CA1051888A - Piperazinyl-pyridine compounds - Google Patents
Piperazinyl-pyridine compoundsInfo
- Publication number
- CA1051888A CA1051888A CA223,696A CA223696A CA1051888A CA 1051888 A CA1051888 A CA 1051888A CA 223696 A CA223696 A CA 223696A CA 1051888 A CA1051888 A CA 1051888A
- Authority
- CA
- Canada
- Prior art keywords
- group
- formula
- piperazinyl
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New derivatives of pyridine are provided of the formula:
(I) in which R1 which may be either in the 3-position or in the 5-position represents a group selected among those of the formulae -CN
New derivatives of pyridine are provided of the formula:
(I) in which R1 which may be either in the 3-position or in the 5-position represents a group selected among those of the formulae -CN
Description
3~39 bis DB/DN
~t5~
The presellt invention re:lates to a process ~or preparing new deri~atives of pyridine having valuable phar-malogical properties~
The new derivatives of pyridine may be represented by the ~ollowing formula :
f~ R1 ~ ~ R2 (I) N
in which R1, which may be in the 3-position or in the 5-positio~ represerL's :
a mono~alkylcarboxa~ido group in which the alkyl radical contains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sull~one or homopiperidinesulfone group, or a su~stituted C1-C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1-C3 alkoxy or a met:hy'-piperazinyl group, when R2, which may be in the 2-, 4- or 6- posi-tion represents a C1 C3-alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position re resent~ :
a sul~amoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contalns 1 to 3 c~rbon atoms~ or a piperdinosulfone, morpholinosulfone, pyrrolidinosulfone or ~-me-thy1piperazinylsul~one ~roup, ~hen R2 ~ which ~..ay be in the 2-, 4- or 6-position represents an isopropylpiperazinyl or hJdroxyethylpiperazinyl group.
According to the invention, said compounds o~
formula (I) are prepared by reacting a compound OI the "_", - 1 ~
formula : R1 ~ II3 in which R1 which may be in t~.e 3~ or 5- position and has the abo~e meanings and X which may be in the 2-~ 4- or 6- position and represents a halogen, preferably chlorine, with a C1-C3-alkylpiperazine or hydroxyethyl-piperazine.
The obtained compounds of formula (13 may be con-verted înto an acid addl-tion salt, preferably an hydrochlo-ride, by a conventional method.
The compounds of this invention have interesting anti-inflammatory9 anti-pyretic and cardiovascular pro-perties.
The anti-inflammatory properties are determined as follows :
The compounds to be tested are given as ~reshly prepared solut~ons or suspensions by oral route to rats one ~o hour before injecting a paw with carrageenin, a known inflammatory agent.
The inflammatory agent either in aqueous solution or suspension is then in~ected into the plantar tissue of the right hind paw of each rat, the le~t paw remaining untreated and serving as control. Each animal receives for example 0.05 nl of an aqueous solution containing 1~ of carrageenin and 0.9% of sodium chloride.
4 hours after injection, the importance of swel~
ling is determined by plethysmography and is expressed as a percent o~ the volume of the control paw.
The anti-inflammatory effect expressed as a per-cent of inhibition is obtained by comparison between rats - i--treated with the anti-inflammatory agen-t and a control group of rats.
The resul-ts of the test for anti-in~lammatory activity are given in table I. In each case, a dose of 100 mg/kg of a compound of formula (I) has been adminîs-tered.
TABIE I
Acute oedema induced by Ref. No. Compound of E~ample carrageenln ~o of inhibi-kion.
LT 137 1 51.2 139 2 44.4 150 6 32.0 333 13 60.8 3~4 14 55.2 335 15 60.0 Phenylbutazone 41 Methiazinic acid 46 Acetosalicylic acid 0 Flu~enamic acid 34 Niflumic acid 32 Some compounds ol this invention also have interesting cardiovascular properties so that they may be used as cerebral, coron2ry and peripheral asodilators and h-r~otension-inducing agents, whereby the hypo~ension acti-vity may occur primarily or secondarily with respect to the peripheral vasodilatation.
''~,' ~ 3 -Af-ter adminis-tration o the compo~nd a-t -the hereafter~indicated doses~ the following parameters have been measured on -the -test animal (dogs) : the electro-cardiogram, the left ventricular pressure, the amplified telediastolic pressure, the deriva-tive of the ventricular pressure with respect -to time (dp/dt), the aortic pressure, the average and pulsatile blood flow of the le~ carotid and femoral artery.
The maill typical cardiovascular propertie~
have been found as follows :
~ ~r Increas of arterial _ __ __ __ ____ Compound E~am- dose flow (,o) Action on blood code ple ¦ mg/kg _ pressure - . _ . . Carotid Femoral LT 333 13 4 to 8I100 100 LT 335 15 2 300 50 No variatio~
4 Fall ~150 to 90 mm Hg) LT 334 16 2 75 Sharp fall (130 to 90 4 50 Sharp fall _ ~ Ib) This invention relates also to pharmaceutical com-30positions containing as active ingredient, at least one com-pound of the formula (I), together with a pharmaceutical , t~, carrier or excipien-t~ The compositions are generally intend-ed for peroral, rectal or parenteral administration and also for external useO Pharmaceutical compositions for oral administration may, for example, be in -the form of dosage uni-ts such as tablets9 dragees or capsules in which at least one of the compo~nds according -to the inven-tion ls mixed with a solid pharmaceutical carrier or excipient.
The composi-tions according to the presen-t inven-tion can also be used in the form of liquid preparations for oral administration especially syrups, elixirs9 aqueous dispersions or solutions.
The compositions according to the present inven-tion can also be in the form of solutions for parenteral administra-tion. Solutions or suspensions for injections can be prepared by using9 for example, distilled water in ~thich at least one compound of formula (I) as ac~i~e ingredient is dissolved or suspended, if desired, in the presence of a solubilizing agent.
