IE921340A1 - Heterocyclic antiserotonin derivatives, their preparation¹and pharmaceutical compositions containing them - Google Patents
Heterocyclic antiserotonin derivatives, their preparation¹and pharmaceutical compositions containing themInfo
- Publication number
- IE921340A1 IE921340A1 IE921340A IE921340A IE921340A1 IE 921340 A1 IE921340 A1 IE 921340A1 IE 921340 A IE921340 A IE 921340A IE 921340 A IE921340 A IE 921340A IE 921340 A1 IE921340 A1 IE 921340A1
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- formula
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- het
- alkyl
- radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of formula: R1-(CH2)n-Het (I> in which -R1 represents a residue of formula: Het represents: . a 4-phenyl-1,2,3,6-tetrahydro-1-pyridyl radical whose phenyl ring is optionally substituted with a halogen atom or an alkyl, alkoxy or hydroxyl radical, . a 4-phenylpiperidino radical whose phenyl ring is optionally substituted with a halogen atom or an alkyl, alkoxy or hydroxyl radical, . a 4-phenyl-1-piperazinyl radical whose phenyl ring is optionally substituted with a halogen atom or an alkyl, alkoxy or hydroxyl radical, - R2 represents a hydrogen atom or an alkyl radical, - n is equal to 1, 2, 3 or 4, their salts, their preparation and the medicaments containing them.
Description
The present invention provides compounds of formula:
R1- (CH2) n-Het in which
- Rj represents a residue of formula:
O
(A) or
Rg-N
(C)
N—
- Het represents a 4-phenyl-l,2,3,6-tetrahydro-l-pyridyl radical whose phenyl ring is unsubstituted or substituted by a halogen atom or an alkyl, alkoxy or hydroxyl radical, a 4-phenylpiperidino radical whose phenyl ring is unsubstituted or substituted by a halogen atom or an alkyl, alkoxy or hydroxyl radical, a 4-phenyl-l-piperazinyl radical whose phenyl ring is unsubstituted or substituted by a halogen atom or an alkyl, alkoxy or hydroxyl radical,
- R2 represents a hydrogen atom or an alkyl radical, and n is 1, 2, 3 or 4, and their salts with organic or inorganic acids. In the above definitions and in those given below, the alkyl and alkoxy radicals contain 1 to 4 carbon atoms each in a straight or branched chain and the halogen atoms are preferably fluorine, chlorine or bromine atoms.
The compounds of formula (I), with the exception of those for which Rj represents a residue of
- 3 formula (C) in which R2 represents a hydrogen atom, may be prepared by the action of a derivative of formula:
R,H (II) in which R, has the same meanings as above, on a halogenated derivative of formula:
Hal-(CH2)0-Het (III) in which Hal represents a halogen atom and Het and n have the same meanings as in the formula (I).
This reaction is generally carried out in the presence of a base such as an alkali metal hydride, an alkali metal hydroxide, an alkali metal bicarbonate or an alkali metal carbonate, in an inert solvent such as dimethylformamide or tetrahydrofuran, at a temperature of between 20°C and the boiling temperature of the solvent.
The compounds of formula (II) are available commercially or may be obtained by applying or adapting the methods described by B.L. HAWBECKER, J. Chem.
Educ., 53 (6), 398 (1976) and in patent US 3164602.
The halogenated derivatives of formula (III) may be obtained by the action of an amine of formula:
Het-H (IV) in which Het has the same meanings as in the formula (I), on a dihalogenated derivative of formula:
Hal-(CH2) n-Hal' (V) in which Hal and Hal' represent a halogen atom, it being possible for the two halogen atoms to be identical or different, and n has the same meanings as in the
- 4 formula (I) .
This reaction is generally carried out in an inert solvent such as dimethylformamide or acetonitrile, in the presence of a base such as an alkali metal carbonate, at a temperature of between 20°C and the boiling temperature of the solvent.
The amines of formula (IV) are available commercially or may be obtained by applying or adapting the methods described by D.K. YUNK et al., J. Med. Chem.,
21, 1301 (1978); L. THUNUS et al., Ann. Pharm., 38, 353 (1980); L. GOOTES et al., Arzneim. Forsch., 17, 1145 (1963) and in patent EP 350403.
