Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1999-03-10
2001-04-24
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C514S267000
Reexamination Certificate
active
06222034
ABSTRACT:
The invention relates to novel 3-substituted pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine derivatives, and the preparation and use thereof for producing pharmaceutical active substances.
Classical antidepressants and the newer selective serotonin reuptake inhibitors (SSRIs) display their antidepressant effect inter alia by inhibition of the active reuptake of the transmitter in the presynaptic nerve endings. Unfortunately, in these cases the antidepressant effect has its onset only after treatment for at least 3 weeks and, in addition, about 30% of patients are therapy-resistant.
Blockade of presynaptic serotonin autoreceptors increases, by abolition of the negative coupling, the serotonin release and thus the transmitter concentration present in the synaptic cleft. This increase in the transmitter concentration is regarded as the principle of the antidepressant effect. This mechanism of action differs from that of previously known antidepressants which activate both the presynaptic and somatodendritic autoreceptors and hence lead to a delayed onset of action only after desensitization of these autoreceptors. Direct autoreceptor blockade bypasses this effect.
According to current knowledge, the presynaptic serotonin autoreceptor is of the 5-HT
1B
subtype (Fink et al., Arch. Pharmacol. 352 (1995), 451). Selective blockade thereof by 5-HT
1B/D
antagonists increases the release of serotonin in the brain: G. W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P. H. Hutson et al. Neuropharmacology 34 (1995), 383-392.
However, the selective 5-HT
1B
antagonist GR 127 935 surprisingly reduces release of serotonin in the cortex after systemic administration. One explanation might be stimulation of somatodendritic 5-HT
1A
receptors in the raphe region by the released serotonin, which inhibits the firing rate of serotonergic neurons and thus serotonin release (M. Skingle et al., Neuropharmacology 34 (1995), 377-382 and 393-402).
One strategy for bypassing the autoinhibitory effects in the serotonergic areas of origin thus pursues blockade of the presynaptic 5-HT
1B
receptors. This theory is supported by the observation that the effect of paroxetine on the release of serotonin in the dorsal raphe nucleus of the rat is potentiated by the 5-HT
1B
receptor antagonist GR 127 935 (Davidson and Stamford, Neuroscience Letts., 188 (1995),41).
The second strategy includes blockade of both types of autoreceptors, namely the 5-HT
1A
receptors, in order to enhance neuronal firing, and the 5-HT
1B
receptors, in order to raise terminal serotonin release (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994), 393).
5-HT
1B/D
antagonists alone or coupled with a 5-HT
1A
receptor-antagonistic component ought therefore to augment the increase in serotonin release in the brain and might therefore have advantages in the treatment of depression and related psychological disorders.
It has now been found that 3-substituted 3,4,5,6,7,8-hexahydropyrido[4′,3′,:4,5]thieno[2,3-d]pyrimidine derivatives of the formula I
where
R
1
is hydrogen, C
1
-C
4
-alkyl, acetyl or benzoyl, a phenylalkyl C
1
-C
4
radical, the aromatic ring being unsubstituted or substituted by halogen, C
1
-C
4
-alkyl, trifluoromethyl, hydroxyl, C
1
-C
4
-alkoxy, amino, cyano or nitro groups, or is a naphthylalkyl C
1
-C
3
radical, a phanylalkanone C
2
-C
3
radical or a phenylcarbamoylalkyl C
2
radical, it being possible for the phenyl to be substituted by halogen,
R
2
is phenyl, pyridyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by halogen atoms, C
1
-C
4
-alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, C
1
-C
4
-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, and each of which may be fused to a benzene nucleus which may be unsubstituted or mono- or disubstituted by halogen atoms, C
1
-C
4
-alkyl, hydroxyl, trifluoromethyl, C
1
-C
4
-alkoxy, amino, cyano or nitro groups, and may contain 1 nitrogen atom, or to a 5- or 6-membered ring which may contain 1-2 oxygen atoms, or may be substituted by a phenyl-C
1
-C
2
-alkyl or -alkoxy group, it being possible for the phenyl to be substituted by halogen, a methyl, trifluoromethyl or methoxy group,
A is NH or an oxygen atom,
B is hydrogen or methyl,
C is hydrogen, methyl or hydroxyl,
X is a nitrogen atom,
Y is CH
2
, CH
2
—C
2
, CH
2
—C
2
—CH
2
or CH
2
—CH,
Z is a nitrogen atom, carbon atom or CH, it also being possible for the linkage between Y and Z to be a double bond,
and n is 2, 3 or 4,
and the salts thereof with physiologically tolerated acids, have valuable pharmacological properties.
Particularly preferred compounds are those where
R
1
is methyl, ethyl, isopropyl, benzyl, subst. benzyl, phenethyl, subst. phenethyl,
R
2
is o-methoxyphenyl, 1-naphthyl, pyrimidin-2-yl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl,
A is NH or an oxygen atom,
X is a nitrogen atom,
Y is CH
2
—C
2
, CH
2
—CH,
Z is a nitrogen atom, carbon atom or CH,
and n is 2 and 3.
Compounds of the formula I according to the invention can be prepared by reacting a compound of the formula II
where R
1
has the abovementioned meaning, R
3
is cyano or a C
1-3
-alkylcarboxylic ester group, R
4
is C
1-3
-alkyl and C is hydrogen, methyl or hydroxyl, with a primary amine of the formula III
where R
2
and B have the abovementioned meanings, and converting the resulting compound where appropriate into the addition salt with a physiologically tolerated acid.
The reaction is expediently carried out in an inert organic solvent, in particular in a lower alcohol, eg. methanol or ethanol, or a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or without solvent.
The reaction is, as a rule, carried out at from 20 to 190° C., in particular from 60 to 90° C., and is generally complete within 1 to 10 hours.
Or a compound of the formula II
where R
1
has the abovementioned meaning, R
3
is cyano or a C
1-3
-alkylcarboxylic ester group, R
4
is C
1-3
-alkyl, and C is hydrogen, methyl or hydroxyl, is reacted with a primary amine of the formula IV
where B has the abovementioned meaning, in an inert solvent, preferably alcohols such as ethanol, at from 60 to 120° C. to give the cyclizdtion product V (D=OH)
which is subsequently converted with a halogenating agent, eg. thionyl chloride or hydrobromic acid, in an organic solvent such as a halohydrocarbon or without solvent at from room temperature to 100° C. into the corresponding halo derivative V (D=Cl, Br). Finally, the halo derivative of the formula V (D=Cl, Br) is reacted with an amine of the formula VI
where X, Y, Z and R
2
have the abovementioned meanings, to give the final product of the formula I according to the invention. This reaction takes place best in an inert organic solvent, preferably toluene or xylene, in the presence of a base such as potassium carbonate or potassium hydroxide, at from 60 to 150° C.
The compounds of the formula I according to the invention can be either recrystallized by recrystallization from conventional organic solvents, preferably from a lower alcohol such as ethanol, or purified by column chromatography.
The free 3-substituted pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine derivatives of the formula I can be converted in a conventional way into acid addition salts by treatment with a solution containing the stoichiometric amount of the appropriate acid. Examples of pharmaceutically suitable acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
The invention accordingly also relates to a therapeutic composition which has a content of a compound of the formula I or pharmacologically suitable acid addition salt thereof as active substance in addition to conventional excipients and diluents, and to the use of the novel compounds for controlling diseases.
The compounds according to the invention can be administered in a conventional w
Bach Alfred
Behl Berthold
Cheetham Sharon
Emling Franz
Kerrrigan Frank
BASF - Aktiengesellschaft
Higel Floyd D.
Keil & Weinkauf
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