CA1305482C - Piperidine derivatives, their preparation and their application in therapy - Google Patents
Piperidine derivatives, their preparation and their application in therapyInfo
- Publication number
- CA1305482C CA1305482C CA000572857A CA572857A CA1305482C CA 1305482 C CA1305482 C CA 1305482C CA 000572857 A CA000572857 A CA 000572857A CA 572857 A CA572857 A CA 572857A CA 1305482 C CA1305482 C CA 1305482C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- hydrogen
- halogen
- bond
- 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 - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
ABSTRACT
A compound which is a piperidine derivative of formula (I) (I) in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R1, which is identical to R, is hydrogen or a halogen, either R1 is H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
A compound which is a piperidine derivative of formula (I) (I) in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R1, which is identical to R, is hydrogen or a halogen, either R1 is H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
Description
f~
PIPERIDINE DERIVATIVES, THEIR PREPARATION
AND THEIR APPLICATION IN THERAPY
The present invention relates to piperidine derivatives, their preparation and their application in therapy.
The present invention provides a compound of formula 5 (I) as shown in Appendix 1, in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R), which is identical to R, is hydrogen or a : halogen, : either R1 is H or OH and R2 is H, or Rl and R2 together denote a bond, R3 is hydrogen or (Cl_4 )alkyl, and R4 is H or OH, including tautomeric forms thereof, 15~ : or a pharmaceutically acceptable acid addition salt thereof.
When R~ is OH, the tautormeric forms of the compounda:~, as~lllust~rated in Appendix 1, form part of the ; :inventlon.
:
:~ ~
:
,~ ,. ,, ,.
~: ~
' ., 5~
Pref~rr~d compo~nds are those in which n is 2, R and R' are flu~ine, ~ is in the 4-position and/or R3 is methyl. Exa~ple~ D~ ~Dmpounds of formula (I~ are shown in the follo~ing tabl~
Compound n _ R ' R1 ¦ R2 R3 R4 M . p . ~ C ) s a l t . _ . . _ ~ . __ 1 2 H ~ OH H H H 7fi __ _ __ . . . .
PIPERIDINE DERIVATIVES, THEIR PREPARATION
AND THEIR APPLICATION IN THERAPY
The present invention relates to piperidine derivatives, their preparation and their application in therapy.
The present invention provides a compound of formula 5 (I) as shown in Appendix 1, in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R), which is identical to R, is hydrogen or a : halogen, : either R1 is H or OH and R2 is H, or Rl and R2 together denote a bond, R3 is hydrogen or (Cl_4 )alkyl, and R4 is H or OH, including tautomeric forms thereof, 15~ : or a pharmaceutically acceptable acid addition salt thereof.
When R~ is OH, the tautormeric forms of the compounda:~, as~lllust~rated in Appendix 1, form part of the ; :inventlon.
:
:~ ~
:
,~ ,. ,, ,.
~: ~
' ., 5~
Pref~rr~d compo~nds are those in which n is 2, R and R' are flu~ine, ~ is in the 4-position and/or R3 is methyl. Exa~ple~ D~ ~Dmpounds of formula (I~ are shown in the follo~ing tabl~
Compound n _ R ' R1 ¦ R2 R3 R4 M . p . ~ C ) s a l t . _ . . _ ~ . __ 1 2 H ~ OH H H H 7fi __ _ __ . . . .
2 2 H H OH H H OH 240-24 fumarate j ..... _ . , 3 2 , ~. _ CH HCH3 OH 163-165 _ 4 2 ~ H H O~ ¦ H CH3 H 211-212 HCl . ~ . _ __ 2 i H I ~ b o n d CU3 OH 177-180 _ 6 2 ~ H ¦ H bond CH3 H 98-100. . , _ __ .
~ 7 2 I F q_F O~ HCH3 OH 166-167 _ , ____ _ ,b 2 F 4-FOU ¦ U CH3 H 170-173 _ .
9 2 F 4-Fbond CH3 H 187-189 umarate : - _ _ __ ~ . , . . _ _ I0 2 4-F~bond CH3 OH 164-165 : : _ _ . _ 11 2 F 4-F tl H ~H3 OH 190-192 oxalate _ ~- ~ _ .:- . .
: 12 ~ F 4-F ~ H CH3 ~ 222-225 HCl _ ~ . _ . _~ _ .- . ~ .....
: 13 2 F 4-~ H: ~ H H 161-163 fumarate ~: ~ _ +--_ _ _ _ 14 2 ~ ! 4-F ~ H U OH 234-235 HCl .
i : :
:
.
::
. .
