PYRIMIDONE DERIVATIVES

DERIVES DE PYRIMIDONE

English Abstract

ABSTRACT
The present invention provides compounds of formula
(2) :-
<IMG>
(2)
and their pharamaceutaically acceptable salts which are
useful as histamine B1-antagonists. In formula (2)
R1 is halogen or nitro; R2 is C1-4 alkyl; R3 is a
C1-3 alkylene group; and R4 is 3-pyridyl; N-oxo-3-
pyridyl; 6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl;
6-hydroxymethyl-3-pyridyl; 4,6-dimethyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-
pyridyl; 5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-
pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl; 4-pyridyl
or N-oxo-4-pyridyl.

Claims

11770
Claim:
1. A process for preparing a compound of formula
(2):-
<IMG>
(2)
and pharmaceutically acceptable salts thereof; where R1
is halogen or nitro; R2 is C1-4 alkyl; R3 is a
C1-3 alkylene group; and R4 is 3-pyridyl; N-oxo-3-
pyridyl; 6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl;
6-hydroxymethyl-3-pyridyl; 4,6-dimethyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-
pyridyl; 5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-
pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl; 4-pyridyl
or N-oxo-4-pyridyl, which comprises reacting a compound of
formula (3) :-
<IMG>
(3)
or a salt thereof, where R1, R2 and R3 are as
defined with reference to formula (2) with a compound
of formula 14) :-
<IMG>
(4)
33

11770
where R4 is as defined with reference to formula (2) and
R6 is a group displaceable with amine, thereafter where
R4 is N-oxo-6-methyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; or N-oxo-5,6-dimethyl-3-
pyridyl; converting the compound of formula (2) so
obtained into the corresponding compound of formula (2)
where R4 is 6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-
4-methyl-3-pyridyl; or 6-hydroxymethyl-5-methyl-3-
pyridyl; and optionally converting the compound of
formula (2) so obtained into a pharmaceutically acceptable
salt, or by reacting a guanidine of formula (10) :-
<IMG>
(10)
where R1, R2 and R3 are as defined with reference to
formula (2) with a compound of formula (11) :-
<IMG>
(11)
where R4 is as defined with reference to formula (4) and
R8 is C1-4 alkyl, benzyl or phenyl; thereafter where
R4 is N-oxo-6-methyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; or N-oxo-5,6-dimethyl-3-
pyridyl; converting the compound of formula (2) so
obtained into the corresponding compound of formula (2)
where R4 is 6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-
4-methyl-3-pyridyl; or 6-hydroxymethyl-5-methyl-3-
pyridyl; and optionally converting the compound of
formula (2) so obtained into a pharmaceutically acceptable
salt.
34

R6 is a group displaceable with amine, thereafter where
R4 is N-oxo-6-methyl-3-pyridyl; N-oxo-4,6-dimethyl-3-
pyridyl; or N-oxo-5,6-dimethyl-3-pyridyl; converting
the compound of formula (2) so obtained into the
corresponding compound of formula (2) where R4 is
6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-
pyridyl; or 6-hydroxymethyl-5-methyl-3-pyridyl; and
optionally converting the compound of formula (2) so
obtained into a pharmaceutically acceptable salt.
2. A process as claimed in claim 1, where R1 is
bromine.
3. A process as claimed in claim 1
where R2 is methyl.
4. A process as claimed in any one of claims 1 to
3, where R4 is pyrid-3-yl, 6-methyl-pyrid-3-yl,
6-hydroxymethyl-pyrid-3-yl or 5,6-dimethyl-6-pyrid-3-yl.

5. A process for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone which comprises reacting 4-bromo-2-(4-aminobutyl)-
3-methylpyridine with 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-
4-pyrimidone and if desired converting to the pharmaceutically
acceptable salt.
6. A process for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(pyrid-4-ylmethyl)-pyrimidone
which comprises reacting 5-bromo-2-(4-aminobutyl)-3-methylpyridine
with 2-methylthio-5-(pyrid-4-ylmethyl)-4-pyrimidone and if desired
converting to the pharmaceutically acceptable salt.
7. A process for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(N-oxo-6-methylpyrid-3-ylmethyl)
-4-pyrimidone which comprises reacting 5-bromo-2-(4-aminobutyl)
-3-methylpyridme with 2-nitroamino-5-(N-oxo-6-methylpyrid-3-
ylmethyl)-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
8. The process of claim 7 wherein the product is reacted
with trifluoroacetic anhydride to obtain 2-[4-(5-bromo-3-
methylpyrid-3-yl)-butylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)
-4-pyrimidone and if desired converting to the pharmaceutically
acceptable salt,
9. A process for the preparation of 2-[4-(5-chloro-3-
methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone which comprises reacting 5-chloro-2-(4-aminobutyl)
-3-methylpyridine with 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)
-4-pyrimidone and if desired converting to the pharmaceutically
acceptable salt.
10. A process for the preparation of 2-[4-(5-nitro-3-
methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone which comprises reacting 3-methyl-5-nitro-2-(4-
aminobutyl)pyridine with 2-nitroamino-5-(6-methylpyrid-3-
ylmethyl)-4-pyrimidone and if desired converting to the
36

pharmaceutically acceptable salt.
11. A process for the preparation of 2-[4-(5-iodo-3-
methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone which comprises reacting 5-iodo-3-methyl-2-(4-
aminobutyl)pyridine with 2-nitroamino-5-(6-methylpyrid-3-
ylmethyl)-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
12. A process for the preparation of 2-[4-(5-fluoro-3-
methylpyridyl-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)
-4-pyrimidone which comprises reacting 5-fluoro-2-(4-aminobutyl)
-3-methylpyridine with 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)
-4-pyrimidone and if desired converting to the pharmaceutically
acceptable salt.
13. The process of Claim 12 wherein the product is reacted
with trifluoroacetic anhydride to obtain 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(5-methyl-6-hydroxymethylpyrid-
3-ylmethyl)-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
14. A procçss for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl(butylamino]-5-(5,6-dimethylpyrid-N-oxo-3-
ylmethyl)-4-pyrimidone which comprises reacting 5-bromo-2-
(4-aminobutyl)-3-methylpyridine with 2-nitroamino-5-
(5,6-dimethyl-N-oxo-pyrid-3-ylmethyl)-4-pyrimidone and if
desired converting to the pharmaceutically acceptable salt.
15. A process for the preparation of 2-[4-(5-bromo-3-
methylpyridyl-2-yl)-butylamino]-5-(N-oxo-pyrid-4-ylmethyl)-4-
pyrimidone which comprises reacting 5-bromo-2-(4-aminobutyl)-3-
methylpyridine with 2-nitroamino-5-(N-oxo-pyrid-4-ylmethyl)-4-
pyrimidone and if desired converting to the pharmaceutically
acceptable salt.
37

16. A process for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(4,6-dimethyl-3-pyridylmethyl)
-4-pyrimidone which comprises reacting 5-bromo-2-(4-aminobutyl)
-3-methylpyridine with 2-nitroamino-5-(4,6-dimethyl-3-pyridylmethyl)
-4-pyrimidone and if desired converting to the pharmaceutically
acceptable salt.
17. A process for the preparation of 2-[4-(5-bromo-3-
methyl-pyrid-2-yl)-butylamino]-5-(5,6-dimethyl-3-pyridylmethyl)
-4-pyrimidone which comprises reacting 5-bromo-2-(4-aminobutyl)
-3-methylpyridine with 2-nitroamino-5-(5,6-dimethyl-3-
pyridylmethyl)-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
18. A composition and pharmaceutically acceptable salts
of the formula 2:
<IMG>
(2)
and pharmaceutically acceptable salts thereof; where R1
is halogen or nitro; R2 is C1-4 alkyl; R3 is a C1-3 alkylene
group; and R4 is 3-pyridyl; N-oxo-3-pyridyl; 6-methyl-3-pyridyl;
N-oxo-6-methyl-3-pyridyl; 6-hydroxymethyl-3-pyridyl; 4,6-
dimethyl-3-pyridyl; N-oxo-4,6-dimethyl-3-pyridyl; 6-hydroxymethyl-
4-methyl-3-pyridyl; 5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-
pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl; 4-pyridyl or
N-oxo-4-pyridyl whenever prepared or produced by the process of
claim 1 or by any obvious chemical equivalent thereof.
38

19. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-
(6-methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 5 or by
any obvious chemical equivalent thereof.
20. 2-[4- (5-bromo-3-methylpyrid-2-yl)-butylamino]-5-
(pyrid-4-ylmethyl)-pyrimidone and pharmaceutically acceptable salts
whenever prepared or produced by the process of claim 6 or by any
obvious chemical equivalent thereof.
21. 2-[4-(5-bromo-3-methylprid-2-yl)-butylamino]-4-(N-oxo-
6-methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 7 or by
any obvious chemical equivalent thereof.
22. 2-[4-(5-bromo-3-methylpyrid-3-yl)-butylamino]-5-(6-
hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically
acceptable salts whenever prepared or produced by the process of
claim 8 or by any obvious chemical equivalent thereof.
23. 2-[4-(5-chloro-3-methylpyrid-2-yl)-butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim g or by
any obvious chemical equivalent thereof.
24. 2-[4-(5-nitro-3-methylpyrid-2-yl)-butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 10 or by
any obvious chemical equivalent thereof.
39

25. 2-[4-(5-iodo-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 11 or by
any obvious chemical equivalent thereof.
26. 2-[4-(5-fluoro-3-methylpyridyl-2-yl)-butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 12 or by
any obvious chemical equivalent thereof.
27. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(5-
methyl-6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone and
pharmaceutically acceptable salts whenever prepared or produced
by the process of claim 13 or by any obvious chemical equivalent
thereof.
28. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(5,6-
dimethylpyrid-N-oxo-3-ylmethyl)-4-pyrimidone and pharmaceutically
acceptable salts whenever prepared or produced by the process of
claim 14 or by any obvious chemical equivalent thereof.
29. 2-[4-(5-bromo-3-methylpyridyl-2-yl)-butylamino]-5-(N-
oxo-pyrid-4-ylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 15 or by
any obvious chemical equivalent thereof.

30. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(4,6-
dimethyl-3-pyridylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 16 or by
any obvious chemical equivalent thereof.
31. 2-[4-(5-bromo-3-methyl-pyrid-2-yl)-butylamino]-5-(5,6-
dimethyl-3-pyridylmethyl)-4-pyrimidone and pharmaceutically acceptable
salts whenever prepared or produced by the process of claim 17 or by
any obvious chemical equivalent thereof.
41

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
SD32. A process for the preparation of 2-[4-(5-bromo-
3-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-
4-pyrimidone which comprises reacting 4-(5-bromo-3-methyl-
pyrid-2-yl)butylguanidine with 2-formyl-4-(2-methyl-5-pyridyl)
propionate and if desired converting to the pharmaceutically
acceptable salt.
SD33. A process for the preparation of 2-[4-(5-bromo-
3-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl-
4-pyrimidone which comprises reacting 5-bromo-3-(4-aminobutyl)-
3-methylpyridine with 2-n-butylthio-5-[6-methylpyrid-3-yl)-
methyl]-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
SD34. A process for the preparation of 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone which comprises reacting 2-(4-aminobutyl)-5-bromo-
3-methylpyridine with 2-benzylthio-5-[(6-methylpyrid-3-yl)
methyl]-4-pyrimidone and if desired converting to the
pharmaceutically acceptable salt.
SD35. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-
(6-methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically
acceptable salts whenever prepared or produced by the process
of claim SD32 or by any obvious chemical equivalent thereof.
SD36. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-
5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically
acceptable salts whenever prepared or produced by the process
of claim SD33 or by any obvious chemical equivalent thereof.
SD37. 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-
5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone and pharmaceutically
acceptable salts whenever prepared or produced by the process
of claim SD34 or by any obvious chemical equivalent thereof.
42

Description

~.~7~960
11770
--1--
COMPOUN~S
This invention relates to certain pyrimidone
derivatives, a process for their preparation, compositions
5 containing them and their use as Histamine Hl-
antagonists.
Histamine, a physiologically active compound
endogenous in mammals, exerts its action by interacting
10 with certain sites called receptors. One type of
receptor is known as a histamine H1-receptor (Ash and
Schild, Brit. J. Pharmac. 1966, 27, 427) and the actions
of histamine at these receptors are inhibited by drugs
commonly called "antihistamines" (histamine Hl-
15 antagonists) a common example of which is mepyramine. Asecond type of histamine receptor is known as the
H2-receptor ~Black et al Nature 1972, 236, 385). The
actions of histamine at these receptors are not inhibited
by mepyramine but are inhibited by burimamide. Compounds
20 which inhibit the actions of histamine at histamine
H2-receptors are called histamine H2-antagonists.
US Patent No 4,154,834 discloses compounds of general
formula (1) :-
z
H~/~A-Het '
Het-(CH2)m~Y-(CH2)n-NH~N~x
(1)
where Het is 2- or 4-imidazolyl optionally substituted by
lower alkyl (preferably methyl), halogen (preferably
chlorine or bromine), trifluoromethyl or hydroxymethyl;
2-pyridyl optionally substituted by one or two groups
35 ~which may be the same or different) selected from lower
alkyl (preferably methyl), lower alkoxy (preferably

~178960
11770
--2--
methoxy), halogen (preferably chlorine or bromine), amino
and hydroxy; 2-pyridyl with a phenyl, carbocyclic or
cyclic ether ring containing 2 oxygen atoms fused to it;
2-thiazolyl; 3-isothiazolyl optionally substituted by
chlorine or bromine; 3-(1,2,5)-thiadiazolyl optionally
substituted by chlorine or bromine, or 2-(5-amino-1,3,4-
thiadiazolyl); Y is sulphur or a methylene group; m is 0,
1 or 2 and n is 2 or 3 such that their sum is 3 or 4 or
when Y is methylene and Het is other than an imidazole
ring, 2; Z is hydrogen or lower alkyl (preferably methyl);
X is oxygen or sulphur; A is a straight or branched
alkylene chain containing from 1-5 carbon atoms or
~(CH2)pW(CH2)q~ where W is oxygen or sulphur and p
and q are such that their sum is from 1 to 4; Het' is a 5
or 6 membered heterocyclic ring selected from pyridine,
pyridine-N-oxide, furan, thiophen, thiazole, oxazole,
isothiazole, imidazole, pyrimidine, pyrazine, pyridazine
or thiadiazole, which ring is optionally substituted by
one or two (which may be the same or different) of the
- 20 groups selected from lower alkyl, lower alkoxy, halo,
hydroxy and amino, or Het' is a pyridine ring with a
carbocyclic or cyclic ether ring containing two oxygen
atoms fused to it, or Het' is a pyridine, imidazole or
thiazole ring which has a benzene ring fused to it; and
pharmaceutically acceptable salts thereof. These
compounds are described as having combined histamine Hl-
and H2- antagonist activity.
In particular US Patent No 4,154,834 discloses
compounds of formula (1) where Het is 2-pyridyl having a
substitutent in position 3, Y is methylene and Het' is
substituted pyridyl. It has now been found that when the
2-pyridyl group Het has a second substituent in position 5
the relative level of Hl to H2 activity increases. A
small number of compounds, which fall within the general
class of compounds of formula (1), have now been found to
, ~

11770
--3--
be useful as histamine Hl-antagonists, that is, for the
treatment of diseases for example bronchial asthma,
rhinitis, hayfever and allergic eczema whose symptoms are
mediated through the action of histamine at Hl-receptors.
Accordingly the present invention provides compounds
of formula (2) :-
H
R~¢N~2 J~CH2R4
H2R3CH2NH 1N O
(2)and pharmaceutically acceptable salts thereof; where
is halogen or nitro; R2 is Cl 4 alkyl; R3 is a
Cl 3 alkylene group; and R is 3-pyridyl; N-oxo-3-
pyridyl; 6-methyl~3-pyridyl; N-oxo-6-methyl-3-pyridyl;
6-hydroxymethyl-3-pyridyl; 4,6-dimethyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-
3-pyridyl; 5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-
pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl; 4-pyridyl
or N-oxo-4-pyridyl.
Rl can represent any one of the halogens, fluorine,
chlorine, bromine or iodine.
Preferably Rl is bromine.
Examples of Cl 4 alkyl groups for R2 are methyl,
ethyl, n-propyl, iso-propyl, n-butyl and t-butyl.
Preferably R2 is methyl.
By way of example -R3- can be methylene, 1,2-
ethanediyl, or 1,3-propanediyl.