The compositlons according to the present in~en tion may also be formulated for rectal admiristrat~on by incorporating the active ingredient in a suppository base, The anti-inflammatory compos~tions according to this invention may also be applied for external use, for example, by incorporatin~ the ac-tive ingredient in an oint-ment base.
The compounds of formula (I~ employed as active ingredients in the compositions according to the inventlon can be administered in varying doses depsnding on the par-ticular compound being usedr the condition of the patient, and the route of administration.
In general, ho~ever, the compounds can be adminis-tered orally or rectally in doses of fro~ 50 to 1000 mg to ~s~
be taken one to four times per day, or parenterally in a single dose of 20 to 500 mg per day.
The following examples 1 to 31 illustrate the preparation of compounds according to this invention.
Exam~les 1 - 3 These examples illus-trate the preparation of th~
followlng compounds ~
~t5~
The presellt invention re:lates to a process ~or preparing new deri~atives of pyridine having valuable phar-malogical properties~
The new derivatives of pyridine may be represented by the ~ollowing formula :
f~ R1 ~ ~ R2 (I) N
in which R1, which may be in the 3-position or in the 5-positio~ represerL's :
a mono~alkylcarboxa~ido group in which the alkyl radical contains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sull~one or homopiperidinesulfone group, or a su~stituted C1-C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1-C3 alkoxy or a met:hy'-piperazinyl group, when R2, which may be in the 2-, 4- or 6- posi-tion represents a C1 C3-alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position re resent~ :
a sul~amoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contalns 1 to 3 c~rbon atoms~ or a piperdinosulfone, morpholinosulfone, pyrrolidinosulfone or ~-me-thy1piperazinylsul~one ~roup, ~hen R2 ~ which ~..ay be in the 2-, 4- or 6-position represents an isopropylpiperazinyl or hJdroxyethylpiperazinyl group.
According to the invention, said compounds o~
formula (I) are prepared by reacting a compound OI the "_", - 1 ~
formula : R1 ~ II3 in which R1 which may be in t~.e 3~ or 5- position and has the abo~e meanings and X which may be in the 2-~ 4- or 6- position and represents a halogen, preferably chlorine, with a C1-C3-alkylpiperazine or hydroxyethyl-piperazine.
The obtained compounds of formula (13 may be con-verted înto an acid addl-tion salt, preferably an hydrochlo-ride, by a conventional method.
The compounds of this invention have interesting anti-inflammatory9 anti-pyretic and cardiovascular pro-perties.
The anti-inflammatory properties are determined as follows :
The compounds to be tested are given as ~reshly prepared solut~ons or suspensions by oral route to rats one ~o hour before injecting a paw with carrageenin, a known inflammatory agent.
The inflammatory agent either in aqueous solution or suspension is then in~ected into the plantar tissue of the right hind paw of each rat, the le~t paw remaining untreated and serving as control. Each animal receives for example 0.05 nl of an aqueous solution containing 1~ of carrageenin and 0.9% of sodium chloride.
4 hours after injection, the importance of swel~
ling is determined by plethysmography and is expressed as a percent o~ the volume of the control paw.
The anti-inflammatory effect expressed as a per-cent of inhibition is obtained by comparison between rats - i--treated with the anti-inflammatory agen-t and a control group of rats.
The resul-ts of the test for anti-in~lammatory activity are given in table I. In each case, a dose of 100 mg/kg of a compound of formula (I) has been adminîs-tered.
TABIE I
Acute oedema induced by Ref. No. Compound of E~ample carrageenln ~o of inhibi-kion.
LT 137 1 51.2 139 2 44.4 150 6 32.0 333 13 60.8 3~4 14 55.2 335 15 60.0 Phenylbutazone 41 Methiazinic acid 46 Acetosalicylic acid 0 Flu~enamic acid 34 Niflumic acid 32 Some compounds ol this invention also have interesting cardiovascular properties so that they may be used as cerebral, coron2ry and peripheral asodilators and h-r~otension-inducing agents, whereby the hypo~ension acti-vity may occur primarily or secondarily with respect to the peripheral vasodilatation.
''~,' ~ 3 -Af-ter adminis-tration o the compo~nd a-t -the hereafter~indicated doses~ the following parameters have been measured on -the -test animal (dogs) : the electro-cardiogram, the left ventricular pressure, the amplified telediastolic pressure, the deriva-tive of the ventricular pressure with respect -to time (dp/dt), the aortic pressure, the average and pulsatile blood flow of the le~ carotid and femoral artery.
The maill typical cardiovascular propertie~
have been found as follows :
~ ~r Increas of arterial _ __ __ __ ____ Compound E~am- dose flow (,o) Action on blood code ple ¦ mg/kg _ pressure - . _ . . Carotid Femoral LT 333 13 4 to 8I100 100 LT 335 15 2 300 50 No variatio~
4 Fall ~150 to 90 mm Hg) LT 334 16 2 75 Sharp fall (130 to 90 4 50 Sharp fall _ ~ Ib) This invention relates also to pharmaceutical com-30positions containing as active ingredient, at least one com-pound of the formula (I), together with a pharmaceutical , t~, carrier or excipien-t~ The compositions are generally intend-ed for peroral, rectal or parenteral administration and also for external useO Pharmaceutical compositions for oral administration may, for example, be in -the form of dosage uni-ts such as tablets9 dragees or capsules in which at least one of the compo~nds according -to the inven-tion ls mixed with a solid pharmaceutical carrier or excipient.
The composi-tions according to the presen-t inven-tion can also be used in the form of liquid preparations for oral administration especially syrups, elixirs9 aqueous dispersions or solutions.
