Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-07
2002-03-12
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S250000
Reexamination Certificate
active
06355647
ABSTRACT:
The invention relates to novel 3-substituted 3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivatives, their preparation and use for preparing active ingredients of drugs.
Classical antidepressants, and the newer selective serotonin reuptake inhibitors (SSRIs), exert their antidepressant effect inter alia by inhibiting active reuptake of the transmitter into the presynaptic nerve endings. Unfortunately, in this case the antidepressant effect has its onset only after treatment for at least 3 weeks and, moreover, about 30% of patients are therapy-resistant.
Blockade of presynaptic serotonin autoreceptors increases, by abolishing negative coupling, the serotonin release and thus the instantaneous transmitter concentration 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 disclosed antidepressants which activate both the presynaptic and somatodendritic autoreceptors and therefore result in the 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 serotonin release in the brain: G. W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), 383-392.
However, surprisingly, the selective 5-HT
1B
antagonist GR 127 935 reduces serotonin release 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 rate of firing of serotonergic neurones and thus serotonin secretion (M. Skingle et al., Neuropharmacology Vol. 34 No. 4 (1995), 377-382, 393-402).
One strategy for bypassing the autoinhibitory effects in serotonergic areas of origin thus aims at blockade of the presynaptic 5-HT
1B
receptors. This hypothesis is supported by the observation that the effect of paroxetine on serotonin release 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 increase 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 cause a greater increase in serotonin release in the brain and might therefore entail advantages in the therapy of depression and related psychological disorders.
It has now been found that 3-substituted 3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivatives of the formula I
where
R
1
is a hydrogen atom, a C
1
-C
4
-alkyl group, an acetyl group, a phenylalkyl C
1
-C
4
radical where the aromatic ring is 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 C
1
-C
3
-alkyl carboxylate radical,
R
2
is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is unsubstituted or mono- or disubstituted by halogen atoms, C
1
-C
4
-alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, C
1
-C
4
-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, and may be fused to a benzene nucleus which may be 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,
A is NH or an oxygen atom,
Y is CH
2
, CH
2
—CH
2
, CH
2
—CH
2
—CH
2
or CH
2
—CH
Z is a nitrogen atom, carbon atom or CH, where the linkage between Y and Z may also be a double bond,
and n is 2, 3 or 4,
or a physiologically tolerated salt thereof, have valuable pharmacological properties.
Particularly preferred compounds are those where
R
1
is hydrogen, ethyl, ethyl carboxylate
R
2
is o-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl
A is an oxygen atom
y is CH
2
—CH
2
Z is a nitrogen atom
and n is 2 and 3.
The novel compounds of the formula I can be prepared by reacting a compound of the formula II
where R
1
has the abovementioned meaning, R
3
is a cyano group or a C
1-3
-alkyl carboxylate group, and R
4
is C
1-3
-alkyl, with a primary amine of the formula III
where R
2
has the abovementioned meaning, and converting the compound obtained in this way where appropriate into the addition salt with a physiologically tolerated acid.
The reaction is expediently carried out in an inert organic solvent, in particular a lower alcohol, eg. methanol or ethanol, or a saturated cyclic ether, in particular tetrahydrofuran or dioxane.
The reaction is, as a rule, carried out at from 20 to 110° C., in particularly 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 a cyano group or a C
1-3
-alkyl carboxylate group, and R
4
is C
1-3
-alkyl, is reacted with a primary amino alcohol of the formula IV
in an inert solvent, preferably alcohols such as ethanol, at from 60° to 120° C. to give the cyclization product V (X=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 halogen derivative V (X=Cl, Br). Finally, the halogen derivative of the formula V (X=Cl, Br) is reacted with an amine of the formula VI
where Y, Z and R
2
have the abovementioned meanings, to give the novel final product of the formula I. This reaction takes place best in an inert organic solvent, preferably toluene or xylene, in the presence of a base, eg. potassium carbonate or potassium hydroxide, at from 60° C. to 150° C.
The novel compounds of the formula I 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 3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidine derivatives of the formula I are converted in a conventional way into the acid addition salts with a solution containing the stoichiometric amount of the appropriate acid. Examples of pharmaceutically acceptable 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 also accordingly relates to a therapeutic composition which comprises a compound of the formula I or its pharmacologically acceptable acid addition salt as active ingredient in addition to conventional excipients and diluents, and to the use of the novel compounds for controlling diseases.
The novel compounds can be administered in a conventional way orally or parenterally, intravenously or intramuscularly.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active ingredient is, as a rule, from about 1 to 100 mg/kg of body weight on oral administration and from 0.1 to 10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical auxiliaries such as tablet bind
Bach Alfred
Dullweber Uta
Emling Franz
Garcia-Ladona Francisco-Javier
Starck Dorothea
Abbott Laboratories
Keil & Weinakuf
Liu Hong
Shah Mukund J.
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