NZ247791A - Pyrrolothienopyrazine derivatives, their preparation and pharmaceutical compositions - Google Patents
Pyrrolothienopyrazine derivatives, their preparation and pharmaceutical compositionsInfo
- Publication number
- NZ247791A NZ247791A NZ247791A NZ24779193A NZ247791A NZ 247791 A NZ247791 A NZ 247791A NZ 247791 A NZ247791 A NZ 247791A NZ 24779193 A NZ24779193 A NZ 24779193A NZ 247791 A NZ247791 A NZ 247791A
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- pyrrolo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The invention relates to the compounds of general formula (I): <IMAGE> in which R1, R2, R3 and A are as defined in the description, to their optical isomers and to their addition salts with a pharmaceutically acceptable acid or base. Medicaments.
Description
New Zealand Paient Spedficaiion for Paient Number £47791
Piiority Date(s):
,SW.3?r.
Complete Specification Filed: ,
Class:
Publication Date: ...?.?. P£P. P.O. Journal, No: .. /?^r?
3 ft: r\ n \ ? n I f>t jgf y *''i i4V V i iVv£hi
N.Z. PATENT OFFICE
JUN 1993
received
NEW ZEALAND PATENTS ACT, 1953
No.:
Date:
COMPLETE SPECIFICATION
NEW PYRROLOTHffiNOPYRAZINE COMPOUNDS, PROCESSES FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
We, ADIR ET COMPAGNIE, a French body corporate, of 1 rue Carle Hebert, F-92415, Courbevoie, Cedex, France,
hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 -(followed by page la)
247791
m *
The present invention relates to new pyrrolothienopyrazine compounds, to processes for the preparation thereof, and to pharmaceutical compositions containing them.
The Applicant has now found new pyrrolothienopyrazine compounds that have a very strong affinity for certain serotoninergic receptors. They exhibit especially a remarkable affinity for 5-HT3 receptors that is selective with regard to the other serotoninergic receptors.
There is known in the literature 4-(4-methylpiperazinyl)-7-(trifluoromethyl)pyrrolo[l,2-a]quinoxaline, which is described solely as an agonist of 5HT-1B serotoninergic receptors (Neale R.F. et al., Eur. J. of Pharmacology, 1987, 136, pp. 1-9 and Macor J.E. et al., J. Med. Chem., 1990, 33, pp. 2087-2093).
More especially, the present invention relates to the compounds of formula (I) :
in which:
- either Ri and R2 together form a double bond and R3 represents a chlorine atom or a group of the formula :
(I)
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2
in which R4 and R5, with the nitrogen atom carrying them, form a group selected from :
- piperazine,
- substituted piperazine,
- substituted piperidine,
- substituted pyrrolidine,
- morpholine substituted by one or more alkyl radicals,
- tetrahydropyridine,
- thiomorpholine,
- azaspirane having from 5 to 12 ring members,
- azaspirane having from 5 to 12 ring members that is substituted by one or more alkyl radicals or oxo groups,
- azacycloalkyl having from 7 to 12 ring members that optionally includes in its skeleton 1 or 2 additional hetero
atoms selected from oxygen, sulphur, and nitrogen,
- azacycloalkyl having from 7 to 12 ring members that is substituted by one or more alkyl radicals or oxo groups and that optionally includes in its skeleton 1 or 2 additional hetero atoms selected from oxygen, sulphur, and nitrogen,
- a group -NH-(CH2)k~NH2 in which k represents an integer 2, 3
or 4,
- and a substituted group -NH-(CH2)k-NH2 in which k represents an integer 2, 3 or 4,
- or Ri represents a hydrogen atom and R2 and R3 together form an
oxo group,
wherein the term "substituted" relating above to the groups piperazine, piperidine, pyrrolidine and -NH-(CH2)k~NH2 indicates that those groups may be substituted by one or more halogen atoms, hydroxy radicals, oxo radicals, radicals Rio or radicals
-C - Rio
II
0
3
2/ "7 "*7
*7 7 9 i
Rio being selected from:
- alkyl,
- alkoxy,
- alkenyl,
- -(CH2)n-Rii or -(CH2)n'-C-Rii wherein n represents
11
0
0 or an integer from 1 to 5, n' represents an integer from 1 to 5, and Rn represents a phenyl, benzhydryl, thienyl, pyrrolyl, pyrrolidinyl, furyl, pyrimidinyl, pyridyl, benzodioxolyl, benzodioxanyl, naphthyl, quinolinyl, isoquinolinyl, cycloalkyl or dicycloalkylmethyl radical, the term cycloalkyl representing a mono- or bi-cyclic group having from 3 to 12 ring members,
it being possible for those radicals Rn themselves to be substituted by one or more radicals selected from halogen, trifluoromethyl, amino, nitro, hydroxy, alkyl, and alkoxy,
- and -(CH2)nl_Ri2 wherein n' is as defined above and R12 represents a group selected from carboxy, alkoxycarbonyl, amino, dialkylamino, -SO2NR13R14 and -CONR13R14 in which each of R13 and R14 independently of the other represents a hydrogen atom or an alkyl radical,
and A represents:
either a group of formula (a)
R6
\
(a)
R7
and forms, with the heterocyclic system carrying it, a pyrrolo[l,2-a]thieno[3,2-e]pyrazine of formula (I/a) :
(I/a)
in which Ri, R2 and R3 are as defined above and each of R6 and R7, which are identical or different, independently of the other represents a group selected from :
- hydrogen,
- alkyl,
- alkyl substituted by one or more halogen atoms or hydroxy radicals,
- acyl,
- alkoxycarbonyl,
- halogen,
- nitro,
- -(CH2)m~phenyl, -(CH2)m~naphthyl or -(CH2)m-pyridyl wherein m represents 0 or an integer from 1 to 4 and wherein the phenyl nucleus is unsubstituted or substituted by one or more radicals Ra, which are identical or different, Ra representing halogen, alkyl, alkoxy, trifluoromethyl or pyrrolidinyl,
- and a group of the formula :
Rb
-<CHa)p in which p represents 0 or an integer 1 or 2, Y represents an oxygen atom, a nitrogen atom or a sulphur atom, and Rb represents a hydrogen atom or an alkyl group,
««n»
- or a group of formula ((5)
R8
X
(P)
r9
and forms, with the heterocyclic system carrying it, a pyrrolo[l,2-a]thieno[2,3-e]pyrazine of formula (I/P) :
R8
Rg S
9
4
N
R3
(I/P)
R2
R1
in which Ri, R2 and R3 are as defined above and Rs and Rg have the same meanings as R5 and R7 as defined above,
with the proviso that when R3 represents a chlorine atom, or when R3 and R2 together form an oxo group, then R6 and R7, or Rs and Rg, may not at the same time be both hydrogen atoms,
their optical isomers, in pure form or in the form of a mixture, when R3, R6, R7, Rs or Rg represents an optically active group,and their addition salts with a pharmaceutically acceptable acid or base, wherein, unless indicated otherwise,
- the terms "alkyl", "alkoxy" and "acyl" represent linear or branched groups having from 1 to 6 carbon atoms,
- and the term "alkenyl" represents an unsaturated, linear or branched group having from 2 to 6 carbon atoms.
2 4779
6
More especially, the invention relates to compounds of formula (I) in which Ri and R2 together form a double bond and R3 " represents a group of the formula :
xr5
wherein R4 and R5 are as defined in formula (I),and, for example, to compounds of formula (I) in which R4 and R5, with the nitrogen atom carrying them, form a piperazine group or a substituted piperazine group, the term "substituted" being as defined in formula (I),
their optical isomers,and their addition salts with a pharmaceutically acceptable acid or base.
Of the pharmaceutically acceptable acids that may be used to form an addition salt with the compounds of the invention there may be mentioned, by way of non-limiting example, hydrochloric, 15 sulphuric, phosphoric, tartaric, malic, maleic, fumaric, oxalic, methanesulphonic, ethanesulphonic, camphoric and citric acids.
Of the pharmaceutically acceptable bases that may be used for converting the compounds according to the invention into salts there may be mentioned, by way of non-limiting example, sodium 20 hydroxide, potassium hydroxide, triethylamine, diethylamine, ethanolamine, arginine, lysine and diethanolamine.
The present invention relates also to a process for the preparation of the compounds of formula (I), characterised in that:
a compound of formula (II) :
0
in which A is as defined in formula (I), is heated, in the presence or in the absence of a solvent, to give a compound of formula (I/a) :
N
0
H
(I/a)
in which A is as defined above,
which is a particular case of the compounds of formula (I) in which Ri represents a hydrogen atom and R2 and R3 together form an oxo group,
which compound of formula (I/a) is subjected to a halogenating agent to give a compound of formula (I/b) :
CI
(I/b)
in which A is as defined above.
which is a particular case of the compounds of formula (I) in which Ri and R2 together form a double bond and R3 represents a chlorine atom,
which is then reacted with an amine of formula (III) :
HN
r5
(III)
in which R4 and R5 are as defined in formula (I), to give a compound of formula (I/c) :
N N
R 4
R5
in which A, R4 and R5 are as defined above,
(I/c)
which is a particular case of the compounds of formula (I) in which Ri and R2 form a double bond and R3 represents a group :
R4
-N
R5
the compounds of formulae (I/a), (I/b) and (I/c) forming the compounds of formula (I) in their entirety,
it being possible for the compounds of formula (I) to be : - purified by one or more purification methods selected from crystallisation, chromatography over activated a silica
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9
column, extraction, filtration, and passage over activated carbon or resin,
- - separated, where applicable, in pure form or in the form of a mixture, into their possible optical isomers,
- and/or converted into a salt with a pharmaceutically acceptable acid or base.