The compositions according to the present inven-tion can also be in the form of solutions for parenteral administra-tion. Solutions or suspensions for injections can be prepared by using9 for example, distilled water in ~thich at least one compound of formula (I) as ac~i~e ingredient is dissolved or suspended, if desired, in the presence of a solubilizing agent.
The compositlons according to the present in~en tion may also be formulated for rectal admiristrat~on by incorporating the active ingredient in a suppository base, The anti-inflammatory compos~tions according to this invention may also be applied for external use, for example, by incorporatin~ the ac-tive ingredient in an oint-ment base.
The compounds of formula (I~ employed as active ingredients in the compositions according to the inventlon can be administered in varying doses depsnding on the par-ticular compound being usedr the condition of the patient, and the route of administration.
In general, ho~ever, the compounds can be adminis-tered orally or rectally in doses of fro~ 50 to 1000 mg to ~s~
be taken one to four times per day, or parenterally in a single dose of 20 to 500 mg per day.
The following examples 1 to 31 illustrate the preparation of compounds according to this invention.
Exam~les 1 - 3 These examples illus-trate the preparation of th~
followlng compounds ~
2-(4'-methyl-1'-piperazinyl) pyridine-3-methylcarboxamide (Exa~ple 1) 2-(4'-methyl~ piperazinyl)-pyridine 3-ethylcarboxamide (Example 2) 2-(4'-methy~ piperazinyl)-pyridine 3-isopropylcarboxamide (Example 3) These compounds are prepared by the following general method :
A mixture of 10 g of a chlorinated compound of formula (II), 30-40 ml of toluene and 10 g of N-methyl-piperazine is heated and boiled under reflux conditions fo~ 4 hours.
After cooling, the solution is evaporated under reduced pressure to obtain an oil. 20 ml water and 20 ~1 ~-TaOH (10~) are added and the mixture is extracted with chloroform. The extraction solution is then dried and distilled.
Particulars of the obtained compounds are set out in the following table.
Starting product of formula (II) Com~ound of Boiling Yield Melting ~0 ~ -R1 Exam~le point c6 point ( l obta~ned ~C/m~ ~C
N Cl i.~,,, ~ t, --CO~ICH3 1(1)184-187~/0.5 6095-g7 CONHC2H5 3(1~5-190/0.8 60 69 CONHCH(CH~)2 4~1)187-192~/Q.5 70 81 (1) crystallizes at rest (2) dis-tilled under ni-trogen bla~ket~
EXA~PLES 4-6 ___ These examples illustrate the preparatlon of the following compou~ds :
2-(4~-meth~1~1'-piperazinyl~-pyridine-5-methylcarboxamide (Example 4) 2-(4'-methyl-1'-piperazi~yl)-pyridine-5-ethylcarboxamide (Example 5) 2-(4'-methyl-1' piperazinyl~-pyridine-5-isopropylcarbo~,~amide (Example 6) These compounds are prepared by the following general method :
A mixture o~ 10 g of chlorinated starting compound o~ formula (II), 30 to 40 ml of toluene and 10 g of N-me~,hyl-~0 piperazine is heated and boiled under reflux conditions during 4 hours. After cooling, the solution thus obtained is evaporated under reduced pressure9 20 ml water and 20 ml ~aOH (10%) are added a-nd the resulting mix~ure is extracted with CHCl3. The extraction solution is dried and then evaporated under reduced pressure. The residue is taken up with petroleum ether and stirred until it crystallizes. The solid proauct is filtered and then crystallized from petro~eum ether~
Partlculars of the obtained compounds are se-t out in the following table :
~ ~ - 7 -~51~
TABLE III
Starting compounds of formula ~II) Product of ~elting Yield Analysis R1 ,~ Example point %
ob-tained ~C
N ~ Cl CONHCH3 4 112-113 60 61.54(1) 7:69 23.93 61.48 2) 7 71 23~75 CONHC2H5 5 85-97 70 62.90 8.06 22. 58 62~75 8~15 22.75 COi~HC3H7iso 7 145-146 70 64.12 8.40 21.37 64 . 03 8.39 21. 50 (1) calculated (2) found.
Examples 7 - 14 The starting compounds of formula (II) are first prepared by the follo~tin~ met'nod :
A mixture of 10 g 4-hydroxy-pyridine-3-sulfonic acid, 40 g of PCl5 and 40 ml of OPCl3 is heated at 125-130C during 2 hours. Af~er cooling, the not reacled OPCl3 is e~aporated under reduced pressure. The residue is taken up with 100 ml of ether and poured into 100 g OI ice. The mixture thus obtained is stirred vigorously unt~l the excess of PCl5 and OPCl3, if any, is decomposed.
The acidity is neutralized by means of NaHC03 and the solution is extracted 3 times wi~h 100 ml of ether. The ether solution is dried by means of anhydrous sodium sulfate and is evaporated under reduced pressure. The remaining sulfochloride is then dissolved in 30-50 ml o diox~ne and poured drop by drop, witn constant stirring, ' .~,,~/
8~
into 200 ml of a cold aqueous solution of the appropriate amine. After addition of the sulflochloride, one waits 10 further minutes and -then one concentrates, i~ necessary, the solution under reduced pressure. The crystalline pro-duct is recovered by filtra~ion, washed and recrystallized from the suitable solventO In some insta-nces, the product is extracted with CHCl3 and distilled under vacuum.
Particulars o~ the starting compounds of ~ormula (II) thus obtained are given in the following table :
T~BLE IV Cl __ I
Starting ~ S02R
compounds of formula (II) ~ N f -R Yield Melting Recristalli- Used ~or ~ Point zation sol-e~ample ~
C vent _~ 75(1)46.5-47.5 a 7 -~ ~ 75( )86-88 a 8 -N ~ 75 143-144 a 9 H
-~? 75173-174.5 a 10 -N ~ CH3 75 - a 11 -~J ~ 75 73-74.5 a 12 ~H2CH20CH3 75 118-119 a 14 ~5H2CH20c2H5 75101.5-102.5 a 15
A mixture of 10 g of a chlorinated compound of formula (II), 30-40 ml of toluene and 10 g of N-methyl-piperazine is heated and boiled under reflux conditions fo~ 4 hours.