The compounds of formula (I), with the exception of those for which represents a residue of formula (C) in which R2 represents a hydrogen atom, may also be prepared by the action of a derivative of formula:
R,-(CH2) „“Hal (VI) in which R, has the same meanings as above, n has the same meanings as in the formula (I) and Hal represents a halogen atom, on an amine of formula (IV).
This reaction is generally carried out in an inert solvent such as dimethylformamide or tetrahydrofuran, in the presence of a base such as an alkali metal bicarbonate or a trialkylamine, at the boiling temperature of the solvent.
The derivatives of formula (VI) may be obtained by the action of a derivative of formula (II) on a dihalogenated derivative of formula (V).
This reaction is generally carried out in an inert solvent such as dimethylformamide, using sodium hydride, at a temperature of between 20°C and the boiling temperature of the solvent.
The compounds of formula (I) for which R!
represents a residue of formula (C) in which R2 represents a hydrogen atom, may be prepared by hydrolysis of a derivative of formula:
(VII) in which Het and n have the same meanings as in the formula (I).
This hydrolysis is carried out in an acid medium (for example sulphuric acid, hydrochloric acid), in an inert solvent such as an alcohol (for example methanol, ethanol), at a temperature of between 20°C and the boiling temperature of the solvent.
The compounds of formula (VII) may be obtained by applying or adapting the method described in the examples.
The compounds of formula (I) for which R, represents a residue of formula (C) in which R2 represents an alkyl radical, may be obtained by alkylation of the corresponding compounds for which R2 represents a hydrogen
- 6 atom.
This reaction is generally carried out using an alkyl halide (for example methyl iodide, ethyl bromide), in an inert solvent such as tetrahydrofuran, in the presence of a base such as potassium trimethylsilanonate, at a temperature of about 20°C.
The reaction mixtures obtained by the various processes described above are treated using conventional physical (extraction, evaporation, distillation, chromatography and the like) or chemical (formation of salts and the like) methods.
The compounds of formula (I), in the form of a free base, may be optionally converted to addition salts with an inorganic or organic acid by action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorine-containing solvent.
The compounds of formula (I) and their salts possess advantageous properties. These compounds possess serotonin-antagonising properties (5-HT2 receptors) and are therefore useful in the treatment of disorders involving serotonin, in particular disorders of the central nervous system, the cardiovascular system and gastrointestinal disorders.
These compounds are useful in particular in the treatment of anxiety, sleep disorders, psychoses and in particular schizophrenia, migraine, asthma, hypertension and urticaria, as analgesics and as inhibitors of platelet aggregation.
- 7 The affinity of the compounds of formula (I) for the central receptor sites for serotonin (type S2) was determined using a technique based on that used by
J.E. LEYSEN et al., Mol. Pharmacol., 21, 301 (1982) which consists in measuring the affinity of the products for the binding sites of tritiated ketanserin. In this test, the ICJ0 of the compounds of formula (I) is generally less than 25 nM.
The compounds of formula (I) are of low 10 toxicity. They are generally nontoxic at 300 mg/kg by the oral route when administered to mice in a single dose.
For therapeutic use, the compounds of formula (I) may be used as they are or in the form of pharmaceutically acceptable salts.
The addition salts with inorganic acids, such as hydrochlorides, sulphates, nitrates, phosphates, or with organic acids, such as acetates, propionates, succinates, oxalates, benzoates, fumarates, maleates, methanesulphonates, isethionate, theophillineacetates, phenolphthalinates, salicylates, methylene-bis-/3oxynaphthoates, or substituted derivatives of these compounds, may be mentioned as pharmaceutically acceptable salts.
The following examples illustrate the invention.