The invention relates also to a process for the preparation of the compounds of formula (I/c), which are a particular case of the compounds of formula (I) in which Ri and R2 together form a 10 double bond and R3 represents a group :
characterised in that: a compound of formula (II) :
a
(ii)
c-n3
II
0
in which A is as defined in formula (I),
is reacted with an amine of formula (III) :
(HI)
in which R4 and R5 are as defined in formula (I),to give a compound of formula (V) :
V
//
NH-C-N
X
RU
R5
(V)
in which A, R4 and R5 are as defined above,
which is then cyclised under the action of a halogenating agent and subjected to alkaline treatment to give a compound of formula (I/c) :
R4
R5
in which A, R4 and R5 are as defined above,
(I/c)
which is a particular case of the compounds of formula (I) in which Ri and R2 together form a double bond and R3 represents a group :
R4
-N
R5
it being possible for the compounds of formula (I/c) to be:
- purified by one or more purification methods selected from crystallisation, chromatography over activated a silica
column, extraction, filtration, and passage over activated carbon or resin,
- separated, where applicable, in pure form or in the form of a mixture, into their possible optical isomers,
11
- and/or converted into a salt with a pharmaceutically acceptable acid or base.
The compounds of formula (II) are readily accessible to the person skilled in the art by alkaline treatment of a compound of formula (a) :
II
0
in which A is as defined in formula (I) and Rb represents a (Ci— C4)-alkyl group,
or by hydrolysis of a compound of formula (b) :
in which A is as defined above, to yield a compound of formula (c) :
II
0
in which A is as defined above,
which compound of formula (c) is then reacted with sodium azide to give the corresponding compound of formula (II) :
0
in which A is as defined above,
it being possible for the compounds of formula (II) to be:
- purified by one or more purification methods selected from crystallisation, chromatography over a silica column, extraction, filtration, and passage over activated carbon or resin,
- separated, where applicable, in pure form or in the form of a mixture, into their possible optical isomers.
The starting materials used in the processes described above are:
- either commercially available,
- or readily accessible to the person skilled in the art by processes described in the literature.
The compounds of formula (I) have very valuable pharmacological properties.
The compounds of the invention are, especially, very powerful selective ligands of 5-HT3 receptors (see the receptor binding studies in Example A of the present Application).
Moreover, their strong affinity for 5-HT3 receptors has been demonstrated both in vitro (measurement of the accumulation of
13
4779
nc-guanidine in NG 108-15 cells, Example B of the present Application) and in vivo (measurement of the BEZOLD-JARISCH reflex, Example C of the present Application).
The compounds of the invention may therefore be used in the prevention and the treatment of anxiety, depression, stress, psychoses, schizophrenia, disorders of the central nervous system, migraine, memory disorders, eating disorders, alcoholism and pain, as well as in the prevention and the treatment of vomiting and gastric emptying disorders.
The invention relates also to pharmaceutical compositions containing as active ingredient at least one of the compounds of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients or carriers.
Of the compositions according' to the invention there may be mentioned, by way of non-limiting example, those which are suitable for oral, parenteral, ocular, per- or trans-cutaneous, nasal, rectal, perlingual or respiratory administration, and especially injectable preparations, aerosols, ocular or nasal drops, tablets, sublingual tablets, gelatin capsules, capsules, lozenges, glossettes, suppositories, creams, ointments and gels.
The preparations so obtained are generally in dosage unit form and may contain, depending on the disorders treated and on the age and sex of the patient, from 0.01 to 100 mg of active ingredient in doses of from 1 to 3 times per day, preferably from 0.01 to 5 mg of active ingredient, especially from 0.1 to 5 mg, for example 1 mg.
The following Examples illustrate the invention and do not limit it in any way.
PREPARATION 1 : 3- (PYRROL-1-YL) - 2-THENOYL AZIDE
14
STEP A : Methyl 3-(pyrrol-l-yl)-2-thenoate
g (0.127 mol) of methyl 3-amino-2-thenoate are added in small portions, while cold, over a period of 5 minutes, to a solution of 16.80 g (0.127 mol) of 2,5-dimethoxytetrahydrofuran in 400 cm3 5 of dioxane in the presence of one equivalent of 4-chloropyridinium hydrochloride. The solution is refluxed for 2 hours, then concentrated under reduced pressure. The residue is taken up in 200 cm3 of water and extracted with 600 cm3 of diethyl ether. The ethereal phase is dried, decolourised with 10 animal charcoal and then concentrated in vacuo. The resulting residual oil crystallises in the form of white crystals. Recrystallisation solvent: diethyl ether-hexane (4/1)
Yield : 68%
Melting point : 60°C 15 Spectral characteristics :
Infrared : v CO : 1700 cm-i v C=C : 1545 cm-i
STEP B : 3-(pyrrol-l-yl)-2-thenoic acid
A solution of 20 g (0.096 mol) of the compound obtained in Step A 20 in a mixture of 150 cm3 of methanol and 100 cm3 of a 6N sodium hydroxide solution is heated under reflux, with stirring, for 3 hours, then the methanol is evaporated off under reduced pressure. The reaction mixture is diluted with 100 cm3 of acidified water and then extracted with 500 cm3 of ether. The 25 ethereal phase is separated off, dried, and then concentrated in vacuo. The residue is recrystallised from diethyl ether, yielding 3-(pyrrol-l-yl)-2-thenoic acid.
Melting point : 170°C Yield : 74%
Spectral characteristics :
Infrared : v CO : 1675 cm-1
v OH : 2980, 2520 cm-1
247791
STEP C : 3-(pyrrol-l-yl)-2-thenoyl azide
" 18 cm3 of triethylamine are added dropwise at 0°C to a solution of 10 g (0.0518 mol) of the compound obtained in Step B in a mixture (50/50) of acetone and 7.18 cm3 of acetonitrile. After 5 30 minutes' stirring, 4.97 cm3 of ethyl chloroformate are added dropwise in such a manner that the temperature remains between 0 and 5°C, and then, after 30 minutes' stirring, 4.04 g (0.062 mol) of sodium azide dissolved in 30 cm3 of water are added. The reaction mixture is stirred at 0°C for 2 hours and then poured 10 onto 1 litre of stirred water. The precipitate that forms is suction filtered, washed with a minimum amount of water, and dried at room temperature.
Recrystallisation solvent : diethyl ether Yield : 84%
Melting point : 100°C
Spectral characteristics :
Infrared : v CON3 : 2150 cm-1 v CO : 1670 cm-1
v (principal) : 1420, 1220, 1000, 780 and 740 cm-1 20 PREPARATIONS 2 TO 7 :
Following the procedure of Preparation 1 but replacing methyl 3-amino-2-thenoate in Step A with the appropriately substituted methyl thenoate, the compounds of the following Preparations are obtained :
PREPARATION 2 ; 5-PHENYL-3-(PYRROL-1-YL)-2-THENOYL AZIDE Recrystallisation solvent : ether Melting point : 64°C
PREPARATION 3 : 5" ( 4-FLOOROPHENYL)-3-(PYRROL-1-YL)-2-THENOYL
AZIDE
Recrystallisation solvent ether Melting point : 108°C
16
4779
PREPARATION 4 : 4-PHENYL-3-(PYRROL-l-YL)-2-THENOYL AZIDE ^ Recrystallisation solvent : ether Melting point : 122°C
PREPARATION 5 : 4-(4-METHOXYPHENYL)-3-(PYRROL-l-YL)-2-THENOYL 5 AZIDE
Recrystallisation solvent : ether Melting point : 106°C
PREPARATION 6 : 5-PHENYL-2-(PYRROL-1-YL)-3-THENOYL AZIDE Recrystallisation solvent : ether 10 Melting point : 72°C
PREPARATION 7 : 4f5-DIMETHYL-2-(PYRROL-1-YL)-3-THENOYL AZIDE Melting point : oil
PREPARATION 8 : 2 - (PYRROL -1 - YL) - 3-THENOYL AZIDE Its preparation is described in the publication of Rault 15 et al., Heterocycles, Vol. 14, no. 5, 1980.
EXAMPLE 1 :
-(4-METHYLPIPERAZIN-l—YL)PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE STEP A : 5-oxo-4,5-dihydro-pyrrolo[l,2-a]thieno[3,2-e]pyrazine Method A :
A suspension of 10 g of 2-(pyrrol-l-yl)-3-thenoyl azide in 150 cm3 of ortho-dichlorobenzene is heated under reflux for one hour. After cooling, the precipitate is suction filtered, washed with diethyl ether and dried, yielding 5-oxo-4,5-dihydro-pyrrolo[1,2-a]thieno[3,2-e]pyrazine.
Recrystallisation solvent : acetone (white crystals)
Yield : 92%
Melting point : 272°C
17
Method B :
1 g of 2-(pyrrol-l-yl)-3-thenoyl azide is heated while dry to 130°C. When the evolution of gas has ceased, the residue is sublimed at 180°C under 0.04 mm Hg.