After cooling, the solution is evaporated under reduced pressure to obtain an oil. 20 ml water and 20 ~1 ~-TaOH (10~) are added and the mixture is extracted with chloroform. The extraction solution is then dried and distilled.
Particulars of the obtained compounds are set out in the following table.
Starting product of formula (II) Com~ound of Boiling Yield Melting ~0 ~ -R1 Exam~le point c6 point ( l obta~ned ~C/m~ ~C
N Cl i.~,,, ~ t, --CO~ICH3 1(1)184-187~/0.5 6095-g7 CONHC2H5 3(1~5-190/0.8 60 69 CONHCH(CH~)2 4~1)187-192~/Q.5 70 81 (1) crystallizes at rest (2) dis-tilled under ni-trogen bla~ket~
EXA~PLES 4-6 ___ These examples illustrate the preparatlon of the following compou~ds :
2-(4~-meth~1~1'-piperazinyl~-pyridine-5-methylcarboxamide (Example 4) 2-(4'-methyl-1'-piperazi~yl)-pyridine-5-ethylcarboxamide (Example 5) 2-(4'-methyl-1' piperazinyl~-pyridine-5-isopropylcarbo~,~amide (Example 6) These compounds are prepared by the following general method :
A mixture o~ 10 g of chlorinated starting compound o~ formula (II), 30 to 40 ml of toluene and 10 g of N-me~,hyl-~0 piperazine is heated and boiled under reflux conditions during 4 hours. After cooling, the solution thus obtained is evaporated under reduced pressure9 20 ml water and 20 ml ~aOH (10%) are added a-nd the resulting mix~ure is extracted with CHCl3. The extraction solution is dried and then evaporated under reduced pressure. The residue is taken up with petroleum ether and stirred until it crystallizes. The solid proauct is filtered and then crystallized from petro~eum ether~
Partlculars of the obtained compounds are se-t out in the following table :
~ ~ - 7 -~51~
TABLE III
Starting compounds of formula ~II) Product of ~elting Yield Analysis R1 ,~ Example point %
ob-tained ~C
N ~ Cl CONHCH3 4 112-113 60 61.54(1) 7:69 23.93 61.48 2) 7 71 23~75 CONHC2H5 5 85-97 70 62.90 8.06 22. 58 62~75 8~15 22.75 COi~HC3H7iso 7 145-146 70 64.12 8.40 21.37 64 . 03 8.39 21. 50 (1) calculated (2) found.
Examples 7 - 14 The starting compounds of formula (II) are first prepared by the follo~tin~ met'nod :
A mixture of 10 g 4-hydroxy-pyridine-3-sulfonic acid, 40 g of PCl5 and 40 ml of OPCl3 is heated at 125-130C during 2 hours. Af~er cooling, the not reacled OPCl3 is e~aporated under reduced pressure. The residue is taken up with 100 ml of ether and poured into 100 g OI ice. The mixture thus obtained is stirred vigorously unt~l the excess of PCl5 and OPCl3, if any, is decomposed.
The acidity is neutralized by means of NaHC03 and the solution is extracted 3 times wi~h 100 ml of ether. The ether solution is dried by means of anhydrous sodium sulfate and is evaporated under reduced pressure. The remaining sulfochloride is then dissolved in 30-50 ml o diox~ne and poured drop by drop, witn constant stirring, ' .~,,~/
8~
into 200 ml of a cold aqueous solution of the appropriate amine. After addition of the sulflochloride, one waits 10 further minutes and -then one concentrates, i~ necessary, the solution under reduced pressure. The crystalline pro-duct is recovered by filtra~ion, washed and recrystallized from the suitable solventO In some insta-nces, the product is extracted with CHCl3 and distilled under vacuum.
Particulars o~ the starting compounds of ~ormula (II) thus obtained are given in the following table :
T~BLE IV Cl __ I
Starting ~ S02R
compounds of formula (II) ~ N f -R Yield Melting Recristalli- Used ~or ~ Point zation sol-e~ample ~
C vent _~ 75(1)46.5-47.5 a 7 -~ ~ 75( )86-88 a 8 -N ~ 75 143-144 a 9 H
-~? 75173-174.5 a 10 -N ~ CH3 75 - a 11 -~J ~ 75 73-74.5 a 12 ~H2CH20CH3 75 118-119 a 14 ~5H2CH20c2H5 75101.5-102.5 a 15
3 (a~ petroleum ether (b.p. 100-140C).