EXAMPLE 1
2H-Benzisothiazoline 1,1-dioxide (1.69 g), 1(3-chloropropyl)-4-(4-fluorophenyl)piperazine (2.56 g)
- 8 and sodium bicarbonate (0.84 g) in dry Ν,Νdimethylformamide (25 cc) are stirred at the reflux temperature of the solvent for 5 hours. The reaction mixture is cooled and poured into a mixture of water (50 cc) and dichloromethane (50 cc). The organic phase is decanted, washed with water (4 x 30 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.4 kPa). The residue is chromatographed on a silica gel column under a pressure of 0.7 bar using dichloromethane followed by ethyl acetate. The solid obtained is recrystallised from boiling acetonitrile (8 cc). 2-{3-[4-(4-fluorophenyl)-1piperazinyl]propyl}-2H-benzisothiazoline 1,l-dioxide (0.43 g) is obtained; m.p. = 116°C.
1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine may be prepared in the following manner: a solution of 1bromo-3-chloropropane (68 cc) and 4-(4fluorophenyl)piperazine (50 g) in acetonitrile (400 cc) is stirred for 20 hours at 25°C with potassium carbonate (97 g). The mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.083 mm, diameter 9 cm, height 60 cm), eluting with ethyl acetate and collecting fractions (500 cc). Fractions 5 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-chloropropyl)-4-(4fluorophenyl)piperazine (44.4 g) in the form of an oil which is used as it is in subsequent syntheses.
- 9 2H-Benzisothiazoline 1,1-dioxide may be prepared according to the method described in patent
US 3164602.
EXAMPLE 2
Phenanthridone (1.95 g), tetrabutylammonium bromide (0.1 g) , potassium carbonate (4.5 g) and 1-(3chloropropyl)-4-(4-fluorophenyl)piperazine (2.6 g) are mixed in dimethylformamide (70 cc). The mixture is heated at boiling temperature for 5 hours and then cooled to a temperature of about 20°C. The filtrate is evaporated to dryness at 40°C under reduced pressure (10 mm Hg;
1.35 kPa). The residue is taken up in water (20 cc) and extracted with ethyl acetate (3 x 50 cc). The organic phases are combined, dried over anhydrous magnesium sulphate and evaporated to dryness at 40°C under reduced pressure (20 mm Hg; 2.7 kPa). The oil obtained is purified by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.1-1.5 bar) using a dichloromethane-methanol mixture (99-1 by volume) as eluent. A yellow solid (1.7 g) is obtained which, when recrystallised from hot ethanol (40 cc), yields l-{3-[4(4-fluorophenyl) -1-piperaz iny1]propyl}phenanthridone (1.3 g); m.p. = 140°C.
Phenanthridone may be prepared according to the method described by B.L. HAWBECKER, J. Chem. Educ., 53 (6), 398 (1976).
EXAMPLE 3
Hydrochloric acid (6 N, 2.65 cc) is poured into
- 10 a solution of l-(3-[4-(4-fluorophenyl)-lpiperazinyl]propyl}-3-isopropenyl-2H-2-benzimidazolinone (2.1 g) in ethanol (30 cc) at a temperature of about 20°C. The solution is heated at boiling temperature for
2 hours and 30 minutes and then cooled to a temperature of about 20°C. The reaction mixture is taken up in distilled water (30 cc), dichloromethane (30 cc) and alkalinised to pH 9 with sodium hydroxide (5 N). The organic phase is extracted with dichloromethane (4 x
cc), dried over magnesium sulphate, treated with vegetable charcoal and concentrated to dryness at 40°C under reduced pressure (2.7 kPa). The residue is recrystallised from boiling acetonitrile (10 cc). 1-(3[4-(4-fluorophenyl)-l-piperazinyl]propyl}-2H-215 benzimidazolinone (1 g) is thus obtained; m.p. = 145°C.
1-(3-(4-(4-Fluorophenyl)-1-piperazinyl]propyl}3-isopropenyl-2H-2-benzimidazolinone may be prepared in the following manner: 3-isopropenyl-2H-2benzimidazolinone (1.74 g), 1-(3-chloropropyl)-4-(420 fluorophenyl)piperazine (2.56 g) and sodium bicarbonate (0.84 g) in dry Ν,Ν-dimethylformamide (20 cc) are stirred at the reflux temperature of the solvent for 6 hours. The reaction mixture is cooled and poured into a mixture of water (30 cc) and dichloromethane (30 cc). The organic phase is decanted, washed with water (3 x 30 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column under a pressure
- 11 of 0.7 bar, eluting with a dichloromethane-ethyl acetate mixture (50-50 by volume). i-{3-[4-(4-fluorophenyl)-lpiperazinyl]propyl}-3-isopropenyl-2H-2-benzimidazolinone (2.1 g) is thus obtained in the form of an oil which is used as it is in subsequent syntheses.