Yield : 82%
STEP B : 5-chloropyrrolo[l,2-a]thieno[3,2-e]pyrazine
A suspension of 6 g of 5-oxo-4,5-dihydro-pyrrolo[1,2-a]-thieno-[3,2-e]pyrazine, obtained in the preceding Step, in 300 cm3 of phosphorus oxychloride and 6 cm3 of pyridine is heated under 10 reflux for 4 hours. The phosphorus oxychloride is then removed in vacuo, and the residue is triturated with a 10% ammonia solution, suction filtered, washed with water and dried, yielding 5-chloropyr rolo-[1,2-a]thieno[3,2-e]pyrazine.
Recrystallisation solvent : acetone (pale yellow crystals 15 subliming at 120°C under 0.04 mm Hg)
Yield : 62%
Melting point : 127°C
STEP C : 5-( 4-methylpiperazin-l-yl)pyrrolo[ 1, 2-a ]thieno[ 3 ,2-e ] pyrazine
0.011 mol of 1-methylpiperazine and 0.020 mol (2.12 g) of sodium carbonate are added to a solution of 0.010 mol (2.08 g) of 5-chloropyrrolo[1,2-a]thieno[3,2-e]pyrazine in 10 cm3 of dimethylformamide. The reaction mixture is heated under reflux for 2 hours and then cooled, and 100 cm3 of water are added. The 25 resulting suspension is extracted 3 times with 100 cm3 of diethyl ether. The organic phases are combined and washed 3 times with 100 cm3 of water and then dried over magnesium sulphate and decolourised on animal charcoal. The solvent is removed under reduced pressure and the resulting residual oil crystallises by 30 cooling, yielding 5-(4-methylpiperazin-l-yl)pyrrolo[l,2-a]thieno-[3,2-e]pyrazine.
\ /
Recrystallisation solvent : isopropanol Yield : 79%
Melting point : 82°C 5 Spectral characteristics :
Infrared : v C-H : 3100, 2940 and 2800 cm-l v (principal) : 1570, 1500, 1270, 1180, 1140, 1010, 960, 870, 785, 740, 710 and 640 cm-l
H NMR (8 ppm) tetramethylsilane (TMS) (DMSO-d6) :
7.73 (H8); 7.34 (H2); 7.22 (H3); 6.89 (He); 6.82 (H7); 3.57 and 2.50 (CH2); 2.24 (CH3)
EXAMPLE 2 :
-(4-METHYLPIPERAZIN-l-YL)PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE FUMARATE
0.011 mol (1.2 g) of a solution of fumaric acid in 75 cm3 of anhydrous acetone is added, while warm, to a solution of 0.010 mol of the compound obtained in Example 1 in 15 cm3 of anhydrous acetone. The reaction mixture is heated under reflux for 15 minutes and then allowed to cool to room temperature. The 20 desired fumarate crystallises in that medium; it is recovered by filtration and then dried and recrystallised from isopropanol. Yield : 91%
Melting point : 200°C Spectral characteristics :
Infrared : v N+- : 2700 cm-l (broad)
v C-H : 3100, 2920 and 2840 cm-l v C=0 : 1680 cm-l
19
v (principal) : 1480, 1410, 1385, 1280, 1180, 1140, 1100, 1050, 1025, 985, 950, 740 and 650 cm-l
EXAMPLE 3 :
- (4-METHYLP IPERAZ IN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 2 , 3-e ] PYRAZINE
Following the procedure of Example 1 but replacing 2-(pyrrol-l-yl)-3-thenoyl azide in Step A with 3-(pyrrol-l-yl)-2-thenoyl azide, the compounds of the following Steps are obtained in succession :
STEP A : 5-oxo-4,5-dihydro-pyrrolo[l,2-a]thieno[2,3-e]-pyrazine 10 Yield : 81%
Melting point : 276°C
STEP B : 5-chloropyrrolo[l,2-a]thieno[2,3-e]pyrazine Recrystallisation solvent : diethyl ether Yield : 61%
Melting point : 180°C
STEP C : 5-(4-methylpiperazin-l-yl)pyrrolo[1, 2-a]thieno[2,3-e]pyrazine
N
/ \
I
\ /
N-CH3
Recrystallisation solvent : isopropanol 20 Yield : 81%
Melting point : 98°C Spectral characteristics :
Infrared : v C-H : 3100, 2960 and 2800 cm-l
v (principal) : 1500, 1450, 1410, 1360, 1260, 1180, 1140, 1015, 950, 800 and 710 cm-l - iH NMR (S ppm) tetramethylsilane (TMS) (DMSO-d6):7.54 (Ha); 7.27 (H2); 7.11 (Hi); 6.76 (H7 and H6); 3.75 and 2.63 (CH2); 2.38 (CH3)
EXAMPLE 4 :
-( 4-METHYLPIPERAZIN-l-YL)PYRROLO[ 1, 2-a ] THIENO[ 2 , 3-e ]PYRAZINE FUMARATE
Following the procedure of Example 2 but replacing the compound of Example 1 with the compound of Example 3, 5-(4-10 methylpiperazin-l-yl )pyrrolo[l,2-a]thieno[2,3-e] -pyrazine fumarate is obtained.
Yield : 93%
Melting point : 190°C Spectral characteristics :
Infrared : v C-H : 3100 cm-l v =N- : 2700, 2300 cm-l v C=0 : 1680 cm-l v (principal) : 1600, 1450, 1350, 1270, 1180, 1150, 1070, 980, 930, 860, 760, 720, 680 and 640 cm-l
EXAMPLES 5 AND 6 :
Following the procedures of Examples 1 and 2 but replacing 1-methylpiperazine in Step C of Example 1 with piperazine, the compounds of the following Examples are obtained in succession:
EXAMPLE 5 :
5- (PIPERAZ IN-l-YL ) PYRROLO [ 1,2-a] THIENO [ 3,2-e ] PYRAZINE Yield : 92%
Melting point : 100°C Spectral characteristics :
Infrared : v N-H : 3200 cm-l 30 v C-H : 2920 and 2820 cm-l
21
v (principal) : 1570, 1520, 1485, 1420, 1270, 1130, 950, 890, 870, 810, 740 and 700 cm-l
EXAMPLE 6 :
- (PIPERAZIN-l-YL) PYRROLO[ 1,2-a ]THIENO[ 3, 2-e ]PYRAZINE FUMARATE Yield : 96%
Melting point : 220°C Spectral characteristics :
Infrared : v NH+-, C-H : 3100-2400 cm-l v C=0 : 1700 cm-l v (principal) : 1570, 1490, 1420, 1380, 1280, 1185, 1135, 1050, 1000, 955, 795, 740, 700 and 640 cm-l
EXAMPLES 7 AND 8 :
Following the procedures of Examples 1 and 2 but replacing 1-methylpiperazine in Step C of Example 1 with 1-benzylpiperazine, the compounds of the following Examples are obtained in succession :
EXAMPLE 7 :
- (4-BENZ YLPIPERAZIN-1-YL ) PYRROLO [ 1, 2-a ] THIENO [ 3,2-e ] PYRAZ INE
Yield : 77%
Melting point : 84°C
Spectral characteristics :
Infrared : v C-H : 3100, 3030, 2940 and 2820 cm-l v (principal) : 1480, 1460, 1410, 1370, 1260, 1150, 1010, 950, 820, 800, 740 and 700 cm-l
EXAMPLE 8 :
-(4-BENZYLPIPERAZIN-1-YL)PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE
FUMARATE
Yield : 95%
Melting point : 192°C
Spectral characteristics :
Infrared : v C-H : 3120, 3000, 2920 and 2880 cm-l
22
v =N+- : 2680-2400 cm-l v C=0 : 1700 cm-l v (principal) : 1640, 1570, 1490, 1390, 1270, 1200, 1110, 990, 950, 750, 710 and 650 cm-l
EXAMPLES 9 AND 10 :
Following the procedures of Examples 1 and 2 but replacing 1-methylpiperazine in Step C with 1-[(pyrrolidin-l-yl) carbonylmethyl]piperazine, the compounds of the following Examples are obtained in succession :
EXAMPLE 9 :
- [ 4- (PYRR0LIDIN-1-YLCARB0NYLMETHYL)PIPERAZIN-l-YL ]PYRROLO [1,2-a]THIENO[3,2-e]PYRAZINE
Yield : 69%
Melting point : 70°C
EXAMPLE 10 :
- [ 4- (PYRROLIDIN-1-YLCARBONYLMETHYL) PIPERAZ IN-l-YL ] PYRROLO [1,2-
a]THIENO[3,2-e]PYRAZINE FUMARATE
Yield : 91%
Melting point : 194°C
EXAMPLES 11 AND 12 :
Following the procedures of Examples 1 and 2 but replacing 1-methylpiperazine in Step C of Example 1 with 1—(4 — chlorobenzhydryl)piperazine, the compounds of the following Examples are obtained in succession ;
EXAMPLE 11 :
—{4—[1—(4-CHLOROPHENYL)-l-(PHENYL)METHYL]PIPERAZIN-l-YL }
PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE
Yield : 65%
Melting point : 140°C
Spectral characteristics :
Infrared : v C-H : 3100, 2980, 2840 and 2800 cm-l v (principal) : 1480, 1410, 1370, 1250, 1160, 1140, 1090, 1000, 950, 870, 760, 740, 720 and 700 cm-l
EXAMPLE 12 :
—{ 4— [ 1— (4-CHLOROPHENYL ) -1- (PHENYL) METHYL ] PIPERAZ IN-l-YL} PYRROLO
[1, 2-a] THIENO [3,2-e] PYRAZ INE FUMARATE
Yield : 91%
Melting point : 176°C
EXAMPLE 13 :
- (1, 2 , 5,6-TETRAHYDROPYRIDIN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 3 , 2-e ] PYRAZINE
Following the procedure of Example 1 but replacing 1-methylpiperazine in Step C of Example 1 with 1,2,5,6-15 tetrahydropyridine, 5- (1,2,5,6-tetrahydropyr idin-l-yl) pyr rolo [1,2-a]thieno[3,2-e]pyrazine is obtained.