,~,",,,.~
.-.;...... _ 9 _ ~5~
Using the compounds of formula (II) prepared as described hereabove, the following compounds of formula (I) are now prepared :
,~,",,,.~
.-.;...... _ 9 _ ~5~
Using the compounds of formula (II) prepared as described hereabove, the following compounds of formula (I) are now prepared :
4-(4'-methyl~ piperazinyl~-pyridine-3-p~rrolidinosulfone (Example 7) 4-(4'-methyl-1'-piperazinyl)~pyridine~3-piperidinosulfone (Example 8) 4-(4'-methyl-1'-plperazinyl)-pyridine-3-~2' methyl-piperi dino)-sulfone (Example 9) 4~ ~ 4 ' -methyl-1'-piperazinyl)-pyridine-3-(3'-meth~1-piperi-dino)-sulfone (Example 10) 4-(4'-methyl-1'-piperazinyl)-pyridine 3-(4'-methylpiperi-dino)-sulfone (Example 11) 4- ( 4 ' -methyl-1'-piperazinyl)-pyridine-3-homopiperidyl-sulfone (Example 12) 4-(4'-meth~l-1'-piperazinyl)-pyridine-3-( 4 " -mechyl-1" -piperazinyl)-ethylsulfonamide (Example 13) 4-(4'-methyl-1'-piperazinyl)-~yridine-3-me-thoxyethyl-sulfonamide (Example 14) 4-(4'-methyl~ piperazinyl)-pyridine-3-ethoxyethylsulfon-amide (Example 15) These compounds are prepared by the ~ollowing method :
10 g of the starting chlorinated compounds o~
formula (II) are placed in a flask with 30-40 ml of toluene and 15 ml of ~-methylpiperazine. The mixture is heated under boiling and reflux conditions during 4 hours. After cooling, the solution is evaporated under reduced pressure. 20 ml of water and 20 ml of NaOH (10%) are added and the resulting mixture is extracted with CHCl3. The chloroform solution is dried and then evaporated under reduced pressure. The residue is recrystallized from -the appropriate solvent.
TABLE V
__.
Compound o~ Y~eld Mel-ting poin-t Recris-tallization Example 5' C' solvent =
7 75 1~ 2 a 8 80 112-113 a 9(H~l) 65 ~ 250 (dec) 10(2 HCl) 60 ~ 220 (dec) b (H2S4~ 65 > 250 (dec) b 12(2 HCl) 60 223.5-225 b 13 65 109.5-111 a 14 80 118 119.5 a 90 91.5 a (a) petroleum ether (100-140C) (b~ precipitation of -the hydrochloride from a solution in acetone.
~Xil 6 ~S - ~
Theqe examples illu~trate ~he preparation of the ~ollowing compou~d~ :
4-(4'-isopropyl~ piperazinyl~-pyridin~-3 sul~o~amide (Exam~le 16) 4-(4'-isopropyl-1'-piperazi~yl~-pyridine-3-methylsul~onamid~
(Example 17) 4-(4'-isopropyl-1'-piperazinyl)-pyridine~3-dLm~thylsulIo~-amlde (Example 18) 4~(4'-isopropyl-1'-piperazinyl)-pyridine-3-e~thylsul~onamide (Example 19) 4 (4'-isopropyl-1'-piper~zinyl)-pyridlne-3-die~hylsulfon-amide ~Example 20) 4-(4'-isopropyl-1'-piperazinyl~-pyridine~3~pyrrolidino~ul fon~ (Ex.ample 21) 4-(4'-isopropyl~1t-piperazlnyl~-pyridine 3-pi~ridinosul~one (Example 22~
4_ ( 4 ~ opropyl-1'-piperazinyl)-pyridine-3-morpholinosulfone (Example 23) 4 (4l-isopropyl-1'-piperazinyl)-pyridine-3-(N-methylpipera-zinyl)-sulfone (Example 24~
These compounds are prepared by -the same method as the compounds of examples 7 to 15, using N-isopropylpipera-zine instead o~ N-methylpiperazine.
The obtained compounds recrystallized frorn petroleum ether have the following melting points TABLE: VI
rt ~O
16 (HCl) 283-284 17 97-98.5 19 84-85.5 22 68.~-69.5 23 130.5-131~5 EXAMPLES 25-3 ?
These examples illustrate the preparatlon o~ the following compound~ :
4-(4'-hydroxyethyl~ piperazinyl)-pyridine-3-sulfonamide (Example 25) 4-(4'-hydroxyethyl-1'-piperazlnyl)-pyridine-3 ethylsulfon-amide (Example 26) 4-(4'-hydroxyethyl-1 ? piperazinyl)-pyridine-3-d~ethylsul-fonamide (Example 27) 4-(4'-hydroxyethyl-1'-piperazinyl)-pyridine-3-isopropyl-sulonamide (Example 28) 4-(4'-hydroxyethyl-1'-piperazinyl)~--pyridine-3-piperidino-sulfone (Example 29) 4-(4~-hydroxye-thyl~ piperazj.myl) pyridlne-3-morpholino~
sulfone (Example 30) 4-(4'~hydroxyethyl-1'-piperazinyl)-pyridine~3-pyrrolidino-sul~one ~xample 31) The above-cited compounc1s are prepared by the same me-thod as the compounds of examples 7~15, using N-hydroxy-ethylpiperazine instead of N-methylp~perazine.
Particulars of said compounds are set ou-t in the followlng table :
TABLE VII
Compound of Yield Meltlng point Recrystallizat~on Example % C solvent - . . . .
222~5 a 26 80 119-120 b 27 60 ~ c (285-290~/Oo1 mm) 28 75 93 b 29 75 116-117~5 b 82.5-84 d 31 75 95-96.5 b (a~ water-alcohol (b) petroleum ether - b.p. 100-140C
(c) distilled under vacuum (d) benzene-hexane Examples of compositions for use according to this invention are given hereinafter :
EXA~PLE 32 Dragees Core ~
Compound of formula (I) 50.0 mg 30 ColloIdal silica 5.0 mg Lactose 42.5 mg Polyvldone 3 5 ~g - 13 _ Glycerol 0.5 mg Maize starch 8.0 mg Talc 10.Q mg Magnesium stearate 0.5 mg Coatin~ :
Gum lac 2.0 mg Gum arabic 5.4 mg New-Coccine 0.1 mg Talc 13.0 mg 10 Colloida~ silica 9.5 mg Saccharose 50.0 mg for one dragee Tablets Core :
Compound of formula ~I)200.C mg Colloidal silica 17.0 mg Stearic acid 4.0 mg Gelatine 4.0 mg 20 Glycerol 1.6 mg Maize starch 52.0 mg Magnesium stearate 1.4 mg for one tablet E ~PLE 34 Capsules Compound of formula (I)100.0 mg Lactose 120.0 mg Rice starch 30.0 mg ~laize starch 30.0 mg 30 Magnesium stearate 5.0 mg Gelatine ) 78.0 mg ) envelope Tartrazine ) 0.2 mg for one capsule EX~MPLE 35 . , . _ . . ~_ Compound of formula (I) 300 mg Witepsol H 12 mass (*) 600 mg for one suppository (*) a mixture of triglycerldes and partial gl~Jcerides of saturated fa-t-ty acids (C12-C1~) originating from plants, furnished by Dynamlt Nobel AG~ Koln-MUlhe:Lm, Wester Germany.
vi_1 Compound of Pormula (I) 20.0 mg Natrium chloride 85.0 mg Distilled water to form 10.0 ml for one ~ial.