~3~S~
.. .. . _ Compound n ¦ R R' Rl ¦ R2 r~3 R4 M.p.(C3 I salt _ ___ _ _ _ _ _ .
li 2 _ 3-F OH ! H Cd3 OH lZ3-125 _ 16 2 F 3-F bond CH3 O~ 114-116 17 3 F 4-F OH ~ H C~13 H 206-207 oxalate 18 3 F 4-F bon~ CH3 H 171-172 fumarate _ __ 19 3 F 4-Fbond C1~3 OH 211-213 fumarate _ _ __ _ _ , 3 F 4-~ OH H t:H3 OH 144-146 - ._ _ _ . _ 21 4 F 4-F bond ~:H3 OH 124-126 _ _ _ _ _ _ __ _ __ _ ___ r According to the invention, a compound of formula lO ~I) may be prepared according to the reaction scheme shown in Appendix 2.
The compound of formula (I) may be prepared by reacting a compound of formula (IV) in which R, R', ~1' R2 and R3 are as defined above with either 2-chloropyrimidine 15 or 2-methylthio-4-pyrimidinone in a protic or aprotic solvent.
A compound of formula (III) in which R, R', R1 and ~R2 are as defined above and R5 is cyano and n' is l, 2 or 3 : or R5 is phthalimido or NR3Trit, in whi~h R3 is hydrogen or 20 (C1 ~alkyl and Trit is triphenylmethyl, and n' is 2, 3 or 4, is hydrogenated in~the presence of Raney nickel if R5 is cyOno, or hydrolyJed In the preser,ce Df hydrarine if ~(5 ~3~S4~2 is phthalimido or in the presence of hydrochloric acid if R5 is NR3Trit, to obtain the compound of formula (IV).
The compound of formula (III) may be prepared by reacting a compound of formula (II) in which R, ~, R1 and R2 are defined above with a compound of formula ~-tCH2 )n ~ -Rs in which X is a labile group, for example chlorine or bromine, and n' and R5 are as defined above.
The ~tarting comp~unds of formula (II) are piperidines described in the literature, for example in US
10 Patent 2,804,422 and Belgian Patent 836,394.
The compounds of formula X-(C~2 )n ~~5 are described in J.D.Billimoria and K.O.Lewis, J. Chem. Soc, 1404, 1968.
A compound of formula (I) in which R~ and R2 together deno~e a bond may also be obtained from the 15 corresponding compound of formula (I) in which Rl is OH and R2 is ~t by dehydration in a strong acid medium.
The compounds of the invention may be useful for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, allergies, vascular or 20 gastrointestinal spasms, hypertension and platelet aggregation, and as antiemeticsu Some compounds also possess antihistaminic activity.
The daily dosage generally ran~es from 5 to 200 mg The compounds of the invention may be administered 25 orally or parenterally.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.
' .
~ ~D~
The present invention further provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, especially for use in a method of treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihi 5 taminic compound.
Finally the present invention provides the use of a compound of formula ~I) in the manufacture of a medicament for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihistaminic compound~
The Examples which follow further illustrate the invention.
The analyses and the IR and NMR spectra confirm the ~tructure of the compounds.
Exa~ple 1. a~-Dipheny~ 2-lpyrimidinylamino)eth 4-piperidinemethanol.
1.1. 2-12-[4-(Hydroxydiphenylmethyl)-l-piperidinyll-ethyl]-1,3~ ,2H~-isoindoledione.
A mixture of 15 g (0.056 mole) of ~,a-diphenyl-4-piperidinemethanol, 14O5 g (0.056 mole) of 2-(2-bromoethyl)-1,3-(lH,2H)isoindoledione and 6.7 g (0.063 mole) of sodium carbonate in 150 ml of methyl isobutyl ketone is brought to refluxing temperature for :: :
.
~3(~S~
~ 7 2 I F q_F O~ HCH3 OH 166-167 _ , ____ _ ,b 2 F 4-FOU ¦ U CH3 H 170-173 _ .
9 2 F 4-Fbond CH3 H 187-189 umarate : - _ _ __ ~ . , . . _ _ I0 2 4-F~bond CH3 OH 164-165 : : _ _ . _ 11 2 F 4-F tl H ~H3 OH 190-192 oxalate _ ~- ~ _ .:- . .
: 12 ~ F 4-F ~ H CH3 ~ 222-225 HCl _ ~ . _ . _~ _ .- . ~ .....
: 13 2 F 4-~ H: ~ H H 161-163 fumarate ~: ~ _ +--_ _ _ _ 14 2 ~ ! 4-F ~ H U OH 234-235 HCl .
i : :
:
.