Yield : 90%
Melting point : 82°C Spectral characteristics :
Infrared : v C-H : 3000, 2900 and 2800 cm-l v (principal) : 1470, 1410, 1370, 1350, 1250, 1135, 1080, 1030, 1010, 940, 790, 700, 640 and 620 cm-l
EXAMPLE 14 :
-(1,2,5,6-TETRAHYDROPYRIDIN-l-YL)PYRROLO[1,2-a]THIENO[3 , 2-e ] 25 PYRAZINE HYDROCHLORIDE
The compound of Example 13 is dissolved in a minimum amount of hot isopropanol, then several drops of concentrated hydrochloric acid are added. The precipitate observed after several minutes is suction filtered, dried and recrystallised from isopropanol, 30 yielding 5-(1,2,5,6-tetrahydropyridin-l-yl)pyrrolo[1,2-a]thieno-[3,2-e]pyrazine hydrochloride.
24
Yield : 94%
Melting point : 218°C " Spectral characteristics :
Infrared : v C-H : 3020 and 2880 cm-l 5 v =N+- : 2800-2600 cm-l v (principal) : 1580, 1500, 1425, 1380, 1350, 1260, 1090, 1030, 955, 930, 880, 830, 700 and 620 cm-l
EXAMPLES 15 TO 37 :
Following the procedure of Example 1 but replacing 1-
methylpiperazine in Step C of Example 1 with the appropriate amines and then, where applicable, subsequently preparing the salt of the resulting compounds with a pharmaceutically acceptable acid, the compounds of the following Examples are obtained :
EXAMPLE 15 :
-(1,4-THIOMORPHOLIN-4-YL)PYRROLO[1,2-a]THIENO [ 3,2-e]PYRAZINE
Yield : 89%
Melting point : 116°C
EXAMPLE 16 :
5-(1,4-THIOMORPHOLIN-4-YL)PYRROLO[1,2-a]THIENO[3 f 2-e]PYRAZINE HYDROCHLORIDE Yield : 93%
Melting point : 238°C
EXAMPLE 17 :
5_( 4-PHENYLPIPERIDIN-l-YL)PYRROLO[ 1, 2-a ]THIENO[ 3, 2-e ] PYRAZINE Yield : 86%
Melting point : 108°C
EXAMPLE 18
-(4-PHENYLPIPERIDIN-l-YL)PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE HYDROCHLORIDE * Yield : 95%
Melting point : 250°C
EXAMPLE 19 :
- (4-PHENYLPIPERAZ IN-l-YL ) PYRROLO [ 1 f 2-a ] THIENO [ 3,2-e ] PYRAZINE
Yield : 83%
Melting point : 140°C
EXAMPLE 20 :
5-(4—PHENYLPIPERAZ IN-l-YL)PYRROLO[1,2-a]THIENO[3,2-e]PYRAZINE DIHYDROCHLORIDE Yield : 96%
Melting point : 248°C
EXAMPLE 21 :
5-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-l-YL]PYRROLO[1,2-a ] THIENO[3,2-e]PYRAZINE Yield : 87%
Melting point : 128°C
EXAMPLE 22 :
5-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-l-YL]PYRROLO[1,2-a ] THIENO[3,2-e]PYRAZINE HYDROCHLORIDE Yield : 92%
Melting point : 208°C
EXAMPLE 23 :
5- [ 4- (ETHOXYCARBONYL) PIPERAZIN-1-YL ] PYRROLO[ 1,2-a ] THIENO[ 3 , 2-e ] PYRAZINE Yield : 85%
Melting point : 104°C
EXAMPLE 24 :
26
- [ 4- (ETHOXYCARBONYL) PIPERAZ IN-l-YL ] PYRROLO [1,2-a] THIENO-
[3,2-e]PYRAZINE HYDROCHLORIDE
Yield : 93%
Melting point : 194°C
EXAMPLE 25 :
- [ 4- (PYRID-2-YL ) PIPERAZIN-1-YL ] PYRROLO[ 1, 2-a ] THIENO [3,2-e] PYRAZINE Yield : 68%
Melting point : 118°C 10 Spectral characteristics :
Infrared : v C-H : 2800 cm-l v (principal) : 1590, 1460, 1480, 1430, 1310, 1250, 1140, 1040, 1000, 950, 770, 730, 700 and 640 cm-l
EXAMPLE 26 :
5- [ 4- (2 , 4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [1,2-a] THIENO [3,2-e] PYRAZINE Yield : 82%
Melting point : 76°C
EXAMPLE 27 :
5- [ 4- ( 2 , 4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] -THIENO-[2,3-e]PYRAZINE HYDROCHLORIDE Yield : 92%
Melting point : 198°C
EXAMPLE 28:
5- [ 4- ( 3 , 4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] THIENO [3,2-e]PYRAZINE Yield : 76%
Melting point : oil
EXAMPLE 29 :
5-[ 4— (3 r 4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [ 1,2-a ] THIENO [2,3-e] PYRAZ INE FUMARATE
Yield : 84%
Melting point : 188°C
EXAMPLE 30 :
-[4-(4-CHLOROPHENYL)PIPERAZIN-l-YL]PYRROLO[1,2-a]THIENO[3 f 2-e] 5 PYRAZINE
Yield : 82%
Melting point : 128°C
EXAMPLE 31 :
- [ 4- ( 4-CHLOROPHENYL) PIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] THIENO [ 3 , 2-e ] 10 PYRAZINE DIHYDROCHLORIDE Yield : 92%
Melting point : 170°C
EXAMPLE 32 :
- [ 4- (4-FLDOROPHENYL) PIPERAZIN-1-YL ] PYRROLO [ 1,2-a ] THIENO[ 3 r 2-e ] 15 PYRAZINE
Yield : 68%
Melting point : 114°C
EXAMPLE 33 :
-[4-(4-FLDOROPHENYL)PIPERAZIN-l-YL]PYRROLO[1,2-a]THIENO[3,2- e ] 20 PYRAZINE DIHYDROCHLORIDE Yield : 93%
Melting point : 174°C
EXAMPLE 34 :
- (4-PROPYLPIPERAZ IN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 3 f 2-e ] PYRAZ INE
Yield : 67%
Melting point : oil
EXAMPLE 35 :
-(4-PROPYLPIPERAZIN-l-YL)PYRROLO[1f 2-a]THIENO[3,2-e]PYRAZINE DIHYDROCHLORIDE 30 Yield : 88%
Melting point : > 260°C ' EXAMPLE 36 :
- {4-ALLYLPIPERAZIN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 3,2-e ] PYRAZINE Yield : 78%
Melting point : oil
EXAMPLE 37 :
- ( 4-ALLYLPIPERAZIN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 3, 2-e ] PYRAZ INE DIHYDROCHLORIDE Yield : 94%
Melting point : 254°C
EXAMPLES 38 TO 41 :
Following the procedure of Example 1 but replacing 2-(pyrrol-l-yl)-3-thenoyl azide in Step A with 3-(pyrrol-l-yl)-2-thenoyl azide and replacing 1-methylpiperazine in Step C with the 15 appropriate amines, the compounds of the following Examples are obtained :
EXAMPLE 38 :
- (4-BENZ YLPIPERAZIN-1-YL) PYRROLO[ 1, 2-a ]THIENO[ 2,3-e ] PYRAZINE Melting point (trihydrochloride) : 163°C
EXAMPLE 39 :
-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-l-YL]PYRROLO[1,2-a ] THIENO[2,3-e]PYRAZINE
Melting point (monohydrochloride) : 195°C
EXAMPLE 40 :
5-[ 4- ( 3,4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [ 1,2-a ] THIENO [2,3-e]PYRAZINE
Melting point (trihydrochloride) : 177°C Spectral characteristics :
p mxi **1
29
Infrared : v (principal) : 3400, 3080, 1590, 1420, 1310, 940 and 700 cm-l
EXAMPLE 41 :
-{4-[4,4-bis( 4-CHLOROPHENYL) BUTYL ] PI PERAZ I N-l-YL} PYRROLO [ 1, 2-a ] 5 THIENO[2,3-e]PYRAZINE
Melting point (trihydrochloride) : 140°C Spectral characteristics :
Infrared : v (principal) : 1590, 1495, 1210, 1150 and 825 cm-l EXAMPLE 42 :
5- (4-ALLYLPIPERAZIN-l-YL) PYRROLO [ 1,2-a ] THIENO [ 2 ,3-e ] PYRAZ INE Melting point (dihydrochloride) : 220°C
EXAMPLE 43 :
- [ 4- (2,4-DICHLOROBENZ YL) PIPERAZ IN-l-YL ] PYRROLO [ 1,2-a ] THIENO [2,3-e]PYRAZINE
Melting point (dihydrochloride)': 155°C EXAMPLE 44 : (second process)
-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-1-YL]PYRROLO[1, 2-a ] THIENO[2,3-e]PYRAZINE
STEP A : N-[3-(pyrrol-l-y1)thien-2-yl]-[ 4-(3-1rif1uoro-20 methylphenyl)piperazin-l-yl]carboxamide
3 g (0.0137 mol) of 3-(pyrrol-l-yl)-2-thenoyl azide (obtained in Preparation 1) and 3.15 g (0.0137 mol) of l-(3-trifluoromethylphenyl)piperazine are refluxed for 2 hours in 70 cm3 of benzene. After cooling, the benzene solution is 25 concentrated under reduced pressure. The residual oil crystallises by the addition of diethyl ether (pink powder).