10 g of the starting chlorinated compounds o~
formula (II) are placed in a flask with 30-40 ml of toluene and 15 ml of ~-methylpiperazine. The mixture is heated under boiling and reflux conditions during 4 hours. After cooling, the solution is evaporated under reduced pressure. 20 ml of water and 20 ml of NaOH (10%) are added and the resulting mixture is extracted with CHCl3. The chloroform solution is dried and then evaporated under reduced pressure. The residue is recrystallized from -the appropriate solvent.
TABLE V
__.
Compound o~ Y~eld Mel-ting poin-t Recris-tallization Example 5' C' solvent =
7 75 1~ 2 a 8 80 112-113 a 9(H~l) 65 ~ 250 (dec) 10(2 HCl) 60 ~ 220 (dec) b (H2S4~ 65 > 250 (dec) b 12(2 HCl) 60 223.5-225 b 13 65 109.5-111 a 14 80 118 119.5 a 90 91.5 a (a) petroleum ether (100-140C) (b~ precipitation of -the hydrochloride from a solution in acetone.
~Xil 6 ~S - ~
Theqe examples illu~trate ~he preparation of the ~ollowing compou~d~ :
4-(4'-isopropyl~ piperazinyl~-pyridin~-3 sul~o~amide (Exam~le 16) 4-(4'-isopropyl-1'-piperazi~yl~-pyridine-3-methylsul~onamid~
(Example 17) 4-(4'-isopropyl-1'-piperazinyl)-pyridine~3-dLm~thylsulIo~-amlde (Example 18) 4~(4'-isopropyl-1'-piperazinyl)-pyridine-3-e~thylsul~onamide (Example 19) 4 (4'-isopropyl-1'-piper~zinyl)-pyridlne-3-die~hylsulfon-amide ~Example 20) 4-(4'-isopropyl-1'-piperazinyl~-pyridine~3~pyrrolidino~ul fon~ (Ex.ample 21) 4-(4'-isopropyl~1t-piperazlnyl~-pyridine 3-pi~ridinosul~one (Example 22~
4_ ( 4 ~ opropyl-1'-piperazinyl)-pyridine-3-morpholinosulfone (Example 23) 4 (4l-isopropyl-1'-piperazinyl)-pyridine-3-(N-methylpipera-zinyl)-sulfone (Example 24~
These compounds are prepared by -the same method as the compounds of examples 7 to 15, using N-isopropylpipera-zine instead o~ N-methylpiperazine.
The obtained compounds recrystallized frorn petroleum ether have the following melting points TABLE: VI
rt ~O
16 (HCl) 283-284 17 97-98.5 19 84-85.5 22 68.~-69.5 23 130.5-131~5 EXAMPLES 25-3 ?
These examples illustrate the preparatlon o~ the following compound~ :
4-(4'-hydroxyethyl~ piperazinyl)-pyridine-3-sulfonamide (Example 25) 4-(4'-hydroxyethyl-1'-piperazlnyl)-pyridine-3 ethylsulfon-amide (Example 26) 4-(4'-hydroxyethyl-1 ? piperazinyl)-pyridine-3-d~ethylsul-fonamide (Example 27) 4-(4'-hydroxyethyl-1'-piperazinyl)-pyridine-3-isopropyl-sulonamide (Example 28) 4-(4'-hydroxyethyl-1'-piperazinyl)~--pyridine-3-piperidino-sulfone (Example 29) 4-(4~-hydroxye-thyl~ piperazj.myl) pyridlne-3-morpholino~
sulfone (Example 30) 4-(4'~hydroxyethyl-1'-piperazinyl)-pyridine~3-pyrrolidino-sul~one ~xample 31) The above-cited compounc1s are prepared by the same me-thod as the compounds of examples 7~15, using N-hydroxy-ethylpiperazine instead of N-methylp~perazine.
Particulars of said compounds are set ou-t in the followlng table :
TABLE VII
Compound of Yield Meltlng point Recrystallizat~on Example % C solvent - . . . .
222~5 a 26 80 119-120 b 27 60 ~ c (285-290~/Oo1 mm) 28 75 93 b 29 75 116-117~5 b 82.5-84 d 31 75 95-96.5 b (a~ water-alcohol (b) petroleum ether - b.p. 100-140C
(c) distilled under vacuum (d) benzene-hexane Examples of compositions for use according to this invention are given hereinafter :
EXA~PLE 32 Dragees Core ~
Compound of formula (I) 50.0 mg 30 ColloIdal silica 5.0 mg Lactose 42.5 mg Polyvldone 3 5 ~g - 13 _ Glycerol 0.5 mg Maize starch 8.0 mg Talc 10.Q mg Magnesium stearate 0.5 mg Coatin~ :
Gum lac 2.0 mg Gum arabic 5.4 mg New-Coccine 0.1 mg Talc 13.0 mg 10 Colloida~ silica 9.5 mg Saccharose 50.0 mg for one dragee Tablets Core :
Compound of formula ~I)200.C mg Colloidal silica 17.0 mg Stearic acid 4.0 mg Gelatine 4.0 mg 20 Glycerol 1.6 mg Maize starch 52.0 mg Magnesium stearate 1.4 mg for one tablet E ~PLE 34 Capsules Compound of formula (I)100.0 mg Lactose 120.0 mg Rice starch 30.0 mg ~laize starch 30.0 mg 30 Magnesium stearate 5.0 mg Gelatine ) 78.0 mg ) envelope Tartrazine ) 0.2 mg for one capsule EX~MPLE 35 . , . _ . . ~_ Compound of formula (I) 300 mg Witepsol H 12 mass (*) 600 mg for one suppository (*) a mixture of triglycerldes and partial gl~Jcerides of saturated fa-t-ty acids (C12-C1~) originating from plants, furnished by Dynamlt Nobel AG~ Koln-MUlhe:Lm, Wester Germany.