960
11770
--4--
Preferably R3 is 1,2-ethanediyl or 1,3-propanediyl.
Preferably the group R4 is an optionally
substituted 3-pyridyl group. Preferably one substituent
occupies position 6. Thus R4 is 6-methylpyrid-3-yl.
Examples of compounds within the scope of this
invention are :-
2-[4-(5-nitro-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone.
2-[4-(5-chloro-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone;
2-[4-(5-iodo-3-methylpyrid-2-yl)butylamino]-5-(6-methyl
-pyrid-3-ylmethyl)-4-pyrimidone;
2-[4-(5-fluoro-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone;
and their pharmaceutically acceptable salts.
Examples of compounds within the scope of this
invention having the pre~erred Rl and R2 substituents
are :-
2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone;
2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(pyrid-
4-ylmethyl)-4-pyrimidone;
2-[4-(5-bromo-3-methyl-pyrid-2-yl)butylamino]-5-(6-
hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone;

1~78g60
11770
--5--
and their pharmaceutically acceptable salts.
2-14-(5-~romo-3-methylpyrid-2-yl)butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone has been shown to
have the particular advantage that unlike other histamine
H -ant~gonists it does not enter the central nervous
system. This has been shown by rat whole body
radiography.
The compounds of formula (2) are shown and described
as 4-pyrimidones which exist in equilibrium with the
corresponding 6-one tautomers. These compounds also
exist to a lesser extent as the hydroxy tautomers, and the
pyrimidine ring may also exist in the following tautomeric
forms :
H~ ~ = HN ~ \ ~
~N H -N~ OH -N H OH
It will be understood that all these tautomeric forms
are within the socpe of the present invention.
The compounds of formula (2) form pharmaceutically
acceptable salts with pharmaceutically acceptable
salt-forming acids. Examples of these acids are
hydrochloric, sulphuric, hydrobromic, phosphoric, tartaric,
citric, maleic, lactic, 2-hydroxyethanesulphonic,
methanesulphonic, toluene-4-sulphonic, ethanedisulphonic,
ethane~ulphonic and camphorsulphonic acids.
The compounds of this invention can be made by a
process which comprises reacting a compound of formula
(3):-
~ CH2R3CH2NH2 (3)

1178960
11770
--6--
or a salt thereof, where Rl, R2 and R3 2re as
defined with reference to formula (2) with a compound of
formula (4) :-
H
HN ~ CH2R4
R6 ~1~0
(4)
where R4 is as defined with reference to formula (2) and
R6 is a group displaceable with amine, thereafter where
R4 is N-oxo-6-methyl-3-pyridyl; N-oxo-4,6-dimethyl-3-
pyridyl; or N-oxo-5,6-dimethyl-3-pyridyl; converting the
compound of formula (2) so obtained into the corresponding
compound of formula (2) where R4 iS 6-hydroxymethyl-
3-pyridyl; 6-hydroxymethyl-4-methyl-3-pyridyl; or
6-hydroxymethyl-5-methyl-3-pyridyl; and optionally
converting the compound of formula (2) So obtained into a
pharmaceutically acceptable salt.
The compounds of formula (2) where R4 is
N-oxo-6-methyl-3-pyridyl; N-oxo-4,6-dimethyl-3-pyridyl;
or N-oxo-5,6-dimethyl-3-pyridyl can be converted into the
corresponding compound of formula (2) where R4 is
6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-
pyridyl; or 6-hydroxymethyl-5-methyl-3-pyridyl; by
reacting with an organic anhydride for example
trif luo roacetic anhydride.
Pharmaceutically acceptable salts of compounds of
formula (2) can be prepared by standard methods, for
example by reacting a solution of the compound of formula
(2) with a solution of the acid.
Examples of groups R6 are Cl 4 alkylthio
' .;

g~O
11770
--7--
(particularly methylthio), benzylthio, chlorine, bromine
and nitroamino. Preferably R6 is nitroamino.
The reaction can be carried out at an elevated
temperature in the absence of a solvent, for example at
from 80 to 170, preferably from 120 to 140, or in a
solvent at an elevated temperature, for example at the
reflux temperature of the reaction mixture. The choice
of solvent is affected by solubility characteristics of
the reactants and the nature of R6. Preferably the
solvent is pyridine, a picoline or mixture of picolines, a
Cl 4 alkanol, preferably ethanol or l-propanol, a Cl 4
alkanol, l,2-ethanediol, a ketone, for example acetone or
2-butanone, a high boiling alkoxyaryl ether for example
anisole, or a polar aprotic solvent, for example dimethyl-
formamide, dimethylacetamide, dimethylsulphoxide,
hexamethylphosphoramide, sulpholane, acetonitrile or
nitromethane.
Compounds of formula (3) can be prepared by carrying
out a Sandmeyer reaction on the corresponding compound of
formula (3a):-
NH R2
~ CH2R ~H2NH2
(3a)
that is by diazoatisation of the amino group Rl and
displacing the diazo group with halo.
Compounds of formula (3) can also be prepared by
halogenating the corresponding compound of formula (3b):-
~,R2
~ ~ CH2R CH2NH2
(3b)

~ )
il7~960
11770
-8-
where ~2 and R3 are as defined With re$erence to
formula (2) with halogen.
$hus a compound of formula (3c):-
Br_~R2
~ N~CH2R3~:H2NH2
(3c)and 8alts thereof where R2 and R3 are as defined with
reference to formula (2) can be prepared by a process,
whiCh comprises reacting a compound of formula (3b):-
N CH2R CH2NH2
(3b)
or a 8alt thereof, where R2 and R3 are as defined with
reference to formula (2), with an electrophilic
brominating agent.
Example8 of electrophilic brominating agents are
bromine or dibromocyanuric acid in a polar medium which
generate~ 8r+. Examples of 8UCh media are oleum and
fluoro8ulphonic acid. Br can al80 be generated from
hydrobromic acid and bromide ion in oxidizing or oxidizing
polar media. For example hydrobromic acid is oxidized by
801utions of sulphur trioxide to bromine which dissociates
giving Br+. The sulphur trioxide solution can be in a
freon for example 1,1,2-trifluorotrichloroethane or in
sulphuric acid i.e. oleum. The hydrobromic acid can be