3-Isopropenyl-2H-2-benzimidazolinone may be prepared according to the method described by Ο. METHCOHN, J. Chem. Soc., PT1, 261 (1982).
EXAMPLE 4
Potassium trimethylsilanonate (1.83 g) is added in portions to a solution of l-{3-[4-(4-fluorophenyl)-1piperazinyl]propyl}-2H-2-benzimidazolinone (4.1 g) in tetrahydrofuran (100 cc) , at a temperature of about 20°C. The stirring is maintained for 30 minutes and then methyl iodide (0.81 cc) is poured in dropwise. The reaction mixture is stirred for 10 hours at a temperature of about 20°C and then the precipitate formed is filtered. The filtrate is concentrated to dryness at 40°C under reduced pressure (2.7 kPa). The residue is recrystallised from boiling acetonitrile (10 cc) and treated with vegetable charcoal. l-{3-[4-(4-fluorophenyl)-1piperazinyl]propyl}-3-methyl-2H-2-benzimidazolinone (1.6 g) is thus obtained; m.p. = 105°C.
The pharmaceutical compositions according to the invention consist of a compound of formula (I) in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is combined with
- 12 any other pharmaceutically compatible product which may be inert or physiologically active. The medicinal products according to the invention may be administered orally, parenterally, rectally or topically.
Tablets, pills, powders (gelatin capsules, cachets) or granules may be used as solid compositions for oral administration. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colourant, a coating (sugared pills) or a varnish.
Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil may be used as liquid compositions for oral administration. These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavouring or stabilising products.
The sterile compositions for parenteral administration may be aqueous or nonaqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic esters for injection, for example ethyl oleate, or other suitable organic solvents may be used as
- 13 solvent or vehicle. These compositions may also contain adjuvants, in particular wetting, isotonising, emulsifying, dispersing and stabilising agents.
Sterilisation may be performed in a number of ways, for example by asepticising filtration, by incorporating sterilising agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or in any other sterile medium for injection.
The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
The compositions for topical administration may be for example creams, pomades, lotions, collyria, collutories, nasal drops or aerosols.
In human therapy, the compounds according to the invention are particularly useful in the treatment of disorders involving serotonin and in particular disorders of the central nervous system, of the cardiovascular system and intestinal disorders. They are in particular useful in the treatment of anxiety, sleep disorders, depression, psychoses and in particular schizophrenia, migraine, asthma, hypertension, urticaria, as analgesics and as inhibitors of platelet aggregation.
The doses depend on the desired effect and on the administration route used; they are generally between
- 14 10 and 300 mg per day orally for an adult with unit doses ranging from 5 to 150 mg of active substance.
Generally, the physician will determine the appropriate dosage according to the age, the weight and all the other factors which are specific to the individual to be treated.
