1 N ~
- or a 3,4-dichloro benzyl group, a 2-methyl thiophene group
_~S ~
(-CH2~ ), a 3-methyl thiophene group (CH2
o
or a 2-methyl furane group (-CH2 ~ ), in which case A-CO-
represents a 2-methoxy 4-amino 5-bromo ben20yl or a 2-methoxy
4-amino 5-chloro benzoyl nucleus;
--4--
~ 3Z2~
- or a cyclohexylmethyl group, in which case A-C0- represents a
2-methoxy ~!-amino 5-bromo benzoyl or a 2-amino 4-methoxy 5-pyri-
midinyl carbonyl nucleus.
It should be noted that in formula (I), the chain A-C0-NH is in the
equatorial position and the nor-tropanes having such a substituent in
the e~uatorial position will be called ~ in what follows.
The present invention provides compounds useful as intermediates in
preparing the compounds of formula 1. In particular the present in-
vention provides
(a) nor-tropane compounds of formula:
2 ~ ~ / N _ R (III)
/~
in which R is
- a benæyl group;
- a benzyl nucleus monosubstituted in the ortho position o-E
formula:
R7
~ CH2--
in which R7 represents a chlorine atom or a methoxy or methyl group;
- a benzyl nucleus monosubstituted in the meta position of
formula:
R8
~3 CH2--
r ~ ~ 5
~Z;~7
in which R8 represents:
. a methyl, methoxy or trifluoromethyl group or a halogen
atom;
- a benzyl nucleus monosubstituted in the para position oE formula:
3 ~ CH2 -
in which Rg represents:
. a lower alkyl, methoxy, ~rifluoromethyl or cyano group or an
atom of chlorine, bromi.ne or fluorine;
- a 3,4-dichloro benzyl group; a 2-methyl thiophen group
(-CH2 ~ ); a 3-methyl thiophen group (-CH2
a 2-methyl furan group (-CH2 ~ ); or
- a cyclohexylmethyl group;
(b) nor-tropane compounds of formula:
R12 - CO - Nl~ _~N (IX)
H
in which R12 represents a methyl or ethoxy group, and
(c) nor-tropane compounds of formula:
,~, CON~I ~ (X)
~_3~ -6-
~L~6~ZZ7
The compound of formula (III) in which R represents the benzyl
group is prepared by the reduction, by means of sodium in amyl alcohol,
of the oxime of ~-benzyl nor-tropane-3 one of formula:
110~ ~ (Vll)
The compounds of formula (III) in which R has the same meanings as
in formula (I), with the exception of the benzyl group are obtained by
a two stage synthesis which consists in condensing cyclohexylmethyl
chloride, 3~4-dichloro benzyl chloride, 2-chloromethyl thiophene,
3-chloromethyl thiophene, 2-chloromethyl furane, or the chlorides of
formulae:
l ~ (VIII)
1 ~ R8 (VIIIa)
1 ~ (VIIIb)
2'~7
in which R7, R8 and R9 have the same meanings as in formula (I), on the
compounds of formula:
R12 - CO - NH ~ N -~~ H (IX)
H
in which R12 represents the methyl or ethoxy group, this condensation
being preferably carried out at reflux in an organic solvent such as ace-
tone, acetonitrile or DMF in the presence of potassium carbonate or trie-
thyl.amine, then in hydrolyzing the acetyl or carbethoxy group
The compounds of formula (IX) are obtained by a two stage synthesis
consisting in treating the compound of formula (III) in which ~ represents
the benzyl group, with acetyl chloride or ethyl chloroformiate, in a
tetrahydrofuran medium and in the presence of an organic base such as
pyridine or triethylamine, then in hydrogenolyzing the product obtained,for example in the presence of palladium on charcoal at 10% in an ethanol
medium at a temperature of 60C and at a pressure of 15 bars.
Finally, the novel compound of formula (X) is obtained by hydro-
genolysis - preferably in an acid medium, in the presence of palladium
on charcoal at 10%, at room temperature, at a pressure of 90 mbars and in
an alcohol medium - of the compound of formula:
OCH3 ~ N - CH2 ~
~ ~ CO NH ~ / (XI)
2 ~
z~
This latter compound is prepared in accordance with the process
described in the parent application for the preparation of the compounds
of formula (I) ~mixed anhydrides method~ by condensing the acid of
formula:
S OCH3
~ COOH
H2N ~ ~ (XII)
with the compound of formula (III) wherein R is a benzyl group.