~1785~60
11770
_g_
derived from the dihydrobromide salt of the compound of
formula (3b), particularly when the reaction is carried
out using sulphur trioxide and freon. Where the sulphur
trioxide solution is oleum, the hydrobromic acid can be
generated from a bromide salt for example an alkali metal
salt in particular potassium bromide.
Compounds of formula (3b) form neutral complexes with
sulphur trioxide. The effect of this is that the pyridine
ring in the compounds of formula (3b) is activated to
bromination. Thus preferably the medium is one which
dissolves sulphur trioxide.
Two preferable media for carryiny out the bromination
lS reactions are oleum and sulphur trioxide in freon. Where
the medium is oleum, in practice it is at least 20~ w/w.
Preferably it is at least 65% w/w. The more concentrated
the oleum, the lower is the temperature at which the
reaction can be carried out. For example where the medium
i5 20% oleum the reaction requires elevated temperatures to
proceed in a short period and at this concentration of
oleum it is carried out at 100C and above. Where the
medium is 65% oleum the reaction can be carried at from
0C to 100C, preferably from 50-60C especially 55-58C,.
Where the medium is sulphur trioxide in freon the
reaction is carried out at from ambient temperature to the
reflux temperature of the solvent.
Compounds of formula (3) and (3a) can also be prepared
by reducing a corresponding cyano compound of formula (5):-
R7 ~ R2
N~CH2R3CN
- (S)

~17~960
11770
-10-
where R7 is halogen, nitro or amino and R2 and R3
are as defined with reference to formula (2) with a
reducing agent which reduces cyano to amino without
reducing the group R in a reaction medium which is
inert to the reagents and product.. For example the
reducing agent can be lithium aluminium hydride or
diborane. The reaction medium can be a dialkyl ether for
example diethyl ether or a cyclic ether for example
tetrahydrofuran or dioxan. Where the reducing agent is
lithium aluminium hydride or diborane it will be
appreciated that the reaction medium is anhydrous.
Compounds of formula (S) where R7 is amino can also
be prepared by reducing the corresponding nitro-compound
of formula ~5) where R is nitro. The reduction can be
carried out by hydrogenation.
Compounds of formula (5) can be prepared by reacting
a disubstituted chloropyridine of formula (6):-
R7 ~ 2
Cl
(6)
where R is as defined with reference to formula (2) andR7 is halogen, nitro or aminot with a malonic acid
ester of formula (7):-
R02C
\ CHR3CN
RO2C /
(7)where R3 is as previously defined and R is an ester
forming group, in the presence of a strong base in an
inert reaction medium, and thereafter de-esterifying and
~; decarboxylating the product.

7~g60
11770
In particular the groups R can be ethyl.
In particular the strong base can be sodium hydride.
The reaction medium is one which is substantially
inert to the reagents and product. In particular the
medium can be dry tetrahydrofuran.
Compounds of formula (3b) can also be prepared by
reacting an alkali metal derivative of a compound of
formula (8):-
ll
~ ~ ~CH3
(8)
where R is as defined with reference to formula (2)
with a compound of formula (9):-
XR3NH2
(9)
or a salt thereof where X is halogen and R3 i9 as
defined with reference to formula (2).
In the compound of formula (9), X can be chlorine,
bromine or iodine. In particular it is chlorine.
The alkali metal derivative can be a lithium, sodium
or potassium derivative. In particular it is the sodium
derivative.
The alkali metal derivative of compour.d of formula
(8) can be prepared in situ by reacting the compound of
formula (8), with an alkali metal amide (in particular
sodamide, where the alkali metal is sodium) in which case
the solvent is preferably liquid ammonia or an alkyl

1~7896~
11770
-12-
alkali metal (in particular butyl lithium, where the
alkali metal is lithium) in which case the solvent is
preferably an ether, for example diethylether or
tetrahydrofuran.
This reaction is carried out at reduced
temperatures. For example where the reaction is carried
out in liquid ammonia, the temperature is at or below the
boiling point of ammonia and where a derivative of formula
(8) is generated in situ from an alkyl alkali metal the
reaction i8 carried out at liquid nitrogen temperature,
preferably in an inert atmosphere.
The compounds of formula (8) and (9) are known or can
be made by known methods.
The compounds of formula (4) :-
HN ~ CH2R4
R6 ~ N ~ O
(4)
are known or can be made by analogy with known processesas disclosed in for exampl,e US Patent No 4,154,834 and
European Patent Specification No 17,679.
Compounds of formula (2) can also be prepared by
reacting a guanidine of formula (10) :-
Rl~CH2R3CH2NHJ~NH
(10)where Rl, R2 and R3 are as defined with reference to
,; formula ~2) with a compound of formula (11) :-

1178960
11770
-13-
H
C~2R4
R80~`o
(11)
where R4 is as defined with reference to formula (4) and
R is C1~4 alkyl tparticularly ethyl) benzyl or phenyl.
The reaction can be carried out by heating the
guanidine of formula (10) with the compound of formula (11)
optionally in a solvent for example an alcohol
correspondin~ to the ester function in the compound of
formula (11) that is R8OH, at an elevated temperature,
preferably in the presence of a base in particular the
sodium alkoxide NaOR8 corresponding to the ester
function of the compound of formula (11).
The guanidines of formula (10) can be prepared by
reacting an amine of formula (3) with a compound of
formula (12) :-
l H2
R ~ NH
g (12)
where R is a leaving group for example methylthio or
3,5-dimethylpyrazolyl.
In accordance with the present teachings, a process is
provided for preparing a compound of formula (2):
~.

117~960
-13a-
R~CH2R3CH2NH~CH2-R4
(2)
and pharmaceutically acceptable salts thereof; where
is halogen or nitro; R2 is Cl 4 alkyl; R3 is a
Cl 3 alkylene group; and R4 is 3-pyridyl; N-oxo-3-
pyridyl; 6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl;
6-hydroxymethyl-3-pyridyl; 4,6-dimethyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; 6-hydroxymethyl-4-methyl-3-
pyridyl; 5,6-dimethyl-3-pyridyl; N-oxo-5,6-dimethyl-3-
pyridyl; 6-hydroxymethyl-5-methyl-3-pyridyl; 4-pyridyl
or N-oxo-4-pyridyl, which comprises reacting a compound of
formula (3) :-
~;N~\CH2R3CH2NH2
(3)or a salt thereof, where Rl, R2 and R3 are as
defined with reference to formula (2) with a compound
of formula (4) :-
H
,l CH2R
HN ~
R6J~ O
(4)
where R4 is as defined with reference to formula (2) andR6 is a group displaceable with amine, thereafter where
R4 is N-oxo-6-methyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; or N-oxo-5,6-dimethyl-3-
pyridyl; converting the compound of formula (2) so

-13b, 1 ~ ~ 96 0
obtained into the corresponding compound of formula (2)
where R4 is 6-hydroxymethyl-3-pyridyl; 6-hydroxymèthyl-
4-methyl-3-pyridyl; or 6-hydroxymethyl-5-methyl-3-
pyridyl; and optionally converting the compound of
formula (2) so obtained into a pharmaceutically acceptable
salt, or by reacting a guanidine of formula (10) :-
R ~ CH2R3CH2~H ~ NH
(10)
where Rl, R2 and R3 are as defined with reference toformula (2) with a compound of formula (11) :-
~X
R80 0
(11)where R4 is as defined with reference to formula (4) and
R8 is C1 4 alkyl, benzyl or phenyl; thereafter where
R is N-oxo-6-methyl-3-pyridyl;
N-oxo-4,6-dimethyl-3-pyridyl; or N-oxo-5,6-dimethyl-3-
pyridyl: converting the compound of formula (2) so
obtained into the corresponding compcund of formula (2)
where R4 is 6-hydroxymethyl-3-pyridyl; 6-hydroxymethyl-
4-methyl-3-pyridyl; or 6-hydroxymethyl-5-methyl-3-
pyridyl; and optionally converting the compound of
formula (2) so obtained into a pharmaceutically acceptable
salt.
The histamine H1-antagonist activity of the
compounds of formula (2) can be demonstrated ln vitro in
the guinea pig ileum test. In this test an isolated
portion of the guinea pig ileum is secured under tension
(500 mg) between an anchorage and a transducer in a 10 ml
tissue bath and immersed in magnesium free Tyrode solution
with constant aeration at a temperature of 30C. The
B