Yield : 90%
Melting point ; 98°C Spectral characteristics : '
Infrared : v NH : 3260 cm-l
BO
v CO : 1640 cm-1
STEP B : 5-[4-(3-trifluoromethylphenyl)piperazin-l-yl]pyrrolo[1,2-a]thieno[2,3-e]pyrazine
The residual oil obtained in the preceding step is stirred in 30 5 cm3 of phosphorus oxychloride and then refluxed for 2 hours. The solution is concentrated in vacuo and the residue is diluted in 150 cm3 of a sodium hydrogen carbonate solution and then extracted with 150 cm3 of ethyl acetate. The organic phase is washed with water, separated off, dried and then concentrated 10 under reduced pressure, yielding 5-[ 4-(3-trifluoromethyl-pheny1)piperazin-l-y1]pyrrolo[1,2-a]thieno[2,3-e]pyrazine.
The salt of 5—[4—(3-trifluoromethylphenyl)piperazin-l-yl]pyrrolo [l,2-a]thieno[2,3-e]pyrazine with hydrochloric acid is obtained by dissolving the title compound in 30 cm3 of isopropanol and 15 then acidifying with 1 cm3 of l'ON concentrated hydrochloric acid. After 10 minutes' stirring, the precipitate is suction filtered, washed with diethyl ether, dried and recrystallised from acetonitrile.
Melting point (dihydrochloride) : 195°C 20 Spectral characteristics :
Infrared : v = NH+ - : 2720, 2420 cm-1 v C=C, C=N : 1595 cm-l
EXAMPLES 45 TO 69 :
Following the procedure of Example 44 but replacing 3-(pyrrol-l-25 yl)-2-thenoyl azide in Step A with the suitably substituted thenoyl azide and using, in Step A, the appropriate amine, the compounds of the following Examples are obtained :
EXAMPLE 45 : (second process)
-(4-BENZYLPIPERAZIN—1-YL)PYRROLO(1,2-a]THIENO[2,3-e]PYRAZINE
9 A 7 7 0 c i i
31
STEP A : N-[3-(pyrrol-l-yl)thien-2-yl]-(4-benzyl-piperazin-1-
yl)carboxamide Melting point : 158°C
STEP B : 5-[4-benzylpiperazin-l-yl)pyrrolo[1,2-a]thieno[2,3-e ] 5 pyrazine
Melting point : (trihydrochloride) : 163°C
EXAMPLE 46 : (second process)
2-PHENYL-5- [ 4- (3-TRIFLUOROMETHYLPHENYL) PIPERAZ IN-l-YL) PYRROLO [ 1, 2-a ] THIENO [2,3-e J PYRAZ INE
STEP A : N-[5-pheny1-3 - (pyrrol-1-y1)thien-2-y1]-[4-( 3 -tr if luorome thy lphenyl) piper azin-l-yl) carboxamide Melting point : 129°C
STEP B : 2-phenyl-5-[4-(3-trifluoromethylphenyl)piperazin-l-yl]pyrrolo[1,2-a] thieno[2,3-e]pyrazine 15 Melting point (monohydrochloride) : 160°C
EXAMPLE 47 :
2-PHENYL-5- ( 4-BENZYLPIPERAZIN-l-YL) PYRROLO [ 1, 2-a ] THIENO [2,3-e]PYRAZINE
STEP A : N-[5-phenyl-3-(pyrrol-l-yl)thien-2-yl]-[4-20 benzylpiperazin-l-yl]
Melting point : 160°C
STEP B : 2-phenyl-5-(4-benzylpiperazin-l-yl)pyrrolo[1,2-a]thieno
[2,3-e]pyrazine Melting point (trihydrochloride) : 182°C
EXAMPLE 48 :
2-(4-FLUOROPHENYL)-5-[4- (3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-l-YL ] PYRROLO [ 1, 2-a ] THIENO [ 2,3-e ] PYRAZ INE
STEP A : N-[5-(4-fluorophenyl)-3-(pyrrol-l-yl)thien-2-yl]-[4-( 3-
trifluoromethylphenyl)piperazin-l-yl]carboxamide Melting point : 134°C
STEP B : 2-(4-fluorophenyl)-5-[4-(3-trifluoromethylpheny1) 5 piperazin-l-yl]pyrrolo[1,2-a]thieno[2,3-e]pyrazine
Melting point (dihydrochloride) : 212°C
EXAMPLE 49 :
1-PHENYL-5-[ 4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-1-YL ] PYRROLO [ 1, 2-a ] THIENO [ 2,3-e] PYRAZ INE
STEP A : N-[4-phenyl-3-(pyrrol-l-yl)thien-2-yl]-[4-(3-trifluoromethylphenyl)piperazin-l-yl]carboxamide Melting point : 192°C
STEP B : l-phenyl-5-[ 4-( 3-trif luoromethylphenyl) piperaz in-1-
yl]pyrrolo[lf2-a]thieno[2,3-e]pyrazine Melting point (monohydrochloride) : 130°C
EXAMPLE 50 :
l-PHENYL-5-[ 4-BENZYLPIPERAZIN-l-YL ] PYRROLO [ 1, 2-a ]THIENO [2,3-e]PYRAZINE
STEP A : N-[4-phenyl-3-(pyrrol-l-yl)thien-2-yl]-[4-
benzylpiperazin-l-yl]carboxamide Melting point : 175°C
STEP B : 1-pheny1-5-[4-benzylpiperazin-l-yl]pyrrolo[1,2-a]
thieno[2,3-e]pyrazine Melting point (trihydrochloride) : 210°C
EXAMPLE 51 :
1- (4-METHOXYPHENYL ) -5- [ 4- ( 3-TRIFLUOROMETHYLPHENYL) PIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] THIENO [ 2,3-e ] PYRAZ INE
STEP A : N-[4-(4-methoxyphenyl)-3-(pyrrol-l-yl)thien-2-yl]-[4-
(3-trifluoromethylphenyl)piperazin-l-yl]carboxamide Melting point : 166°C
STEP B : 1-(4-methoxypheny1)-5-[4-(3-1rifluoromethyIphenyl 5 piperazin-l-yl]pyrrolo[1,2-a]thieno[2,3-e]pyrazine
Melting point (monohydrochloride) : 162°C
EXAMPLE 52 :
2-PHENYL-5-[ 4- { 3-TRIFLUOROMETHYLPHENYL) PIPERAZ IN-l-YL] PYRROLO[ 1, 2-a ] THIENO[ 3,2-e ] PYRAZINE
STEP A : N-[5-phenyl-2-(pyrrol-l-yl)thien-3-yl]-[4-(3-trifluoromethylpheny1)piperazin-l-yl]carboxamide Melting point : 160°C
STEP B : 2-phenyl-5-[4-(3-trifluoromethylphenyl)piperazin-l-yl] pyrrolo[1,2-a]thieno[3,2-e]pyrazine 15 Melting point (dihydrochloride) : 135°C
EXAMPLE 53 :
2-PHENYL- 5- (4-METHYLPIPERAZ IN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 3 ,2-e ] PYRAZINE
STEP A : N-[5-phenyl-2-(pyrrol-l-yl)thien-3-yl]-[4-20 methylpiperazin-l-yl]carboxamide
Brown oil
STEP B : 2-phenyl-5-(4-methylpiperazin-l-yl)pyrrolo[l,2-a]thieno
[3,2-e]pyrazine Melting point (dihydrochloride) : > 260°C
EXAMPLE 54 :
2-PHENYL-5-(4-BENZYLPIPERAZIN-l-YL)PYRROLO[ 1, 2-a ] THIENO[ 3, 2-e ] PYRAZINE
STEP A : N-[5-phenyl-2-(pyrrol-l-yl)thien-3-yl]-[4-benzylpiperazin-l-yl]carboxamide
Brown oil
STEP B : 2-phenyl-5-(4-benzylpiperazin-l-yl)pyrrolo[1,2-a]
thieno[3,2-e]pyrazine Melting point (dihydrochloride) : 186°C
EXAMPLE 55 :
2-PHENYL-5 —[4-(ETHOXYCARBONYL)PIPERAZIN-1-YL]PYRROLO[1,2-a ] THIENOt 3,2-e]PYRAZINE
STEP A : N-[5-phenyl-2-(pyrrol-l-yl)thien-3-yl]-[4-(ethoxycarbonyl)piperazin-l-yl]carboxamide
Brown oil
STEP B : 2-phenyl-5-[4-(ethoxycarbonyl)piperazin-l-yl]pyrrolo-
[1,2-a]thieno[3,2-e]pyrazine Melting point : 136°C
EXAMPLE 56 :
2 -PHENYL- 5- (PIPERAZ IN-l-YL) PYRROLO [ 1,2-a ] THIENO [ 3,2-e ] PYRAZ INE
STEP A : 2-phenyl-5-(piperazin-l-yl)pyrrolo[1,2-a]thieno[3,2-e] pyrazine
Melting point (trihydrochloride) : 206°C EXAMPLE 57 :
2, 3-DIMETHYL-5- ( 4-BENZYLPIPERAZ IN-l-YL) PYRROLO [ 1 f 2-a ] THIENO [ 3, 2-e]PYRAZINE
STEP A : N-[4,5-dime thy1-2-(pyrrol-l-y1)thien-3-y1]-(4 -
benzy lpiperazin-l-yl)carboxamide Melting point : 168°C