The following preparations are given by way of examples to illus-
trate the invention.
EXAMPLE l: ~3-3- ~5-(2-amino 4-methoxy pyrimidinyl) carbonyl~
amino nor-tropane (X)
A solution of 148.5 g of maleate of~ -3- ~5-(2 amino 4-methoxy 4-
pyrimidinyl) carbonyl~ amino N-benzyl nor-tropane ~(I), code N 2,
obtained as in Example l~in the parent in l,SOO ml of alcohol at
50% was hydrogenolyzed in an autoclave at room temperature and at a
pressure of 90 mbars, in the presence of 25 g of palladium on charcoal
at 10%. It was filtered, the solvent evaporated, the residue crystall-
ized in acetone and recrystallized in alcohol at 90%. 120 g of the
desired product were thus isolated.
. Yield: 98%
. Melting point: 22Q C
. Molecular weight: 412.41
6192~
Empirical formula: C17H25N506 + 7/5 H20
. Elementary analysis:
Calculated (%) 48~69 6 01 16 98
EXAMPLE 2: ~-3-amino N-benzyl nor-tropane dimaleate (III)
Code Number: 98
A suspension of 60 g of N-benzyl nor-tropane oxime (VII) in 750 ml
of amyl alcohol was heated to 40C and 50 g of sodium were introduced
at a rate such that the temperature of the reaction mixture rose to
135-140 C. Then the reaction medium was diluted with 300 ml of water,
the organic phase was decanted, and extracted by means of 400 ml of HCl
6N, and the aqueous phase was washed with isopropyl ether. Then,
the aqueous phase was alkalized with concentrated potash, extracted with
methylene chloride, dried on sodium sulfate, the solvent was evaporated
and the residue distilled. 83 g (yield 59%) of liquid, Ebo 15 =
109-111 C was obtained which was added to an acetone solution of
maleic acid. The precipitate obtained was filtered and recrystallized
in absolute alcohol.
. Melting point: 150 C
. Empirical formula; C22H28N208 ~ 4.5 H20
. Molecular weight: 462.87
. Elementary analysis:
--10--
2Z~
Calcu~ ~d ~%) 57 08 6 45 6.05
. NMR spectrum of the base (C~Cl ): c~ppm =
7.28, m, and 3.53, s, 7H (benzylic)
centered on 3.17, m, : 2H (trop~nic) at position 1 and 5
centered on 2.82, m, : lH (tropanic) at position 3
1.52, s, 2 NH2 protons
hetween 2.20 and 1.15, m, 8 tropanic protons
(the displacement of the tropanic protons in the presence
of Europium salt EU(FOD)3 and particularly of the proton
at position 3, as well as the study of the value of the
sum of the couplings of the multiplet signal of the pro-
ton at 3, in accordance with the law of KARPLUS, showed
that proton -3 is at an axial position, this by analogy
with the N~ spectra in the presence of Europium of the
derivatives ~and~ -3-amino tropane).
EXANPLE 3: ~-3-ami ~-parafluorobenzyl nor-tropane (III)
Code ~umber: 103
1st stage: ~-3-acetamido nor-tropane (IX)
To a solution cooled to O C of 96 g of ~-3-amino N-benzyl
nor-tropane r(III), code number 98, prepared in Example 2~ in 70 ml of
triethylamine and 9OO ml of tetrahydrofurane were slowly added 28 ml of
--11-- .
~6g:~Z27
acetyl chloride. After 12 hours at room temperature 50 ml of water were
added, the solvent was evaporated, the ~emaining aqueous phase was
extracted with 200 ml of methylene chloride, washed with water, dried
on sodium sulfate and the solvent was evaporated. 80 g of raw product
were obtained which were dissolved in 1000 ml of alcohol. 1 ml of hydro-
chloric alcohol 5N was added and the solution was hydrogenolyzed in the
presence of 8 g of palladium on charcoal at 10% in an autoclave, at a
temperature of 60 C and a pressure of 15 bars. Then, it was filtered,
the filtrate evaporated and the residue crystallized in ethyl acetate.