1~78960
11770
-14-
output feom the transducer is amplified. The amplified
output is in turn fed to a flat bed recorder. Measured
amounts of histamine are added to the tissue bath so that
the histamine concentration increases step-wise until the
force of the contraction reaches a maximum. The tissue
bath is washed out and filled~with fresh magnesium free
Tyrode solution containing compound under test. The
solution is left in contact with the tissue for 8 min. and
measured amounts of histamine are added again until a
maximum contraction is recorded. The assay is repeated
with increasing concentrations of test compound and the
d~se of histamine giving 50% of maximum contraction is
noted. A dose ratio (DR) was calculated by comparing the
concentrations of histamine required to produce 50%
maximum response in the absence and in the presence of the
antagonist. A plot of Log DR-l against LOG D (the
concentration of compound under test) is made and the
point of intersection with the Log (DR-l) ordinate is
taken as the measure of the activity (PA2 value). The
compounds of Examples 1 to 12 have PA2 values greater
than 8.
The histamine N2-antagonist activity of the
compounds of formula (Il can be demonstrated in vitro in
the guinea pig atrium test; In this test a spontaneously
beating isolated portion of the guinea pig right atrium is
secured under tension (300 mg) between an anchorage and a
transducer in a lS ml tissue bath and immersed in McEwens
solution with constant aeration at a temperature of
37C. The output from the transducer is amplified.
Output is in turn fed to a flat bed recorder. Measured
amounts of histamine are added to the tissue bath so that
the histamine concentration increases step-wise until the
rate of beating reaches a maximum. The tissue bath is
washed out and filled with fresh McEwens solution
; containing compound under test. The solution is left in

7~960
11770
-15-
contact with the tissue for 60 min. and measured amounts
of histamine are added again until a maximum rate is
recorded. The assay is repeated with increasing
concentrations of test compound and the dose of histamine
giving 50% of maximum rate is noted. A dose ratio tDR)
was calculated by comparing the concentrations of
histamine required to produce 50% maximum response in the
absence and in the presence of the antagonist. A plot of
Log DR-l against LOG D (the concentration of compound
under test) is made and the point of intersection with the
Log (DR-l) ordinate is taken as the measure of the
activity ~PA2 value). The compounds of Examples 1 to
12 have PA2 values of less than 7.5.
The activity of compounds of for~ula (2) as histamine
Hl-antagonists can be demonstrated in vivo by the
inhibition of histamine induced bronchoconstriction.
Guinea pigs of either sex are anaesthetised by
intraperitoneal injection of sodium pentobarbitone, 90
mg/kg. The trachea is cannulated. The animal is
respired artificially with a fixed volume of air just
adequate to inflate the lungs. The pressure needed to
inflate the lungs is monitored from the respiratory system
using a low pressure transducer. Intravenous injection
of histamine causes dose-dependent increases in the
pressure to inflate the lungs reflecting the
bronchoconstrictor action of histamine. Responses to
histamine can be antagonised using histamine Hl-receptor
antagonists.
Dose-response curves to histamine are established at
20, 40, B0, 160 and 320 nmols/kg. Antagonists are then
administered by intravenous injection and 5 minutes later
a new histamine dose-response curve is established
increasing the doses of histamine as necessary. The
effect of the antagonist can be quantified by the

96C)
11770
-16-
displacement, to the right, of the histamine dose-response
curve, expressed as~a dose-ratio. A series of doses of
antagonists may be given to each animal allowing
calculation of dose-ratios for each dose of antagonist.
The compounds of the Examples hereafter cause displacement
of hista~ine dose-response curves with a dose-ratio of 10
at doses of less than 0.8 micromole kg 1 i.v~
The activity of the compounds of formula (2) as
histamine ~2-antagonists can be demonstrated in vivo by
the inhibition of histamine-stimulated secretion of
gastric acid from the lumen~perfused stomachs of rats
anaesthetised with urethane. This procedure is referred
to in Ash and Schild, Brit. J. Pharmac. Chemother., 27,
247 (lg66). The compounds of the Examples hereafter
cause 50% inhibition of maximal acid secretion at doses of
0.1 to 30 micromole kg 1 i.v.
In order to use the compounds of the invention as
histamine ~l-antagonists, they can be formulated as
pharmaceutical compositions in accordance with standard
pharmaceutical procedure.
The invention also includes pharmaceutical compositions
comprising a compound of formula (2) or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
carrier.
Compounds of formula (2) and their pharmaceutically
acceptable salts can be administered topically or
systemically.
Topical formulations for administration to the skin
include lotions and creams. Topical formulations for
administration to the respiratory tract include solutions
for application via a nebulizer or as an aerosol, or a
.

:~7~96~)
11770
-17-
microfine insufflatable powder. The active ingredient in
an insufflatable powder has a small particle size i.e.
less than 50 microns and preferably less than 10 microns.
The active material is co-presented with a solid carrier
for example lactose which has a particle size of less than
50 microns.
Systemic administration can be achieved by rectal,
oral or parenteral administration. A typical suppository
formulation comprises the active compound with a binding
agent and/or lubricating agent for example gelatine or
cocoa butter or other low melting vegetable waxes or
fats. Typical parenteral compositions consist of a
solution or suspension of the active material in a sterile
aqueous carrier of parenterally acceptable oil.
Compounds of formula (2) which are active when given
orally can be formulated as syrups, tablets, capsules and
lozenges. A syrup formulation generally consists of a
suspension or solution of the compound in a liquid carrier
for example ethanol, glycerine or water with a fla~ouring
or colouring agent. Where the composition is in the form
of a capsule, the solid in granular form optionally with a
binding agent is encased in a gelatin shell. Where the
composition is in the form of a tablet, any suitable
pharmaceutical carrier routinely used for preparing solid
formulations can be used. Examples of such carriers
include magnesium stearate, starch, lactose, glucose,
sucrose, and cellulose. Preferably the composition is in
unit dose form for example a tablet, capsule or metered
aerosol so that the patient may administer to himself a
single dose.
Where appropriate, small amounts of bronchodilators
and anti-asthmatics for example sympathomimetic amines
particularly isoprenaline, isoetharine, salbutamol, phenyl-

1~ 60
11770
-18-
ephrine and ephedrine; xanthine derivatives particularly
theophylline and aminophylline; and corticosteroids
particularly prednisolone and adrenal stimulants
particularly ACTH can be included. As in common practice,
the compositions will usually be accompanied by written or
printed directions for use in the medical treatment
concerned, in this case as a histamine Hl-antagonist for
treatment of, for example, asthma, hayfever rhinitis or
allergic eczema.
Each dosage unit for oral administration contains
preferably from 1 to 200 mg of a compound of formula (2)
or a pharmaceuticaly acceptable salt thereof calculated as
the free base.
The pharmaceutical compositions of the invention will
normally be administered to a man for the treatment of
rhinitis, hayfever, bronchial asthma or allergic eczema.
An adult patient will receive an oral dose of between 15
mg and 400 mg and preferably between 15 mg and 200 mg or
an intravenous, subcutaneous or intramuscular dose of
between 1 mg and 50 mg, and preferably between 1 mg and 10
mg of compound of formula (I) or pharmaceutically
acceptable salt thereof calculated as the free base, the
composition being administered 1 to 4 times per day.
The following Examples illustrate the invention.

