CA1160227A - DERIVATIVES OF .beta.-3-AMINO-N-NOR-TROPANES - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Nor-tropane derivatives useful as intermediates, particularly in the preparation of therapeutically useful aroylamino-3 and heteroaroylamino-3 nor-tropanes, substitued in position 8.

Description

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:

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:

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:

,~ CO-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;

-' ~ ~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:

~ 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 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:

~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;

~ 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:

~ CH2--in which R7 represents a chlorine atom or a methoxy or methyl group;
- a benzyl nucleus monosubstituted in the meta position of formula:

~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:

~ 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:

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:

~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.

. 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).

~zz~
~J ~o ~o~g ~3 l- o ~ o~o~ ~
- -- - - ~
~ H
~:d ~ ~b~ ~ 5 _ ~' ._ _ _ ~ P~ ~
r~
r~
_ _~ 1~ ~ ~L~
~moh ~ ~:
I~ i-- ~ ~ ~It I'. Z
~0~ ~0~ ~0~~o~z al-~: ~ ~ ~o ~ p, ~ ~ _ ~ ~ ~

~ ~ ~ ~ ~ 0~ //
~o Oo ~o a~ tD 1-/--/--n ~ ~n ~ 0~. ~DV~
0~ ~ ~ \\
__ tS \\
~ æ
O o O ~I_~ O ~--O~0 _ _ n _l ~ ~n ,_ ~
W ~O
1:~
_ O ~ i H t~i 1~ 1~ 1~ v P~ El ~ Ei 11 11 w ~ 11 11 11 C~ ~il 11 a~ ~ ~D
_ ~ ~ ~ ~ g ~ ~ g P ~D P H
. . . C~ . . ~ Pl rt p~ H
r~ ,~ 0 ~ 1 1~ P~ ~o y ~ ~i ~ ~ H
~; ~ ~ .n ~ ~ (~ rt ~ ~n F~ ~ ~ ~ C 'C _~
Ei ~ _ ~ ~ ~ ~ s~ P~ Ei ~n P tn - El `~ El 3 1 P P
) ~ ~ ~ - f~ P~ p) .~ . ~~ Ei ~ C ~El~ ~: F~ Ei ~:
~1 0 ~11 Z ~ p~ 11 P~ 11 ~n ~ 1~-:1 ~ rtFi n ~t ~ ~ ~1 u~ ~n ~ o ~ ~ I ~ J {~
R.~ J~ ~I ~ _I t" ~ co \ ~ ~ _ ~ p~
1~ Ei ~, rr P - ~ p _ 5:
. _ W ~ ~ 11 tD ~ .

O .~ - F) ~ . ~ ci '~) P~ p~ P~i' tD p~ ~ ~ tD
Ei rr p ~ ~ o P P F~ n . :L ~ ~ ~o ~ ~t o , _ ..... ~ Ei P~ ~ ~n P~ ~ ~ O ~
r~ co ~ ~ ~ co ~ :~ ~n _ P
_ ~ _ I_ U~ ~ CO ~n a~ ~, I_ ~ ~ O
cr~ F~1 _ ~ ~ I.n Ei ~i .

Z;~7 _ ~3 __ ~ ~ Or:7! O W

w ~ n _ __ . __ __ ___ ________ _ ~ ~
_ P~ o _ __ ~_ ___ .___ ~ ~
~X C` ~ . ~:

æ ~ P P) ~ l~
: ~ ~,~ ~ ~
_ , I_ ~ r~
\\
~ O _~_ 0~ ~s _ _ cq ~J.
~ ~ ~rD
_ __ ''""'' 1~ '"''' 1~ ~, I~ ~ ~ U~ ~
~ ft ~ 1~ ~ ID
~ ~ g ~
. ~ 3 3 l~ ~ ~i~
~ ~ p O~ ~
. ' ~ C ~ P~ ~ H H
g rt r~ 3 p 1~ 1 ~ H
1~ 1 11 ~ ~ I 11 IJ- _~
i- P ~ o ~ i ' 3 h~ 3 ~, ~, ~a . ~ ~ P
P~ P. P~ ~
~ ~ ~ ~n ~ ~ P~ ~.