0 52 g of the expected product were thus obtained.
. Yield: 77%
. NMR spectrum (CDC13):cfppm =
6.38, d, (J = 7Hz), amidic protons (-C0-NH-) (exchangeable)
Centered on 4.18, m, 1 tropanic proton at 3
3.60, m, tropanic protons at 1 and 5
2.70, s, N-H proton (exchangeable)
1.96, s, 3 acetyl protons (CH3C0-)
between 2.20 and 1.15, m, 8 tropanic protons.
By the same process, but using ethyl chloroformiate (instead of
0 acetyl chloride), ~-3-ethoxycarbonylamino nor-tropane (IX) was obtained.
. Melting point: 252 C
. Empirical formula: CloHlgClN202
. Molecular weight: 234.72
. Elementary analysis:
5
-12-
~6~ 7
L ¦ c ~ N ~
Calculated (%) 51.17 8.16 11.94
Obtained (%) 50.98 8.05 11.98
. NMR spectrum (CDC13): ~ ppm =
5.55, d, -N~-COO-
4.08, q, and 1.1~, t, (J = 7Hz): -COOCH2-CH3
1.96, s, : NH-
3.51, m, tropanic protons at 1 and 5
3.91, m, tropanic proton at 3
centered on 1.72, m, tropanic protons at 2, 4, 6 and 7.
2nd stage: ~-3-amino N-p-fluorobenzyl nor-tropane (IIIj
Code Number: 103
A solution of 17 g of ~ -3-acetamido nor-tropane ~ IX) obtained in
the preceding stag ~ , of 21 g of p-fluorobenzyl chloride and of 18 ml
of triethylamine in 250 ml of acetone was heated to reflux for 12 hours.
Then it was filtered, the filtrate was evaporated, and the residue was
dissolved in 200 ml of methylene chloride, washed with water, dried on
sodium sulfate and the solvent was evaporated. 21 g of raw product were
obtained which was dissolved in 250 ml of sulphuric acid at 10% and the
solution was heated to reflux for 24 hours. It was washed with 100 ml
of methylene chloride. The aqueous solution was alkalized with concentra-
ted potash, extracted with methylene chloride, dried on sodium sulfate
and the solvent was evaporated. 17 g of raw product were obtained,
yield 96%, which was used directly in the synthesis of the corresponding
compound of formula (I) with code N 19 and described in Example 1.
227
. NMR spectrum (CDC13):Grppm =
centered on 7.08, m, and 3.52, s, 6H(benzylic)
centered on 3.15, m. tropanic protons at 1 and 5
centered on 2.94, m, 1 tropanic proton at 3
between 2.20 and 1.15, m, 8 tropanic protons
1.11, s, NH2 (exchangeable)
By the same process, but from ~-3-ethoxycarbonylamino nor-tropane
(IX) described in the preceding stage, the/3-3-amino N-parafluorobenzyl
nor-tropane (III) of code number 103 was also obtained.
~y the same process, but from the corresponding reagents, the
~-3-amino N-nor-tropanes of formula (III) were obtained. Apart from the
compounds of formula (III) given in table III, the majority of the com-
pounds (III) were used unpurified (after checking by thin layer chroma-
tography) in the synthesis of the corresponding compounds of fo~mula (I).
-14-
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~o Oo ~o a~ tD 1-/--/--
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n _l ~ ~n ,_ ~
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1:~
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1~ 1~ 1~ v P~ El ~ Ei
11 11 w ~ 11 11 11 C~ ~il 11 a~ ~ ~D
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r~ ,~ 0 ~ 1 1~ P~ ~o y ~ ~i ~ ~ H
~; ~ ~ .n ~ ~ (~ rt ~ ~n F~ ~ ~ ~ C 'C _~
Ei ~ _ ~ ~ ~ ~ s~ P~ Ei
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) ~ ~ ~ - f~ P~ p)
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Z;~7
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w ~ n
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''""'' 1~ '"''' 1~ ~,
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g rt r~ 3 p 1~ 1 ~ H
1~ 1 11 ~ ~ I 11 IJ- _~
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--16--
Z~7
The compounds of this divisional application are useful in inter-
mediates in preparing the compound of the present,
-17-