117~
11770
--19--
EXAMæLES
Example 1
(a) 2-(2-Cyanoethyl)malonic acid diethyl ester
(148.3g) was reacted with sodium hydride (15.3g) in
tetrahydrofuran at 20C. 2-Chloro-3-methyl-5-nitro-
pyridine (lOOg) was added and the internal temperature
was raised to 100C (some tetrahydrofuran was distilled
off) over 14 hrs. The reaction mixture was partitioned
between water and chloroform, the chloroform extract was
dried, treated with charcoal and filtered through a silica
bed and ~hen evaporated to dryness. Crystallisation of
the residue from ethanol gave 4-(3-methyl-5-nitropyrid-2-
yl)-4,4-bis(carbethoxy)-butyronitrile (99g) m.p~ 64-65.5C.
(b) 4-(3-Methyl-5-nitropyrid-2-yl)-4,4-bis(carbethoxy)-
butyronitrile (99g) was stirred in a mixture of ethanol
(1200ml) and sodium hydroxide solution (1130ml, molar) for
16 hours. The pH was lowered to 2 by the addition of
hydrochloric acid, and the ethanol was distilled off.
The product was extracted with chloroform to leave an oil
(57.1g). This oil was extracted with dilute hydrochloric
acid (554ml; 1.5N), re-extracted with more dilute
hydrochloric acid and the combined acid extracts were
treated with charcoal, filtered and then extracted with
chloroform, to give 5-nitro-2-(3-cyanopropyl)-3-methyl-
pyridine (49.5g) m.p. 51.5-53C.
(c) 5-Nitro-2-(3-cyanopropyl)-3-methylpyridine (5.9g)
was hydrogenated in ethanol (150ml) with palladium on
charcoal (0.59g of 10%) at 140 kPa, for 2.5 hrs. The
filtered solution was concentrated to dryness, the residue
was triturated with ether to give 5-amino-2-(3-cyano-
propyl)-3-methylpyridine (4.70g) m.p. 103-105C.

g6V
11770
-20-
(d) 5-Amino-2-(3-cyanopropyl)-3-methylpyridine
(23.0g) was reduced with lithium aluminium hydride
(12.47g) in a mixture of tetrahydrofuran (750ml) and
diethylether (750ml) over 3 hours, to give 5-amino-
2-(4-aminobutyl)-3-methylpyridine (20.8g) as an amber
oil. N.M.R. (CDC13):- assignment, ~ (p.p.m.)
multiplicitY; -CH2 CH2 CH2 -2'
3-CH3, 2.22, s; CH2(cH2)2cH2NH2~
5-NH2, ca 3.5, broad resonance; 4-pyridyl proton, 6.77,
d: 6-pyridyl proton, 7.88, d;
(e~ 5-Amino-2-(4-aminobutyl)-3-methylpyridine (5.11g)
in hydrobromic acid (48%, 47ml) was reacted with cuprous
bromide (4.98g) and copper bronze (0.18g). A solution of
sodium nitrite (2.45g) in water 116ml) was added at 5 to
8C over 45 minutes, the reaction mixture was allowed to
stir at 5 to 8C for a further hour and then stirred at
room temperature for 3.5 hours. The reaction mixture was
diluted with water, and hydrogen sulphide gas was passed,
while the pH was progressively raised to 11 by the
addition of sodium hydroxide solution. The precipitated
copper salts were filtered off at intervals during the
above procedure. The product was then extracted at pH 11
with chloroform to give 5-bromo-2-(4-aminobutyl)-3-methyl-
pyridine (4.95g) m.p. 35-37C.
(f) 5-Bromo-2-(4-aminobutyl)-3-methylpyridine (2.12g)
and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone
(3.18g) were refluxed in pyridine (12ml) for 9.5 hrs.
The pyridine was removed in vacuo and the residue was
re-evaporated with n-propanol (2 x 50ml), triturated with
chloroform, filtered and the solution was chromatographed
on silica in chloroform-methanol (10:1). The product was
crystallised from ethanol-ether to give 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-yl-
methyl)-4-pyrimidone (2.44g) m.p. 151-152C.

:~'7~S~60
11770
-21-
21H24BrN50
Requires C, 57.01; H, 5.46; N, 15.83; Br, 18.06;
Found C, 56.83; H, 5.30; N, 15.69; Br, 18.11;
ExamPle 2
Reacting 5-bromo-2-(4-aminobutyl)-3-methylpyridine,
the product from Example l(e) (0.5g), with 2-methylthio-5-
(pyrid-4-ylmethyl)-4-pyrimidone (0.57gm) under conditions
analogous to those described in Example l(f) gave 2-[4-(5-
bromo-3-methylpyrid-2-yl)-butylamino]-5-(pyrid-4-ylmethyl)-
pyrimidone (0.15gm) m.p. 176-177.5C.
20 22 5
Requires C, 56.08; H, 5.17; N~ 16.35; Br, 18.65;
Found C, 56.18; H, 5.08; N, 16.45; Br, 18.43;
ExamPle 3
Reacting 5-bromo-2-(4-aminobutyl)-3-methylpyridine,
the product from Example l(e) (1.04g), with 2-nitroamino-
5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.42g)
under conditions analogous to those described in Example
l(f) gave 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-
5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.48g)
m.p. 193-194.5C.
C21H24BrN502
Requires C, 55.03; H, 5.28; N, 15.28; Br, 17.43;
Found C, 54.67; H, 5.41; N, 15.09; Br, 17.60;
Example 4
2-[4-(5-Bromo-3-methylpyrid-2-yl)butylamino]-5-(N-
oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidone (the product of
Example 3) (0.9g; was reacted with trifluoroacetic

1~7~9~i
11770
-22-
anhydride (1.65g) in dichloromethane (6ml) for two days,
followed by removal of the solvent in vacuo, dissolution
of the residue in chloroform, washing of the chloroform
solution with 10% sodium bicarbonate solution, and
concentrating the chloroform solution to dryness gave
2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(6-hydroxy-
methylpyrid-3-yl-methyl)-4-pyrimidone (0.42g), m.p.
61-70C - resolidifying ca 120C, remelts 160-165C.
C2lH24BrN502~ 1-23H2
Requires C, 52.50; H, 5.50; N, 14.58;
Found C, 52.34; H, 5.35; N, 14.49;
(Weight loss 40-80C, 4.6~ = 1.23 H20)
ExamPle 5
(a) Reaction of 5-amino-2-(4-aminobutyl)-3-methyl-
pyridine (the product of Example l(d)) (1.5g), with sodium
nitrite, cuprous chloride, copper bronze and hydrochloric
acid under conditions analogous to those of Example l(e)
gave 5-chloro-2-(4-aminobutyl)-3-methylpyridine (l.Og)
m.p. 118-120C.
(b) Reaction of 5-chloro-2-(4-aminobutyl)-3-methyl-
pyridine lfrom Example S(a)] (l.Og) with 2-nitroamino-5-
(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.23g) under
conditions analogous to those described in Example l(f)
gave 2-[4-~5-chloro-3-methylpyrid-2-yl)butylamino]-5-
(6-methylpyrid-3-ylmethyl)-4-pyrimidone ~0.53g) m.p.
140-141C.
C21 H24 Cl N50
Requires C, 63.39; H, 6.08; N, 17.60; C1, 8.91;
Found C, 63.18; H, 6.22; N, 17.42; Cl, 9.18;
;