_. ~ ~ 1 ~ m Z~7 The compounds of this divisional application are useful in inter-mediates in preparing the compound of the present,

Claims (16)

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

1. A process for preparing a compound of the general formula:

(IIIa) in which X is selected from:
- hydrogen, benzyl, a benzyl nucleus monosub-stituted in the ortho position of formula:

in which R7 represents a chlorine atom or a methoxy or methyl group;
- a benzyl nucleus monosubstituted in the meta position of formula:

in which R8 represents a methyl, methoxy or tri-fluoromethyl group or a halogen atom;
- a benzyl nucleus monosubstituted in the para position of formula:

in which R9 represents a lower alkyl, methoxy, trifluoromethyl ox cyano group or an atom of chlorine, bromine or fluorine;
- a 3-4-dichloro benzyl group; a 2-methyl thiophen group (-CH2 );
a 3-methyl thiopen group (-CH2 );
a 2-methyl furan group (-CH2 ); and - a cyclohexylmethyl group;
X' is selected from hydrogen, the group R12CO in which R12 is methyl or ethoxy, and the group and salts of the compound of formula (IIIa):
the process being selected from:
a) when X is benzyl and X' is hydrogen:
reducing the oxime of formula VII) b) when X is a monosubstituted benzyl, as de-fined above, or a 3,4-dichloro benzyl, a 2-methyl thiophen, a 3-methyl thiophen, a 2-methyl furan or a cyclohexylmethyl group and X' is hydrogen:
condensing a compound selected from cyclohexyl-methyl chloride, 3,4-dichloro benzyl chloride, 2-chloro-methyl thiophen, 3-chloromethyl thiophen, 2-chloromethyl furan, or the chlorides of formulae:

(VIII) (VIIIa) (VIIIb}

in which R7, R8 and R9 have the same meanings as in formula (IIIa) with a compound of formula:

(IX) in which R12 is as defined above then hydrolyzing the acetyl or carbethoxy group;

c) when X is hydrogen and X' is R12CO- reacting a compound of formula (IIIa) in which X is benzyl and X' is hydrogen with acetyl chloride or ethyl chloroformate and hydrogenolysing the product;

d) when X is hydrogen and X' is hydrogenolysing the compound:

( XI ) and, if required, converting the product to a salt.

2. A process as claimed in claim 1 in which, in a) the oxime of formula (VII) is reduced by sodium in amyl alcohol.

3. A process as claimed in claim 1 in which in b) the condensation is carried out at reflux in an organic solvent in the presence of a base.

4. A process as claimed in claim 3 in which the solvent is selected from acetone, acetonitrile and dimethylformamide.

5. A process as claimed in claim 3 in which the base is selected from potassium carbonate and triethylamine.

6. A process as claimed in claim 1 in which, in c), the compound of formula (IIIa) is reacted in a tetra-hydrofuran medium in the presence of an organic base.

7. A process as claimed in claim 6 in which the organic base is selected from pyridine and triethylamine.

8. A process as claimed in claim 1 in which, in c), the hydrogenolysis is carried out in the presence of palladium on charcoal.

9. A process as claimed in claim 1 in which, in step d) the hydrogenolysis is carried out in the presence of palladium on charcoal in acid medium.

10. A process for preparing .beta.-3-amino N-benzyl nor-tropane and its salts that comprises reducing N-benzyl nor-tropane oxime and, if required, converting the product into a pharmaceutically acceptable salt.

11. A process for preparing .beta.-3-acetamido nor-tropane and its salts that comprises reacting .beta.-3-amino N-benzyl nor-tropane with acetyl chloride and, if required, converting the product into a pharmaceutically acceptable salt.

12. A process for preparing .beta.-3-ethoxycarbonylamino nor-tropane and its salts that comprises reacting .beta.-3-amino N-benzyl nor-tropane with ethyl chloroformate and, if re-quired, converting the product into a pharmaceutically acceptable salt.

13. A compound having the general formula (IIIa) set out in claim 1 when produced by a process claimed in claim 1 or by its obvious chemical equivalent.

14. .beta. -3-Amino N-benzyl nor-tropane and its phar-maceutically acceptable salts when prepared by the process as claimed in claim 10 or by its obvious chemical equiva-lent.

15. .beta.-3-Acetamido nor-tropane and its salts when prepared by the process claimed in claim 11 or by its ob-vious chemical equivalent.

16. .beta. -3-Ethoxycarbonylamino nor-tropane and its salts when produced by the process claimed in claim 12 or by its obvious chemical equivalent.