::
. .
~3~S~
.. .. . _ Compound n ¦ R R' Rl ¦ R2 r~3 R4 M.p.(C3 I salt _ ___ _ _ _ _ _ .
li 2 _ 3-F OH ! H Cd3 OH lZ3-125 _ 16 2 F 3-F bond CH3 O~ 114-116 17 3 F 4-F OH ~ H C~13 H 206-207 oxalate 18 3 F 4-F bon~ CH3 H 171-172 fumarate _ __ 19 3 F 4-Fbond C1~3 OH 211-213 fumarate _ _ __ _ _ , 3 F 4-~ OH H t:H3 OH 144-146 - ._ _ _ . _ 21 4 F 4-F bond ~:H3 OH 124-126 _ _ _ _ _ _ __ _ __ _ ___ r According to the invention, a compound of formula lO ~I) may be prepared according to the reaction scheme shown in Appendix 2.
The compound of formula (I) may be prepared by reacting a compound of formula (IV) in which R, R', ~1' R2 and R3 are as defined above with either 2-chloropyrimidine 15 or 2-methylthio-4-pyrimidinone in a protic or aprotic solvent.
A compound of formula (III) in which R, R', R1 and ~R2 are as defined above and R5 is cyano and n' is l, 2 or 3 : or R5 is phthalimido or NR3Trit, in whi~h R3 is hydrogen or 20 (C1 ~alkyl and Trit is triphenylmethyl, and n' is 2, 3 or 4, is hydrogenated in~the presence of Raney nickel if R5 is cyOno, or hydrolyJed In the preser,ce Df hydrarine if ~(5 ~3~S4~2 is phthalimido or in the presence of hydrochloric acid if R5 is NR3Trit, to obtain the compound of formula (IV).
The compound of formula (III) may be prepared by reacting a compound of formula (II) in which R, ~, R1 and R2 are defined above with a compound of formula ~-tCH2 )n ~ -Rs in which X is a labile group, for example chlorine or bromine, and n' and R5 are as defined above.
The ~tarting comp~unds of formula (II) are piperidines described in the literature, for example in US
10 Patent 2,804,422 and Belgian Patent 836,394.
The compounds of formula X-(C~2 )n ~~5 are described in J.D.Billimoria and K.O.Lewis, J. Chem. Soc, 1404, 1968.
A compound of formula (I) in which R~ and R2 together deno~e a bond may also be obtained from the 15 corresponding compound of formula (I) in which Rl is OH and R2 is ~t by dehydration in a strong acid medium.
The compounds of the invention may be useful for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, allergies, vascular or 20 gastrointestinal spasms, hypertension and platelet aggregation, and as antiemeticsu Some compounds also possess antihistaminic activity.
The daily dosage generally ran~es from 5 to 200 mg The compounds of the invention may be administered 25 orally or parenterally.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.
' .
~ ~D~
The present invention further provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, especially for use in a method of treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihi 5 taminic compound.
Finally the present invention provides the use of a compound of formula ~I) in the manufacture of a medicament for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihistaminic compound~
The Examples which follow further illustrate the invention.
The analyses and the IR and NMR spectra confirm the ~tructure of the compounds.
Exa~ple 1. a~-Dipheny~ 2-lpyrimidinylamino)eth 4-piperidinemethanol.
1.1. 2-12-[4-(Hydroxydiphenylmethyl)-l-piperidinyll-ethyl]-1,3~ ,2H~-isoindoledione.
A mixture of 15 g (0.056 mole) of ~,a-diphenyl-4-piperidinemethanol, 14O5 g (0.056 mole) of 2-(2-bromoethyl)-1,3-(lH,2H)isoindoledione and 6.7 g (0.063 mole) of sodium carbonate in 150 ml of methyl isobutyl ketone is brought to refluxing temperature for :: :
.
~3(~S~
5 hours.
After eYaporation of the solvent, the residue is taken up ~ith ~ater and chloroform. The organic phase is washed with ~ater, dr;ed, filtéred and evaporated.
S An oil is obtained, ~hich crystall~es after purificat;on on a sil;ca column. A product meLting at 166-169C is obtained.
la2~ 1-(2-Aminoethyl)-a,~diphenyl-4 piperidinemethanol.
A soLution of 11~7 9 ~0~026 mole) of ~he above derivative in 200 ml of methanol containing 1.3 ml of hydrazine is stirred for 12 h at room temperature. The mixture is evaporated to dryness and the residue ~aken up ~ith ~ater and acidified ~ith hydrochloric acid. The insoluble material is filtered off and the aqueous phase then extracted with methylene chloride.