1:1'7~960
11770
-23-
Example 6
(a) 5-Nitro-3-methyl-2-cyanopropylpyridine (29) in
tetrahydrofuran (20ml) was reduced with diborane (0.045
mole) in tetrahydrofuran (45ml) over 2 hours 20 minutes.
The reaction mixture was added slowly to ethanol (lOOml),
stirred for 1 hour, acidified with hydrochloric acid
(lOOml, molar), stirred for 20 minutes and concentrated to
low volume. The solution was washed with chloroform,
basified with sodium hydroxide to pH 12 and extracted with
chloroform to give 3-methyl-5-nitro-2-(4-aminobutyl)
pyridine, as an oil (0.9g) N.M.R. (CDC13) assignment,
~(p.p.m~), multiplicitY; (CH2)2CH2NH2~ 1-4-1-9
m; NH2, 1.98, broad s; 3-CH3 2.48, s,
CH2(CH2)2CH2NH2, 2.7-3.1, m; 4-H pyridyl, 8.21,
d; 6-H pyridyl, 9.19, d.
(b) The product from Example 6(a) (0.85g) was heated
under reflux in pyridine (5ml) with 2-nitroamino-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone (1.25g) under
nitrogen, for 6 hours. The pyridine was removed ln vacuo
and the residue was chromatographed on silica in
chloroform-methanol to give 2-[4-(5-nitro-3-methylpyrid-2-
yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone
(0.345g) m.p. 141-142C.
21 24 6 3
RequiresC, 61.75; H, 5.92; N, 20.58;
FoundC, 61.20; H, 5.92; N, 20.48;
Example 7
(a) 5-Amino-2-[4-aminobutyl~-3-methylpyridine (2.17g)
in 20~ s~lphuric acid (25ml) at -5C was reacted with a
solution of sodium nitrite (lg) in water (5ml) over 20
minutes. After a further 15 minutes at -9C the reaction

li785~
11770
-24-
mixture was added to a mixture of potassium iodide (4g)
and cuprous iodide (0.5g) in water t65ml) at 10C and then
stirred at room temperature for 30 minutes. Saturated
sodium thiosulphate solution (lOml) was added and the pH
was brought to 12 with sodium hydroxide. Chloroform
extraction of the reaction mixture gave 5-iodo-3-methyl-2-
(4-aminobutyl)pyridine as a dark oil (2.45g). N.M.R.
(CDC13) assignment, ~(p.p.m.), multiplicity;
(CH2)2CH2NH2, 1.4-2.0, m; NH2, 1.69, s;
3-CH3, 2.28, s; CH2(cH2)2cH2NH2~
4-H pyridyl, 7.75, m; 6-H pyridyl, 8.57, m;
(b) The product of Example 7(a) (0.6g) and
2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone
(0.6g) were heated in pyridine (3ml) for 5 hours. After
removal of the pyridine in vacuo the residue was
chromatographed in chloroform-methanol on silica to give
2-[4-(5-iodo-3-methylpyrid-2-yl)butylamino]-5-(6-methyl-
pyrid-3-ylmethyl)-4-pyrimidone m.p.l60-161.5C.
Example 8
(a) A cooled (0C) mixture of 5-amino-2-[4-amino-
butyl]-3-methylpyridine (0.86g) and fluoroboric acid (5
ml) in ethanol (30ml) was reacted with amyl nitrite (3 ml)
over 15 minutes and then stirred for a further 15 minutes,
diluted with diethyl ether at O~C to give 5-diazo-2-(4-
aminobutyl)-3-methylpyridine fluoroborate (1.88g)
m.p. 80-120C (dec).
This salt (1.78g) was added portionwise to petroleum
ethee (75ml) stirred at 95-100C to give an oil which
solidified on cooling. The petroleum ether was decanted
and the solid was partitioned between water and chloroform.
The pH of the aqueous portion was raised to 13 with sodium
hydroxide and the product was extracted with chloroform to

96~)
11770
-25-
give 5-fluoro-2-(4-aminobutyl)-3-methylpyridine (0.69g) as
an amber oil.
N.M.R. (CDC13) assignment ~(p.p.m.) multiplicity; NH2,
1.39, broad s; CH2CH2CH2CH2NH2, 1.4 - 1.9, m;
3-CH3, 2-3, s; CH2(CH2)CH2NH2, 2.6 - 2.8, m; 4-H
pyridyl, 7.14, d of d; 6-H pyridyl, 8.19, d;
~b) The product from Bxample 8(a) (0.60g) was
refluxed in pyridine (3ml) with 2-nitroamino-5-~6-methyl-
pyrid-3-yl-methyl)-4-pyrimidone (0.86g) for 7 hours to
give, after concentration, chromatography in chloroform-
methanol, and crystallisation from acetonitrile,
2-[4-(5-fluoro-3-methylpyridyl-2-yl)butylamino]-5-(6-methyl-
pyrid-3-ylmethyl)-4-pyrimidone, (1.04g) m.p. 131.5-133.5C.
C21H24FN50
Requires C, 66.16; ~, 6.35; N, 18.37;
Found C, 66.25; H, 6.36; N, 18.13;
Example 9
The product from Example l(e) (2.1 gm) and
2-nitroamino-5-(5,6-dimethyl-N-oxo-pyrid-3-ylmethyl)-4-
pyrimidone (2.51 gm) were refluxed in pyridine (6 ml) for
13.5 hrs. The pyridine was removed in vacuo, and the
last traces of pyridine were removed by azeotroping with
n-propanol. The residue was then dissolved in hot
ethanol (50 ml) and any undissolved solid filtered off.
The filtrate was concentrated while hot to 20 ml volume
and on cooling white crystals deposited. These were
recrystallised from ethanol and dimethylformamide to give
2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(5,6-
dimethylpyrid-N-oxo-3-ylmethyl)-4-pyrimidone (2.5 gm)
m.p. 204-206C.

7~39t~
11770
-26-
22 26 5 2
Requires C, 55.81 H, 5.60 N, 15.00 Br, 17.23:
Found C, 55.93 H, 5.54 N, 14.82 Br, 16.92;
Example 10
The product from Example l(e) (1.06 gm) and 2-nitro-
amino-5-(N-oxo-pyrid-4-ylme~hyl)-4-pyrimidone (1.14 gm)
were refluxed in anisole (4 ml) for 7.5 hrs. The anisole
was removed in vacuo. The residue obtained was
chromatographed on silica in chloroform-methanol ~4:1).
The product was crystallised from acetonitrile-water (9:1)
to give 2-[4~(5-bromo-3-methylpyridyl-2-yl)-butylamino]-5-
(N-oxo-pyrid-4-yl methyl)-4-pyrimidone (0.40 gm)
m.p. 110-115C.
C20H22BrN5o2 Requires C 54.06 H 4.99 N 15.76 Br 17.98
C20H22BrN5O2Ø62H2O Requlres C 52.70 H 5.14 N 15.37 Br 17.54
Found C 52.68 H 4.92 N 15.45 Br 18.26
ExamPle 11
A mixture of 5-bromo-2-(4-aminobutyl)-3-methyl
pyridine, (0.68 g) and 2-nitroamino-5-(4,6-dimethyl-3-
pyridylmethyl)-4-pyrimidone (0.83 g) in anisole (25 ml)
were refluxed for 4 hrs. Petroleum ether was added to
precipitate the product which was then chromatographed on
a silica gel column eluting with chloroform. The product
was crystallised from ethyl acetate to give 2-[4-(5-
bromo-3-methylpyrid-2-yl)-butylamino]-5-(4,6 dimethyl-3-
pyridylmethyl)-4-pyrimidone (0.77 g) m.p. 110-112C.