STEP B : 2,3-dimethyl-5-(4-benzylpiperazin-l-yl)pyrrolo[1, 2-a ]
thieno[3,2-e]pyrazine Melting point (trihydrochloride) : 164°C
EXAMPLE 58 :
2-PHENYL-5- (4-METHYLPIPERAZIN-l-YL)PYRROLO [ 1, 2-a]THIENO[ 2 , 3-e ] PYRAZINE
Melting point (trihydrochloride) : 196°C EXAMPLE 59 :
- (4-PHENYLPIPERIDIN-l-YL) PYRROLO [ 1, 2-a ] THIENO [ 2 , 3-e ] PYRAZ INE 10 Melting point (hydrochloride) : 185°C
EXAMPLE 60 :
—[ 4-(3,4-DICHLOROPHENYL) PIPERAZ IN-l-YL ] PYRROLO [ 1,2-a ] THIENO [3,2-e]PYRAZINE
EXAMPLE 61 :
5- [ 4- (4-METHOXYPHENYL) PIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] THI ENO [3,2-e]PYRAZINE
EXAMPLE 62 :
-(2 , 6—DIMETHYLMORPHOLIN—4-YL)PYRROLO[ 1, 2-a]THIENO[ 3 , 2-e ]PYRAZINE EXAMPLE 63 :
5-{[2-(BENZYLAMINO)ETHYL]AMINE}PYRROLO[1,2-a]THIENO[3, 2-e] PYRAZINE
EXAMPLE 64 :
2-PHENYL-5-[ 2, 5-DIMETHYLPIPERAZ IN-l-YL ] PYRROLO [ 1, 2-a ] THI ENO [ 3 , 2-e]PYRAZINE
EXAMPLE 65 :
2-PHENYL-5- [ 4- (4-NITROPHENYL) PIPERAZ IN-l-YL ] PYRROLO[ 1, 2-a ] THIENO-[3f2-e]PYRAZINE
3,3,5-TRIMETHYLPERHYDROAZEPIN-l-YL)PYRROLO[ 1,2-a ]THIENO[ 3, 2-e ] PYRAZINE
EXAMPLE 67 :
^ 5-(HOMOPIPERAZIN-l-YL)PYRROLO[ 1, 2-a]THIENO[ 3,2-e]PYRAZINE EXAMPLE 68 :
-[4-(4-CHLOROPHENYL)-4-HYDROXYPIPERIDIN-l-YL]PYRROLO[1,2-a] THIENO[3,2-e]PYRAZINE
EXAMPLE 69 :
2-PHENYL-5- [ 4- ( 4-FLOOROPHENYL) -4-HYDROXYPIPERIDIN-l-YL ] PYRROLO [1,2-a]THIENO[3,2-e]PYRAZINE
EXAMPLE 70 :
-OXO— 1 -PHENYL—4 , 5-DIHYDRO-PYRROLO[ 1,2-a ]THIENO[ 2,3-e ]PYRAZINE
1 g (0.0034 mol) of 4-phenyl-3-{pyrrol-l-yl)-2-thenoyl azide is 15 added in small fractions to 30 cm3 of ortho-dichlorobenzene heated to 180°C. After 5 minutes at that temperature, the solution is cooled. The resulting precipitate is suction filtered, washed with diethyl ether and dried.
Yield ; 77%
2q Melting point : 250°C
Spectral characteristics :
Infrared : v NH : 3120, 2900 cm-l v CO : 1625 cm-l
EXAMPLE 71 :
5-OXO- 2-PHENYL-4 , 5-DIHYDRO-PYRROLO [ 1, 2-a ] THIENO [ 2 , 3-e ] PYRAZINE
Following the procedure of Example 70 but replacing 4-phenyl-3-(pyrrol-l-yl)-2-thenoyl azide with 5-phenyl-3-(pyrrol-l-yl )-2-thenoyl azide, 5-oxo-2-phenyl-4,5-dihydro-pyrrolo(l,2-a]thieno-[2,3-e]pyrazine is obtained.
37
Melting point : 291°C Spectral characteristics :
Infrared : v (NH) : 3120, 2800 cm-l v CO : 1650 cm-l
EXAMPLE 72 :
-OXO-2-PHENYL-4 r 5-DIHYDRO-PYRROLO [ 1,2-a ] THIENO [3,2-e] PYRAZINE
Following the procedure of Example 70 but replacing 4-phenyl-3-(pyr rol-l-yl)-2-thenoyl azide with 5-phenyl-2-(pyrrol-l-yl)-3-thenoyl azide, 5-oxo-2-phenyl-4,5-dihydro-pyrrolo[1, 2-a] thieno-10 [3,2-e]pyrazine is obtained.
Yield : 78%
Melting point : 255°C Spectral characteristics :
Infrared : v NH : 3100, 2800 cm-l 15 v CO : 1640 cm-l
EXAMPLES 73 TO 78 :
Following the procedure of Example 1 or 3 but replacing 1-methylpiperazine in Step C with the appropriate amines, the compounds of the following Examples are obtained :
EXAMPLE 73 :
- [ 4- (4-FLDOROBENZYL) PIPERAZ IN-l-YL ]-4H-PYRROLO [ 1,2-a ] THIENO [2,3-e]PYRAZINE
Melting point (dihydrochloride) : 170°C EXAMPLE 74 :
5-[ 4-(4-FLDOROBENZYL) PIPERAZ IN-l-YL ]-4H-PYRROLO[ 1,2-a ] THIENO [ 3 , 2-e]PYRAZINE
Melting point (dihydrochloride) : 180°C EXAMPLE 75 :
38
- [ 2- (N,N-DIMETHYLAMINO) ETHYLAMINO ] -4H-PYRROLO [ 1,2-a ] THIENO [2,3-ejPYRAZINE
Melting point (dihydrochloride) : 215°C EXAMPLE 76 :
5- [ 4- (3-PHENYLPROP-2—EN-l-YL) PIPERAZ IN-l-YL ] -4H-PYRROLO [ 1,2-a ] THIENO[ 3,2-e]PYRAZINE Melting point (dihydrochloride) : 208°C
EXAMPLE 77 :
—{4 — £ 2-(2-TRIFLUOROMETHYLPHENYL)ETHYL]PIPERAZIN-1-YL}-4H-10 PYRROLO [ 1,2 -a ] THIENO [ 3, 2-e ] PYRAZ INE
Melting point (dihydrochloride) : 130°C
EXAMPLE 78 :
-{4-{2-[ (METHYLAMINO) SULPHONYL] ETHYL} PIPERAZ IN-l-YL}-4H-PYRROLO [ 1,2-a ] THIENO [ 3 , 2-e ] PYRAZ INE
EXAMPLE 79 :
3-[4-(4H-PYRROLO[1,2-a] THIENO[3,2-e]PYRAZIN-5-YL)PIPERAZIN-l-YL] PROPIONIC ACID
EXAMPLE 80 :
2-BENZYLOXY-5-(4-BENZYLPIPERAZIN-l-YL)-4H-PYRROLO[1,2-a] 20 THIENO[3,2-e]PYRAZINE
PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION EXAMPLE A :
RECEPTOR BINDING STUDY OF COMPOUNDS OF THE INVENTION A-l : Study of binding to 5-HT3 serotoninergic receptors
The binding of compounds of the invention to 5-HT3 receptors was determined for each compound by measuring the displacement of 3H
zacopride (specific ligand of 5-HT3 receptors) in rat area postrema homogenates.
PROTOCOL :
Aliquots (50-100 ill) of a membrane suspension (2.5-5.0 mg of 5 protein/cm3) are incubated for 30 minutes at 25°C in a tris-HCl buffer, 25 mM, pH 7.4, in the presence of 0.3-0.4 nM of 3h zacopride (83 Ci/mmol) (total volume : 0.5 cm3). Incubation is stopped by filtering the samples through Whatman GF/B filters, which are then washed and dried. Finally, the radioactivity 10 retained on the filters is counted by spectrometry in a liquid medium (Aquasol). Non-specific binding is assessed under the same conditions using samples containing in addition 1 yM of ondansetron (5-HT3 antagonist).
The displacement curves obtained by adding increasing 15 concentrations of a test compound to the incubation medium are analysed in order to determine the affinity of the test compounds for 5-HT3 receptors.
A-2 : Study of the binding of compounds of the invention to 5-HTia, 5-HTib, 5-HTic, 5-HTid and 5-HT2 serotoninergic 20 receptors
The binding of compounds of the invention (tested on each receptor at 6 different concentrations: from 10-4 m to 10-9 m) is measured :
- for 5-HTia receptors, by the displacement of 8-OH-DPAT in rat 25 hippocampus homogenates,
- for 5-HTib receptors, by the displacement of 5-hydroxy-tryptamine in rat cortex, striatum and globus pallidus homogenates,
- for 5-HTic receptors, by the displacement of N-methyl-30 mesulergine in rat frontal cortex and hippocampus homogenates,
- for 5-HTid receptors, by the displacement of 5-OH-tryptamine in rat cortex, striatum and globus pallidus homogenates,
- for 5-HT2 receptors, by the displacement of aminoiodo ketaneserine in rat frontal cortex homogenates.