The aqueous phase is alkalinized and extracted ~ith methylene chloride~ The organîc phase is ~ashed ith ~a~er, dried, fileered and evaporated.
A white product melting at 164-1~6C is obtained.
20 ~1.3. c~a-Diph~enyl~ Z-(2-pyrimid;nylamino)ethyl~-4-pip~ridinemethanol.
2 9 (6.4 x 10 3 mole) of 1-t2-~minoethyl)-~,~
: : :
diphenyl-4-pipèridinemethanol is brought to reflux for 20 h ~ith 0.75 9 (6.5 x 10 3 mole3 of 2-chLoropyrimidine and 0O56 9 of ~odium bicarbonate in 25 ml of ethanol.
:
The m;xture is evaporated under vacuum and the residue taken up with methylene chloride and ~ater. The : ' i 4~
organic phase is dried, filtered and evapora~ed.
Atter chromatographic purification of the re-sidual oil, a solid product melting at 76C is obtained.
Example 2. 2-{[2-{4-t~ist4-fluorophenyl~methyl]-l~
piperidyl}ethyl~a~ino}-4(1H)-pyrimidinone.
2.1. 2-{4-l~is(4-fluorophenyl)~ethyl]-1-piperidyl}ethane-ni~rile.
A mixture of 28.7 9 (0~1 mole) of 4-~bist4-fluoro-phenyl)methyl~piperidine, 11.7 9 (û.11 mole) of sodium carbonate, ~.3 ml (0.1 mole) of 2-chloroethanenitrile and a fe~ crystaLs of sodiu~ ;odide in 150 ml of methyl isobutyl ketone is heated to reflux for 4 h.
The reaction mi~ture is evaporated and the resi-due taken up ~;th methylen~ chloride ~nd ~ater, The organic phase i5 dr;ed, filtered and evaporated.
The residual oil crystallizes in isopropyL ether.
(M.p. 114-116C).
2.2. 2-{4-~9ist4-fluorophenyl)~ethyl~ piperidyl}-ethanamine.
20 ~ 11.0 g t3.4 x 10 2 mole) of the above product~
dis~olved in 150 ml of ethanol saturated ~ith ~mmonia, is hydro9enated at ROOC in the presence of Raney nickel under a hydrog~n pressure of 60 bars.
~ hen the absorpt;on of hydrogen is complete, the catalyst ;s filtered of~ ~nd the residue evaporated to dryness.
The residual oil is distilled. (8.p~ 180C
:
' ':
~3~`5~
under 0.05 mm of mercury).
~.3~ 2-[[2-~4-C~;s(4-fluorophenyl)methyl~-1-piperidyL}-ethyllamino}-4~1H)-pyrimidinone.
2 9 (1.4 x 10 2 mole) of S-methyLthiouracil and 4.6 g ~1.4 x 10 ~ mols) of 2-{4-~bis(4-fLuorophenyL)-~ethyl~ piperidyl~ethanamine in 75 ml of toluene is heated under reflux for 48 h under an ~rgon atmopshere.
The solvent is evaporated off and the residual oil purified by chromatography on a sil;ca column.
The hydrochloride is prepare~ in isopropanol.
(M.p. 234-237C).
E~an~Le 3. 2-{~2-{4-C8is(4-fluorophenyl)methylene3-1-piperidyl}ethyl]methylamino}-4(1H)-pyrim;dinone.
3.1. 4-C~is(4-fluorophenyl)methylene]-N-methyl-1-piperi-dineethanamine.
14.3 9 (0.05 mole) of 4-~bist4-fluorophenyl)-~ethylene]p;peridine and 9.5 9 (0.025 mo~e) of 2-bromo-N-~ethyl-N-(triphenylmethyl)ethanamine dissolved in 7~ ml of toluene are heated to reflux.
~hen the reaction is complete, the mi~ture is cool~d and the precipitate filtered off. The filtrate is ~vaporated and the residua~ oil taken up ~ith 250 ml of N HCl. The ~ixture is heated to 50C for 1 h and left standing overnight, and the precipitate is filtered off. The f;ltrate is extracted ~ith ether and the aqueous phase is then alkalini~ed w;th sodium hydroxide and extr~cted with methylene chloride. The org~nie 131..~S~Z
_ g _ phase is washed ~ith water~ dried, filtered and evaporated.
A product is obtained in the form of an o;l, ~h;ch is used in the crude state for the next stage of 5 the synthesis.