9~i~
11770
-27-
C22H26N5BrO~ 1.27 ~2
Requires C. 5s.00; H. ~.01; N. 14.58; Br. 16.63
Found C. 54.87; H. 5.93; N. 14.38; Br. 16.33
(Wt loss 40-110C = 1.33 H2O).
ExamPle 12
A mixture of 5-bromo-2-(4-aminobutyl)-3-methyl
pyridine, (0.68 g) and 2-nitroamino-5-(5,6-dimethyl-3-
pyridylmethyl)-4-pyrimidone (0.83 g) in anisole (25 ml)
were refluxed for 4 hrs. Excess petroleum ether was
added to precipitate the product which was then
chromatographed on a silica gel column in CHC13. The
product crystallised under ether to give 2-[4-(5-bromo-3-
methyl-pyrid-2-yl)-butylamino]-5-(5,6-dimethyl-3-pyridyl-
methyl)-4-pyrimidone (0.6 g) m.p. 126-8C.
C22H26N5BrO- 0.6 H2
Requires C. 56.45; ~. 5.87; N. 14.96; Br. 17.07
Found C. 56.44; H. 5.68; N. 14.82; Br, 16.96
ExamPle 13
Trifluoroacetic anhydride (1.9 ml) was mixed with a
suspension of the product ~rom Example 8 (1.6 gm), in dry
dichloromethane (10 ml) and the mixture was allowed to
stand for two days. The solvent was removed in vacuo,
and the residue was dissolved in chloroform. The
chloroform solution was washed with 10% sodium bicarbonate
solution. Evaporation of the chloroform gave a solid
(1.7 gm) which was crystallised from ethanol (10 ml) and
adding water (20 ml). Solid obtained was recrystallised
from acetonitrile-water (9:1) to give 2-[4-(5-bromo-3-
methylpyrid-2-yl)-butylamino-]-5-(5-methyl,

1~'7~96()
11770
-28-
6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone (0.99 gm)
m.p. 136-141C.
C22H26BrN5O2 Re~uires C 55.93 H 5.54 N 14.82 Br 16.92
C22H26BrN5O2.2ØH2O Requires C 51.97 H 5.95 N 13.73 Br 15.72
Found C 51.82 H 5.89 N 13.83 Br 15.48
Example 14
A solution of 1,2-ethanedisulphonic acid (15.3 g~ in
methanol (48 ml) was added to a solution of 2-[4-(5-bromo-
3-methylpyrid-2-yl)-butylamino]-5-~6-methyl-pyrid-3-yl-
methyl)-4-pyrimidone (20 g) in methanol (68 ml). A solid
crystallised on cooling which was removed by ~iltration,
washed with cold methanol and dried to yield the neutral
ethanesulphonate salt of 2-[4-(5-bromo-
3-methylpyrid-2-yl)-butylamino]-5-(6-methyl-pyrid-3-yl-
methyl)-4-pyrimidone (31g) m.p. 182-5~C.
21H24NsOBr-l-5c2H6o6s2.2H2o
20 Require8 C, 37.75; H, 4.88; N, 9.17; S, 12.60; Br, 10.46
Found C, 37.60; H, 4.78; N, 9.10; S, 12.30; Br, 10.71
Example 15
~25 A pharmaceutical composition for oral administration
is prepared containing
% by weight
r2-[4-(5-bromo-3-methylpyrid-2-yl)- 55
¦butylamino]-5-(6-methylpyrid-3-yl-
A ~ methyl)-4-pyrimidone
¦Dibasic calcium phosphate dihydrate 20
~Approved coloring agent 0.5
Polyvinylpyrrolidone 4.0

i~7~
11770
-29-
by weight
~Microcrystalline Cellulose 8.0
B ~Maize Starch 8.0
¦Sodium glycollate 4.0
~agnesium Stearate o.s
by mixing together the ingredients A (substituting lactose
or microcrystalline cellose for dibasic calcium phosphate
dihydrate if desired), adding a concentrated solution of
polyvinylpyrrolidone and granulating, drying and screening
the dried granules; adding the ingredients B to the dried
granules and compressing the mixture into tablets
containing 5 mg, 25 mg or 50 mg of the free base.
ExamPle 16
A pharmaceutical composition for injectable
adm~nistration is prepared by forming a solution of
2-[4-(5-bromo-3-methyl-pyrid-2-yl)-butylamino]-5-(6-
methylpyrid-3-ylmethyl)-4-pyrimidone hydrochloride salt in
sterile water to give a 1 to 5~ w/w solution. The
solut~on i8 clarified by filtration and filled into vials
which are sealed and sterilised. A suitable vial contains
2 ml of the solution.

1~l78960
--SD30--
SUPPLEMENTARY DISCLOSURE 11770
Example 17
(i) A mixture of ~4-(5-bromo-3-methylpyrid-2-yl)]-
butylamine (4.a6g) and cyanimide (2.76g) in propan-l-ol
(50 ml) was acidified to a pH in the range pH 8-9 and
refluxed for 24 hr. The propan-l-ol was evaporated at
reduced pressure. The residue was dissolved in methanol
(50 ml). The solution was filtered and the filtrate was
diluted with propan-l-ol (200 ml). The dilute solution
was chilled in ice. The precipitate which formed was
collected by filtration and dried in vacuo at 80C for
3 hr. to yield 4-(5-bromo-3-methylpyrid-2-yl)butyl-
guanidine hydrogen sulphate (3.42 g).
(ii) 2-Formyl-4-(2-methyl-5-pyridyl)propionate
(0.89g) was added to a mixture of 4-(5-bromo-3-methyl-
pyrid-2-yl)butylguanidine hydrogen sulphate (1.50g) and
sodium methoxide (0.65g) in methanol (50 ml) and the
mixture was heated under reflux with stirring for 24 hr.
The methanol was evaporated at reduced pressure and the
residue was mixed with water. The aqueous mixture was
extracted with methylene chloride and the extract dried
and evaporated. The residue was chromatographed on a
silica column eluting with 5% v/v methanol in chloroform.
The eluate was collected and the solvent evaporated
to yield 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-
5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(1.32g)
m.p. 156-157C (uncorrected).

-SD31~ 9 6 0
11770
Example 18
(a) 5-[(6-Methylpyrid-3-yl)methyl]-2-thiouracil (2.33 g)
and n-butylbromide (1.37 g) were added to a solution of
sodium hydroxide (0.8 g) in aqueous ethanol (58 ml).
The mixture was heated to 70C with stirring and was
stirred at this temperature for 1 hr. The mixture was
then allowed to cool to room temperature and to stand
overnight. The reaction mixture was acidified to pH 5
with glacial acetic acid. The solution was concentrated
under reduced pressure and a solid formed which was
recovered by filtration, washed with water and dried. A
portion (1.1 g) of this solid was recrystallised from
ethanol to produce 2-n-butylthio-5-[(6-methylpyrid-3-yl)-
methyl]-4-pyrimidone (0.8 g), m.p. 171-2C.
(b) 2-n-Butylthio-5-[(6-methylpyrid-3-yl)methyl]-4-
pyrimidone (0.5 g) and 5-bromo-3-(4-aminobutyl)-3-methyl-
pyridine (0.462 g) were fused at 160C for 8 hr. The
melt was cooled, triturated with diethyl ether and the
solid so produced was recrystallised from ethanol to yield
2-[4-(5-bromo-3-methylpyrid-2-ylJbutylamino]-5-(6-methyl-
pyrid-3-ylmethyl)-4-pyrimidone (0.4 g), m.p. 151-4C.
Example 19
(a) 5-[(6-Methylpyrid-3-yl)methyl]-2-thiouracil (2.33 g)
and benzylbromide (1.71 g) were added to a solution of
sodium hydroxide (0.8 g) in ethanol (58 ml) and the
mixture was warmed to 50C with stirring. After 10
mins., the mixture was removed from the heat and allowed
to stand (ca. 16 hr). The reaction mixture was acidified
to pH 5 with glacial acetic acid and concentrated at
reduced pressure to ca. 40 ml. The solid which
'.~3

~ -SD32-
-2~7~g6~
precipitated was filtered off, washed with water and
dried to yield crude 2-benzylthlo-5-l(6-methylpyrid-3-yl)-
methyl]-4-pyrimidone (2.1 g), m.p. 235-7C, part of which
was used in the next step without further purification.
(b) 2-Benzylthio-5-[(6-methylpyrid-3-yl)methyl]-4-
pyrimidone (0.5 g) and 2-(4-aminobutyl)-5-bromo-3-methyl-
pyridine (0.413 g) were fused at 160C for 7 hr. The
melt was allowed to cool, triturated with diethyl ether
and the solid so obtained was recrystallised from
ethanol/diethyl ether to yield 2-[4-(5-bromo-3-methyl-
pyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-
pyrimidone (0.33 g), m.p. 151-4C.
B