CONCLUSION :
It appears that the compounds of the invention have a very strong affinity for 5-HT3 receptors. The compounds of the invention prove also to have a high selectivity for 5-HT3 receptors, as compared with the other serotoninergic receptors.
EXAMPLE B :
MEASUREMENT OF THE ACCUMULATION OF "C-GUANIDINE IN NG 108-15 CELLS
The accumulation of HC-guanidine in NG 108-15 cells is measured and makes it possible to study' the interaction of the compounds 15 tested with 5-HT3 receptors, knowing that that accumulation is stimulated by the agonists of the 5-HT3 receptors.
The hybrid clone (neuroblastoma-glioma) NG 108-15 is cultured under standard conditions (Dulbecco medium to which 40 mM sodium bicarbonate, 1.8 mM L-glutamine, 0.1 mM hypoxanthine, 1 yM 20 aminopterine, 16 jiM thymine and 10% of foetal calf serum are added) at 37°C in an atmosphere enriched with CO2 (7%). At confluence (— 3.5 x 105 cells in boxes 35 mm in diameter), the culture medium is aspirated and the carpet of cells is washed rapidly with 3 cm3 of a HEPES buffer (20 mM) containing 145 mM 25 NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2 and 20 mM glucose, pH 7.4. After removal of the washing solution, there are gradually poured into each culture box 1.5 cm3 of the same buffer (except that the concentration of NaCl is reduced to 135 mM), to which 10 mM guanidinium chloride plus 100-250 nCi of nc-guanidi-30 ne, 10 yM substance P, and an agonist of 5-HT3 receptors have been added, in the presence or in the absence of the test
41
compound. Incubation is for a period of 10 minutes at 37°C. The medium is then aspirated, and the cells are washed rapidly twice with 3 cm3 of the washing buffer in which the NaCl has been completely replaced by an equimolar concentration of choline 5 chloride. Finally, the carpet of cells is taken up in 0.5 cm3 of 0.4N sodium hydroxide solution, and the accumulated radioactivity is counted by spectrometry in a liquid medium (Aquasol).
Under those experimental conditions, agonists of 5-HT3 receptors (10 11M - 0.1 pM), such as serotonin, 2-methyl-5-tryptamine and 10 phenyl biguanide, increase fivefold the intracellular accumulation of ^C-guanidine, and that effect can be completely eliminated by 10-100 nM of a selective 5-HT3 antagonist (ondansetron, zacopride).
By means of this test it is possible to show that certain 15 compounds of the invention are powerful antagonists of 5-HT3 receptors.
EXAMPLE C :
BEZOLD-JARISCH BRADYCARDIAC REFLEX
Bradycardia (BEZOLD-JARISCH reflex) is induced by intravenous 20 injection of 5-HT3 agonists in rats anaesthetised with urethane. That response consists in sudden but transitory bradycardia induced by stimulation of 5-HT3 receptors on the vagal afference. This model is therefore completely suitable for revealing any agonistic or antagonistic effects of compounds which are 25 potential ligands of 5-HT3 receptors.
PROTOCOL :
The animal (adult-male rat - Sprague-Dawley strain, 250-300 g) is first anaesthetised with urethane (1.4 g/kg i.p.) then tracheotomised for the insertion of a tracheal cannula. A 30 catheter (0.3 mm) is introduced into the abdominal aorta via the femoral artery in order to record continuously the arterial
42
pressure and the cardiac rhythm. The pharmacological agents are injected into the saphenous vein, which has been cannulated for that purpose. The i.v. injection of 30 pg of serotonin, of 2-methyl-5-hydroxytryptamine or of phenyl biguanide brings about a 5 sudden (-80%) and transitory (for approximately 4-5 seconds) fall in the cardiac rhythm, and that effect can be completely prevented by the prior administration (i.v.) of various selective antagonists, such as zacopride or ondansetron (in a dose of 1 pg/kg).
RESULTS :
It appears, in this test, that the compounds of the invention behave like powerful ligands of 5-HT3 receptors and have either an antagonistic or an agonistic action.
EXAMPLE E :
PHARMACEUTICAL COMPOSITION : TABLETS
Tablets containing 5 mg of 5-(4-benzylpiperazin-l-yl)pyrrolo[l, 2-a]thieno[3,2-e]pyrazine
Preparation formula for 1000 tablets :
-(4-benzylpiperazin-l-yl)pyrrolo-[1,2-a]thieno[3,2-e]
pyrazine 5 g wheat starch 2.5 g corn starch 1.5 g lactose 8.5 g magnesium stearate 0.2 g
silica 0.1 g hydroxypropylcellulose 0.2 g
EXAMPLE F :
PHARMACEUTICAL COMPOSITION : TABLETS
Tablets containing 1 mg of 5-(4-benzylpiperazin-l-yl)pyrrolo[l,2-a]thieno[3,2-e]pyrazine
/ "a® nam
/ /
iS <>V ff
43
Preparation formula for 1000 tablets : 5-(4-benzylpiperazin-l-yl)pyrrolo-[1,2-a]thieno[3,2-e]
pyrazine 1 g wheat starch 2.5 g corn starch 1.5 g lactose 8.5 g magnesium stearate 0.2 g silica 0.1 g hydroxypropylcellulose 0.2 g
44
Claims (12)
1. Compounds of formula (I) : (I) in which : - either Ri and R2 together form a double bond and R3 represents a chlorine atom or a group of the formula : -N \ R4 R5 in which R4 and R5, with the nitrogen atom carrying them, form a group selected from : 10 - piperazine, - substituted piperazine, - substituted piperidine, - substituted pyrrolidine, - morpholine substituted by one or more alkyl radicals, 15 - tetrahydropyridine, - thiomorpholine, - azaspirane having from 5 to 12 ring members, 45 - azaspirane having from 5 to 12 ring members that is substituted by one or more alkyl radicals or oxo groups, - azacycloalkyl having from 7 to 12 ring members that atoms selected from oxygen, sulphur, and nitrogen, - azacycloalkyl having from 7 to 12 ring members that is substituted by one or more alkyl radicals or oxo groups and hetero atoms selected from oxygen, sulphur, and nitrogen, - a group -NH-(CH2)k~NH2 in which k represents an integer- 2, 3~~" or 4, - and a substituted group -NH-(CH2)k~NH2 in which k represents an integer 2, 3 or 4, - or Ri represents a hydrogen atom and R2 and R3 together form an oxo group, wherein the term "substituted" relating above to the groups piperazine, piperidine, pyrrolidine and -NH-(CH2)k-NH2 indicates that those groups may be substituted by one or more halogen atoms, hydroxy radicals, oxo radicals, radicals Rio or radicals optionally includes 1 or 2 additional hetero that optionally includes 1 or 2 additional -C - Rio II 0 Rio being selected from : fl* - alkyl, |rJ - alkoxy, V* - alkenyl, - -{CH2)n-Rn and -(CH2)n'-C-Rn wherein n represents II 0 0 or an integer from 1 to 5, n1 represents an integer from 1 to 5r and Rn represents a phenyl, benzhydryl, thienyl, pyrrolyl, pyrrolidiriyl, furyl, pyrimidinyl, pyridyl, 247791 benzodioxolyl, benzodioxanyl, naphthyl, quinolinyl, isoquinolinyl, cycloalkyl or dicycloalkylmethyl radical, the' II || term cycloalkyl representing a mono- or bi-cyclic group having from 3 to 12 ring members, it being possible for those radicals Rn themselves_.to be substituted by one or more radicals selected from halogen, trifluoromethyl, amino, nitro, hydroxy, alkyl, and alkoxy, - and -(CH2)n'~Rl2 wherein n' is as defined above and R12 represents a group selected from carboxy, alkoxycarbonyl, amino, dialkylamino, -SO2NR13R14 and -CONRi3Ri4 in which- each1 of R13 and R14 independently of the other represents a hydrogen atom or an alkyl radical, \ and A represents : - either a group of formula (a) : R7 (a) and forms, with the heterocyclic system carrying it, a pyrrolo[l,2-a]thieno[3,2-e]pyrazine of formula (I/a) : r6 R7 XT Y r3 R2 (I/a) r1 / /■: 47 10 15 in which Ri, R2 and R3 are as defined above and each of Rg and R7, which are identical or different, independently of the other represents a group selected from : - hydrogen, - alkyl, - alkyl substituted by one or more halogen atoms or hydroxy radicals, - acyl, - alkoxycarbonyl, - halogen, - nitro, - -(CH2)m-phenyl, -(CH2)m-naphthyl or -(ch2)m-pyridyl wherein m represents 0 or an integer from 1 to 4 and wherein the phenyl nucleus is unsubstituted or substituted by one or more radicals Ra, which are identical or different, Ra representing halogen, alkyl, alkoxy, trifluoromethyl or pyrrolidinyl, - and a group of the formula' : Rb -(CH2)p 20 in which p represents 0 or an integer 1 or 2, Y represents an oxygen atom, a nitrogen atom or a sulphur atom, and Rb represents a hydrogen atom or an alkyl group, or a group of formula (0) : R8 (P) r9 25 and forms, with the heterocyclic system carrying it, a pyrrolo[l,2-a]thieno[2,3-e]pyrazine of formula (1/0) : R8> Rg S 3 N\^ 4 N R3 (I/p) R2 r1 in which Ri, R2 and R3 are as defined above and Rs and Rg have the same meanings as R6 and R7 as defined above, with the proviso that when R3 represents a chlorine atom, or when R3 and R2 together form an oxo group, then Rg and R7, or Rs and Rg, may not at the same time be both hydrogen atoms, their optical isomers, in pure form or in the form of a mixture, when R3, R6, R7, Rs or Rg represents an optically active group, and their addition salts with a pharmaceutically acceptable acid or base, wherein, unless indicated otherwise, - the terms "alkyl", "alkoxy" and "acyl" represent linear or branched groups having from 1 to 6 carbon atoms, - and the term "alkenyl" represents an unsaturated, linear or branched group having from 2 to 6 carbon atoms.