vi_1 Compound of Pormula (I) 20.0 mg Natrium chloride 85.0 mg Distilled water to form 10.0 ml for one ~ial.
Claims (10)
1. A process for the preparation of new derivates of pyridine of the following formula:
in which R1, which may be in the 3-position or in the 5-position represents :
a mono-alkylcarboxamido group in which the alkyl radical con-tains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sulfone or homopiperidinosulfone group, or a substituted C1 - C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1 - C3 alkoxy or a methyl-piperazinyl group, when R2 which may be in the 2-, 4- or 6-position represents a C1 - C3 - alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position re-presents :
a sulfamoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contains 1 to 3 carbon atoms, or a piperdinosulfone, morpholinosulfone, pyrrolidinosulfone or N-methylplperazinylsulfone group, when R2, which may be in the 2-, 4- or 6-position represents an isopropylpiperazinyl or hydroxyethylpiperazinyl group, said process comprising reacting a compound of the formula wherein R1 has the above meanings and X, which may be in the 2-, 4- or 6-position represents a halogen, with respectively a C1-C3-alkylpiperazine or with isopropylpiperazine or hydroxyethylpiperazine , the obtained compound of formula (I) being converted, if desired, into an acid addition salt.
in which R1, which may be in the 3-position or in the 5-position represents :
a mono-alkylcarboxamido group in which the alkyl radical con-tains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sulfone or homopiperidinosulfone group, or a substituted C1 - C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1 - C3 alkoxy or a methyl-piperazinyl group, when R2 which may be in the 2-, 4- or 6-position represents a C1 - C3 - alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position re-presents :
a sulfamoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contains 1 to 3 carbon atoms, or a piperdinosulfone, morpholinosulfone, pyrrolidinosulfone or N-methylplperazinylsulfone group, when R2, which may be in the 2-, 4- or 6-position represents an isopropylpiperazinyl or hydroxyethylpiperazinyl group, said process comprising reacting a compound of the formula wherein R1 has the above meanings and X, which may be in the 2-, 4- or 6-position represents a halogen, with respectively a C1-C3-alkylpiperazine or with isopropylpiperazine or hydroxyethylpiperazine , the obtained compound of formula (I) being converted, if desired, into an acid addition salt.
2. A process according to claim 1, in which a compound of formula (I), wherein R1 which is in the 3-position represents a (4-methylpiperazinyl)-ethylsulfon-amido group, whereas R2 which is in the 4-position repre-sents a methylpiperazinyl group, is prepared by reacting a compound of the formula (III) in which Hal represents a halogen atom, with methyl-piperazine.
3, A process according to claim 1, in which a compound of formula (I), wherein R1 which is in the 3-position represents a methoxyethylsulfonamido group, whereas R2 which is in the 4-position represents a methyl-piperazinyl group, is prepared by reacting a compound of the formula (IV) in which Hal represents a halogen atom, with methylpiperazine.
4. A process according to claim 1, in which a compound of the formula (I), wherein R1 which is in the 3-position represents an ethoxyethylsulfonamido group, whereas R2 which is in the 4-position represents a methyl-piperazinyl group, is prepared by reacting a compound of the formula :
(V) in which Hal represents a halogen atom, with methylpiperazine.
(V) in which Hal represents a halogen atom, with methylpiperazine.
5. A process according to claim 1, in which a compound of -the formula (I), wherein R1 which is in the 3-position represents a methylcarboxamido group, whereas R2 which is in the 2-position represents a methylpiperazinyl group, is prepared by reacting a compound of the formula :
(VI) in which Hal represents a halogen atom, with methylpiperazine.
(VI) in which Hal represents a halogen atom, with methylpiperazine.
6. New derivatives of pyridine represented by the following formula :
in which R1, which may be in the 3-position or in the 5-position represents :
a mono-alkylcarboxamido group in which the alkyl radical contains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sulfone or homopiperidinosulfone group, or a substituated C1-C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1-C3 alkoxy or a methylpiperazinyl group, when R2, which may be in the 2-, 4- or 6-position repre-sents a C1-C3-alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position represents a sulfamoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contains 1 to 3 carbon atoms, or a piperidinosulfone, morpholinosulfone, pyrrolidinosulfone or N-methylpiperazinylsulfone group, when R2, which may be in the 2-, 4- or 6-position represents an isopropylpipera-zinyl or hydroxyethylpiperazinyl group, as well as the acid addition salts of the compounds of formula (I), when prepared by the process according to claim 1.
in which R1, which may be in the 3-position or in the 5-position represents :
a mono-alkylcarboxamido group in which the alkyl radical contains 1 to 5 carbon atoms, a pyrrolidinosulfone, piperidinosulfone, methylpiperidino-sulfone or homopiperidinosulfone group, or a substituated C1-C3-alkylsulfonamido group in which the alkyl radical is substituted by a C1-C3 alkoxy or a methylpiperazinyl group, when R2, which may be in the 2-, 4- or 6-position repre-sents a C1-C3-alkylpiperazinyl group ;
or R1, which may be in the 3-position or in the 5-position represents a sulfamoyl group, a monoalkylsulfonamido or dialkylsulfonamido group, in which the alkyl radical contains 1 to 3 carbon atoms, or a piperidinosulfone, morpholinosulfone, pyrrolidinosulfone or N-methylpiperazinylsulfone group, when R2, which may be in the 2-, 4- or 6-position represents an isopropylpipera-zinyl or hydroxyethylpiperazinyl group, as well as the acid addition salts of the compounds of formula (I), when prepared by the process according to claim 1.