The following examples illustrate the compositions according to the invention:
EXAMPLE A
Gelatin capsules containing a dose of 50 mg of active product and having the following composition are prepared using conventional techniques:
- 1—{3—[4—(4-Fluorophenyl)-1-piperazinyl]propyl}-2H-2-benzimidazolinone ........... 50 mg
- Cellulose ................................ 18 mg
- Lactose .................................. 55 mg
- Colloidal silica ......................... 1 mg
- Carboxymethylstarch sodium ............... 10 mg
- Talc ..................................... 10 mg
- Magnesium stearate ....................... 1 mg
EXAMPLE B
Tablets containing a dose of 50 mg of active product and having the following composition are prepared using conventional techniques:
- 2-{3-[4-(4-Fluorophenyl)-lpipera z iny1]propyl}-2H-benz isothiazoline 1,1-dioxide .................. 50 mg
- Lactose ................................. 104 mg
- 15 ~
- Cellulose ............................... 40 mg
- Polyvidone .............................. 10 mg
- Carboxymethylstarch sodium .............. 22 mg
- Talc ................... 10 mg
- Magnesium stearate ...................... 2 mg
- Colloidal silica ........................ 2 mg
- Mixture of hydroxymethylcellulose, glycerine, titanium oxide (72-3.5-24.5) qs 1 finished coated tablet of .......... 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product and having the following composition is prepared:
- l-{3-[4-(4-Fluorophenyl)-1piperazinyl]propyl}phenanthridone ..... 10 mg
- Benzoic acid .......................... 80 mg
- Benzyl alcohol ........................ 0.06 cc
- Sodium benzoate ....................... 80 mg
- Ethanol, 95 % ......................... 0.4 cc
- Sodium hydroxide...................... 24 mg
- Propylene glycol ...................... 1.6 cc
- Water qs 4 cc
Claims (13)
1. A compound of formula: Rj-(CH 2 ) n -Het (I) in which: 5 - R, represents a residue of formula: - Het represents a 4-phenyl-l,2,3,6-tetrahydro-l-pyridyl radical whose phenyl ring is unsubstituted or substituted by a 10 halogen atom or an alkyl, alkoxy or hydroxyl radical, a 4-phenylpiperidino radical whose phenyl ring is unsubstituted or substituted by a halogen atom or an alkyl, alkoxy or hydroxyl radical, a 4-phenyl-l-piperazinyl radical whose phenyl 15 ring is unsubstituted or substituted by a halogen atom or an alkyl, alkoxy or hydroxyl radical, - R 2 represents a hydrogen atom or an alkyl radical, and - n is 1, 2, 3 or 4, the said alkyl and alkoxy radicals containing 1 to 20 4 carbon atoms each in a straight or branched chain, and its salts with organic or inorganic acids.
2. A compound according to claim 1 which is 2-{
3. -[4-(4-fluorophenyl)-1-piperaz inyl]propyl}-2Hbenzisothiazoline 1,1-dioxide. 25 3. A compound according to claim 1 which is - 17 l-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}phenanthridone.
4. A compound according to claim l which is l-{3-[4-(4-fluorophenyl)-l-piperazinyl]propyl}-2H-25 benzimidazolinone.
5. A compound according to claim 1 which is 1-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-3-methy12H-2-benzimidazolinone.
6. A process for preparing a compound of 10 formula (I) according to claim 1, other than a compound in which R, represents a residue of formula (C) where R 2 represents hydrogen, which comprises reacting a derivative of formula: R,H (II) 15 in which R, has the same meaning as above, with a halogenated derivative of formula: Hal-(CH 2 ) n -Het (HI) in which Hal represents a halogen atom, and Het and n are as defined in claim 1, isolating the product, and 20 optionally converting it into a salt.
7. A process for preparing a compound of formula (I) according to claim 1, other than a compound in which Rj represents a residue of formula (C) wherein R 2 represents hydrogen, which comprises reacting a 25 derivative of formula: R,-(CH 2 ) n -Hal (VI) in which Rj has the same meaning as above, n is as defined -18in claim 1 and Hal represents a halogen atom, with an amine of formula: Het-H (IV) in which Het is as defined in claim 1, isolating the 5 product, and optionally converting it into a salt.
8. A process for preparing a compound of formula (I) according to claim 1 in which R, represents a residue of formula (C) in which R 2 represents hydrogen, which comprises hydrolising a derivative of formula: (VII) in which n and Het are as defined in claim 1, isolating the product and optionally converting it into a salt.
9. A process for preparing a compound of formula (I) according to claim 1 in which R, represents a 15 residue of formula (C) in which R 2 represents an alkyl radical, which comprises alkylating a corresponding compound in which R 2 represents a hydrogen atom, isolating the product, and optionally converting it into a salt.
10. A process for preparing a compound of 20 formula (I) according to claim 1 substantially as described in any one of Examples 1 to 4.
11. A compound of formula (I) according to claim 1 when prepared by a process as claimed in any one of claims 6 to 10. - 19
12. A pharmaceutical composition which contains, as active material, at least one compound of formula (I) according to any of claims l to 5 or ll.