2. Compounds of formula (I) according to claim 1 in which Ri and R2 together form a double bond and R3 represents a group of the formula : -^R4 xr5 wherein R4 and R5 are as defined in claim 1, their optical isomers,and their addition salts with a pharmaceutically acceptable acid or base.
3. Compounds of formula (I) according to claim 1 in which Ri and R2 together form a double bond and R3 represents a group of the formula : Xr5 wherein R4 and R5, with the nitrogen atom carrying them, form a 10 piperazine group or a substituted piperazine group, the term "substituted" being as defined in claim 1,their optical isomers,and their addition salts with a pharmaceutically acceptable acid or base.
4. A compound of formula (I) according to claim 1 which is 5— (4— 15 benzylpiperazin-l-yl)pyrrolo[l,2-a]thieno[3,2-e]pyrazine, and its addition salts with a pharmaceutically acceptable acid.
5. A compound of formula (I) according to claim 1 which is 5-(piperazin-l-yl)pyrrolo[1,2-a]thieno[3,2-ejpyrazine, and its addition salts with a pharmaceutically acceptable acid. 20
6. A compound of formula (I) according to claim 1 which is 5-(4-methylpiperazin-l-yl)pyrrolo[1,2-a]thieno[3,2-e]pyrazine, and its addition salts with a pharmaceutically acceptable acid. 50
7. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that : a compound of formula (II) : '/ V // C-n3 (II) 0 in which A is as defined in formula (I) according to claim 1, is heated, in the presence or in the absence of a solvent, to give a compound of formula (I/a) : (I/a) in which A is as defined above, which is a particular case of the compounds of formula (I) according to claim 1 in which Ri represents a hydrogen atom and R2 and R3 together form an oxo group, which compound of formula (I/a) is subjected to a halogenating agent to give a compound of formula (I/b) : (I/b) 51 in which A is as defined above, which is a particular case of the compounds of formula (I) according to claim 1 in which Ri and R2 together form a double bond and R3 represents a chlorine atom, which is then reacted with an amine of formula (III) : in which R4 and R5 are as defined in formula (I) according to claim l,to give a compound of formula (I/c) : in which A, R4 and R5 are as defined above, which is a particular case of the compounds of formula (I) according to claim 1 in which Ri and R2 form a double bond and R3 represents a group : HN (HI) i (I/c) -N the compounds of formulae (I/a), (I/b) and (I/c) forming the compounds of formula (I) according to claim 1 in their entirety, 247791 it being possible for the compounds of formula (I) according to claim 1 to be : - purified by one or more purification methods selected from crystallisation, chromatography over a silica column, extraction, filtration, and passage over activated _.c_arbon and/or resin, - separated, where applicable, in pure form or in the form of a mixture, into their optical isomers, - or converted into a salt with a pharmaceutically acceptable acid or base. ■ "
8. Process for the preparation of compounds of formula (I/c), which are a particular case of the compounds of formula (I) according to claim 1 in which Ri and R2 together form a double bond and R3 represents a group : characterised in that : a compound of formula (II) -N R4 r5 c-n3 (ii) in which A is as defined in formula (I) according to claim 1, is reacted with an amine of formula (III) : Muni sr.n* i 4/791 53 R4 \ (HI) R5 in which R4 and R5 are as defined in formula (I) according to claim l,to give a compound of formula (V) : NH-C-N \ R5 (V) in which A, R4 and R5 are as defined above, which is then cyclised under the action of a halogenating agent and subjected to alkaline treatment to give a compound of formula (I/c) : /R4 N N ^ r5 (I/c) 10 in which A, R4 and R5 are as defined above, which is a particular case of the compounds of formula (I) according to claim 1 in which Ri and R2 together form a double bond and R3 represents a group : 54 it being possible for the compounds of formula (I/c) to be~:^~" - purified by one or more purification methods selected from crystallisation, chromatography over a silica column, extraction, filtration, and passage over activated carbon or resin, - separated, where applicable, in pure form or in the form of a mixture, into their optical isomers, - or converted into a salt with a pharmaceutically acceptable acid or base.
9. Pharmaceutical composition containing as active ingredient at least one of the compounds of formula (I) according to claim 1 or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients or carriers.
10. Pharmaceutical composition according to claim 9 that can be used in the prevention and the treatment of anxiety, depression, stress, psychoses, schizophrenia, disorders of the central nervous system, migraine, memory disorders, eating disorders, alcoholism, pain, and. in the prevention and the treatment of vomiting and gastric emptying disorders.
11. Compounds of formula (I) as defined in claim 1 substantially as herein described with reference to the examples.
12. A process for the preparation of compounds of formula (I) as defined in claim 1 substantially as herein described with reference to the examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9206800A FR2691967B1 (en) | 1992-06-05 | 1992-06-05 | NOVEL PYRROLOTHIENOPYRAZINIC COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
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| Publication Number | Publication Date |
|---|---|
| NZ247791A true NZ247791A (en) | 1994-12-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ247791A NZ247791A (en) | 1992-06-05 | 1993-06-04 | Pyrrolothienopyrazine derivatives, their preparation and pharmaceutical compositions |
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| Country | Link |
|---|---|
| EP (1) | EP0573360B1 (en) |
| JP (1) | JPH0794460B2 (en) |
| AT (1) | ATE170187T1 (en) |
| AU (1) | AU659738B2 (en) |
| CA (1) | CA2097779A1 (en) |
| DE (1) | DE69320542T2 (en) |
| DK (1) | DK0573360T3 (en) |
| ES (1) | ES2123038T3 (en) |
| FR (1) | FR2691967B1 (en) |
| NZ (1) | NZ247791A (en) |
| ZA (1) | ZA933942B (en) |
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| EP3268003B1 (en) | 2015-03-12 | 2020-07-29 | Merck Sharp & Dohme Corp. | Thienopyrazine inhibitors of irak4 activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4997433A (en) * | 1990-01-16 | 1991-03-05 | Marlowe Goble E | Endosteal fixation stud and system |
| FR2659332B1 (en) * | 1990-03-08 | 1994-04-29 | Adit Et Cie | NOVEL PYRROLO [1,2-A] THIENO [3,2-F] DIAZEPINES [1,4], THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2660310B1 (en) * | 1990-03-27 | 1992-06-05 | Adir | NOVEL 4H-PYRROLO [1,2A] THIENO [2,3-F] DIAZEPINE [1,4] DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
1992
- 1992-06-05 FR FR9206800A patent/FR2691967B1/en not_active Expired - Fee Related
-
1993
- 1993-06-03 DK DK93401416T patent/DK0573360T3/en active
- 1993-06-03 DE DE69320542T patent/DE69320542T2/en not_active Expired - Fee Related
- 1993-06-03 ES ES93401416T patent/ES2123038T3/en not_active Expired - Lifetime
- 1993-06-03 EP EP93401416A patent/EP0573360B1/en not_active Expired - Lifetime
- 1993-06-03 AT AT93401416T patent/ATE170187T1/en not_active IP Right Cessation
- 1993-06-04 NZ NZ247791A patent/NZ247791A/en unknown
- 1993-06-04 ZA ZA933942A patent/ZA933942B/en unknown
- 1993-06-04 AU AU40059/93A patent/AU659738B2/en not_active Ceased
- 1993-06-04 JP JP5134922A patent/JPH0794460B2/en not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| ES2123038T3 (en) | 1999-01-01 |
| DE69320542D1 (en) | 1998-10-01 |
| AU659738B2 (en) | 1995-05-25 |
| FR2691967A1 (en) | 1993-12-10 |
| DE69320542T2 (en) | 1999-04-29 |
| AU4005993A (en) | 1993-12-09 |
| CA2097779A1 (en) | 1993-12-06 |
| JPH06172363A (en) | 1994-06-21 |
| ATE170187T1 (en) | 1998-09-15 |
| ZA933942B (en) | 1993-12-30 |
| EP0573360A1 (en) | 1993-12-08 |
| DK0573360T3 (en) | 1999-05-25 |
| EP0573360B1 (en) | 1998-08-26 |
| JPH0794460B2 (en) | 1995-10-11 |
| FR2691967B1 (en) | 1995-06-09 |
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|---|---|---|---|
| ASS | Change of ownership |
Owner name: LES LABORATOIRES SERVIER, FR Free format text: OLD OWNER(S): ADIR ET COMPAGNIE |