7. 4-4'-methyl-1'-piperazinyl-pyridine-3-(4"-methyl-1" -piperazinyl)-ethylsulfonamide, when prepared by the process according to claim 2,
8. 4-(4'-methyl-1'-piperazinyl)-pyridine-3-methoxyethylsulfonamide, when prepared by the process according to claim 3.
9. 4-(4'-methyl-1'-piperazinyl)-pyridine-3-ethoxyethylsulfonamido, when prepared by the process according to claim 4.
10. 2-(4'-methyl-1'-piperazinyl)-pyridine-3-methylcarboxamide, when prepared by the process according to claim 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1509474 | 1974-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1051888A true CA1051888A (en) | 1979-04-03 |
Family
ID=10052924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,696A Expired CA1051888A (en) | 1974-04-04 | 1975-04-02 | Piperazinyl-pyridine compounds |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS50140469A (en) |
| BE (1) | BE827326A (en) |
| CA (1) | CA1051888A (en) |
| DE (1) | DE2514334A1 (en) |
| ES (1) | ES436109A1 (en) |
| FR (1) | FR2266506A1 (en) |
| LU (1) | LU72195A1 (en) |
| NL (1) | NL7503975A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6635765B2 (en) | 2000-03-20 | 2003-10-21 | Teva Pharmaceutical Industries, Ltd. | Processes for preparing torsemide intermediate |
| US7423147B2 (en) | 2004-03-31 | 2008-09-09 | Janssen Pharmaceutical, N.V. | Pyridine compounds as histamine H3 modulators |
| US7777031B2 (en) | 2006-05-30 | 2010-08-17 | Janssen Pharmaceutica Nv | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US8883776B2 (en) | 2007-11-20 | 2014-11-11 | Janssen Pharmaceutica N.V. | Cycloalkyloxy- and heterocycloalkyloxypyridine compounds as modulators of the histamine H3 receptor |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4994456A (en) * | 1989-03-01 | 1991-02-19 | Nisshin Flour Milling Co., Ltd. | Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same |
| DE19918021C1 (en) | 1999-04-21 | 2000-06-29 | Ruetgers Organics Gmbh | Preparation of chlorinated pyridine sulfonic acid chloride derivatives from hydroxypyridine sulfonic acids and phosphorus trichloride/chlorine gas; useful as intermediates for drugs, e.g. torasemide |
| WO2005118543A1 (en) * | 2004-06-03 | 2005-12-15 | Ono Pharmaceutical Co., Ltd. | Kinase inhibitor and use thereof |
| JP2007031391A (en) * | 2005-07-29 | 2007-02-08 | Koei Chem Co Ltd | Method for producing alkylaminopyridine carbonitrile |
-
1975
- 1975-03-27 ES ES436109A patent/ES436109A1/en not_active Expired
- 1975-03-28 BE BE154892A patent/BE827326A/en unknown
- 1975-04-02 DE DE19752514334 patent/DE2514334A1/en not_active Withdrawn
- 1975-04-02 CA CA223,696A patent/CA1051888A/en not_active Expired
- 1975-04-02 LU LU72195A patent/LU72195A1/xx unknown
- 1975-04-02 FR FR7510222A patent/FR2266506A1/en not_active Withdrawn
- 1975-04-03 NL NL7503975A patent/NL7503975A/en not_active Application Discontinuation
- 1975-04-04 JP JP4175475A patent/JPS50140469A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6635765B2 (en) | 2000-03-20 | 2003-10-21 | Teva Pharmaceutical Industries, Ltd. | Processes for preparing torsemide intermediate |
| US6670478B2 (en) | 2000-03-20 | 2003-12-30 | Teva Pharmaceutical Industries, Ltd. | Process for preparing torsemide intermediate |
| US7423147B2 (en) | 2004-03-31 | 2008-09-09 | Janssen Pharmaceutical, N.V. | Pyridine compounds as histamine H3 modulators |
| US7947718B2 (en) | 2004-03-31 | 2011-05-24 | Janssen Pharmaceutica Nv | Isoxazole compounds as histamine H3 modulators |
| US7777031B2 (en) | 2006-05-30 | 2010-08-17 | Janssen Pharmaceutica Nv | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US8637520B2 (en) | 2006-05-30 | 2014-01-28 | Janssen Pharmaceutica Nv | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US8940731B2 (en) | 2006-05-30 | 2015-01-27 | Janssen Pharmaceutica Nv | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US9321729B2 (en) | 2006-05-30 | 2016-04-26 | Janssen Pharmaceutica Nv | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US8883776B2 (en) | 2007-11-20 | 2014-11-11 | Janssen Pharmaceutica N.V. | Cycloalkyloxy- and heterocycloalkyloxypyridine compounds as modulators of the histamine H3 receptor |
Also Published As
| Publication number | Publication date |
|---|---|
| LU72195A1 (en) | 1975-08-20 |
| JPS50140469A (en) | 1975-11-11 |
| ES436109A1 (en) | 1977-01-01 |
| NL7503975A (en) | 1975-10-07 |
| FR2266506A1 (en) | 1975-10-31 |
| BE827326A (en) | 1975-09-29 |
| DE2514334A1 (en) | 1975-10-09 |
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