13. A pharmaceutical composition according to 5 claim 10 for the treatment of diseases involving serotonin.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9105169A FR2675800A1 (en) | 1991-04-26 | 1991-04-26 | HETEROCYCLIC ANTISEROTONINE DERIVATIVES AND PREPARATION AND MEDICAMENTS CONTAINING SAME. |
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IE921340A1 true IE921340A1 (en) | 1992-11-04 |
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ID=9412290
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IE921340A IE921340A1 (en) | 1991-04-26 | 1992-04-24 | Heterocyclic antiserotonin derivatives, their preparation¹and pharmaceutical compositions containing them |
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EP (1) | EP0511074A1 (en) |
CA (1) | CA2103561A1 (en) |
FR (1) | FR2675800A1 (en) |
IE (1) | IE921340A1 (en) |
MX (1) | MX9201847A (en) |
WO (1) | WO1992019606A1 (en) |
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US5620993A (en) * | 1995-06-07 | 1997-04-15 | Merck & Co., Inc. | Alpha-1a adrenergic receptor antagonists |
DE19746612A1 (en) * | 1997-10-22 | 1999-04-29 | Basf Ag | New 2-substituted 1,2-benzisothiazole derivatives |
US6960579B1 (en) * | 1998-05-19 | 2005-11-01 | Alcon Manufacturing, Ltd. | Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders |
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US7183410B2 (en) | 2001-08-02 | 2007-02-27 | Bidachem S.P.A. | Stable polymorph of flibanserin |
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EP1945214A1 (en) | 2005-10-29 | 2008-07-23 | Boehringer Ingelheim International GmbH | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
DE602007004615D1 (en) | 2006-06-30 | 2010-03-18 | Boehringer Ingelheim Pharma | FLIBANSERIN FOR THE TREATMENT OF HARNINE INCONTINENCE AND ASSOCIATED DISEASES |
CA2660476C (en) | 2006-08-14 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Formulations of flibanserin and method for manufacturing the same |
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JP2011510040A (en) * | 2008-01-24 | 2011-03-31 | ノイロサーチ アクティーゼルスカブ | 4-Phenyl-piperazin-1-yl-alkyl-benzimidazol-2-one derivatives and their use as monoamine neurotransmitter reuptake inhibitors |
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FR2628425B1 (en) * | 1988-03-08 | 1992-04-03 | Rhone Poulenc Sante | ISOINDOLINONE DERIVATIVES, THEIR PREPARATION METHODS AND THE MEDICINAL PRODUCTS CONTAINING THEM |
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-
1991
- 1991-04-26 FR FR9105169A patent/FR2675800A1/en not_active Withdrawn
-
1992
- 1992-04-21 CA CA 2103561 patent/CA2103561A1/en not_active Abandoned
- 1992-04-21 EP EP92401110A patent/EP0511074A1/en not_active Withdrawn
- 1992-04-21 WO PCT/FR1992/000353 patent/WO1992019606A1/en active Application Filing
- 1992-04-22 MX MX9201847A patent/MX9201847A/en unknown
- 1992-04-24 IE IE921340A patent/IE921340A1/en not_active Application Discontinuation
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
US11058683B2 (en) | 2001-10-20 | 2021-07-13 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
US10335407B2 (en) | 2005-08-03 | 2019-07-02 | Sprout Pharmaceuticals, Inc. | Use of flibanserin in the treatment of obesity |
US10874668B2 (en) | 2005-08-03 | 2020-12-29 | Sprout Pharmaceuticals, Inc. | Use of Flibanserin in the treatment of obesity |
US10166230B2 (en) | 2007-09-12 | 2019-01-01 | Sprout Pharmaceuticals Inc. | Treatment of vasomotor symptoms |
Also Published As
Publication number | Publication date |
---|---|
MX9201847A (en) | 1992-10-01 |
WO1992019606A1 (en) | 1992-11-12 |
CA2103561A1 (en) | 1992-10-27 |
FR2675800A1 (en) | 1992-10-30 |
EP0511074A1 (en) | 1992-10-28 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FC9A | Application refused sect. 31(1) |