3.2. 2-{~2-{4-t~is~4-fluorophenyl~methylene]-1-piperi-dyl}ethyllmethylamino~-4t1H)-pyrim;dinone.
1 9 (2.~ x 10 3 mole) of the above amine, dis-solved in S0 ~l of toluene, is heated to reflux under 1n argon for 48 h with 0.5 g (2.9 x 10 3 mole) of S-(methyl)-thiourac;l~ The solution i5 evaporated to dryness ~nd the residual oil puritied by chromatography on a silica column. A product melting at 164-165C ;s ob~ained.
: Example 4. 1-{2-lMethyl-(2-pyrimidinyl)amino]ethyl}-~, ~-di-phenyl-4-piperidinemethanol.
4.1. 1-C2-(Methyla~ino)ethyl]-~-diphenyl-4-piperi-d;nemethanol.
A m;xture of 26.7 9 (0.1 mole) of ~ diphenyl-piperidinemethanoL, 38 ~ (0.1 mole) of N-methyl-N-tri-20~- tyl-2-bromoethanamine and 8.4 9 (0.1 ~ole) of sodium : : bicarbonate in 400 ~l of methyl isobutyl ketone is heated to reflux for:48 h. ~he mixture is then filtered ~hile .
boilin~ and the filtrate left to stand, the precipitate ~obtained is filtered oft and dried.
25: M.p. 202-205~C.
: The precipitate is taken up ~i~h 300 ml of N HCl and stirred for 4 h at room:temperature. The mixture is :: :
~ :
~31~5~
filtered and the prec;pitate ~ashed with water.
The filtrate ;s alka~;nized ~;th concentrated sodium hydroxide and extract~d ~ith methylene chloride.
The organic phase ;s ~ashed ~;th water, dr;ed, filtered S and evaporated~ A product ~elting at 168-170C is obtained.
4.2. 1-C2-~Me~hyl-(2-pyrimidinyl)amino~ethyl}-~,a-di-phenyl-4-p;peridinemethanol.
4.9 9 tO.015 mole~ of 1-C2-(nethyLam;no)ethyl-N,~-diphenyl-4-piperidinemethanol, 1.7 g (0.015 mole~ of 2-chloropyri~idine and 1.3 9 of sodium bicarbonate in 75 ml of ethanol are brought to refLux under an argon atmosphere~ Refluxing is maintained for 24 h and the mixture is cooled and filtered. ~he filtrate is eYapora-1S ted~ the res;due taken up with ether and the organic phase ~ashed uith wa~er, dried, f;ltered and e~aporated.
The hydrochloride ;s prepared in ethanol.
M.p. 211-212C.
E~an~l- S. 4-(~iphenylmethylene)-N-methyi-N-(2-pyrimi-dinyl~ pip~ridineeth-namine.
: : The hydrochloride of Example 4 is taken up in 100 ml of bN hydrochloric acid and ehe ~ixture is brought ~ to reflux frJr 2 h. The solut;on is coo~ed and poured : into ice. The mixture is alkalinized ~ith sodium hy-droxide and extracted ~i~h methylene chloride. The organic phase is ~ashed ~ith water, dried, filtered and : evaporated. A product melting at ~8-100C is obtained.
Example 6. 2-~2-{4-tBis(b-fluorophenyl)hydroxyme~hyl]-1-piperidyl}~thyL~methylamino'3-4tlH)-pyrimidinone.
After eYaporation of the solvent, the residue is taken up ~ith ~ater and chloroform. The organic phase is washed with ~ater, dr;ed, filtéred and evaporated.
S An oil is obtained, ~hich crystall~es after purificat;on on a sil;ca column. A product meLting at 166-169C is obtained.
la2~ 1-(2-Aminoethyl)-a,~diphenyl-4 piperidinemethanol.
A soLution of 11~7 9 ~0~026 mole) of ~he above derivative in 200 ml of methanol containing 1.3 ml of hydrazine is stirred for 12 h at room temperature. The mixture is evaporated to dryness and the residue ~aken up ~ith ~ater and acidified ~ith hydrochloric acid. The insoluble material is filtered off and the aqueous phase then extracted with methylene chloride.
The aqueous phase is alkalinized and extracted ~ith methylene chloride~ The organîc phase is ~ashed ith ~a~er, dried, fileered and evaporated.
A white product melting at 164-1~6C is obtained.
20 ~1.3. c~a-Diph~enyl~ Z-(2-pyrimid;nylamino)ethyl~-4-pip~ridinemethanol.
2 9 (6.4 x 10 3 mole) of 1-t2-~minoethyl)-~,~
: : :
diphenyl-4-pipèridinemethanol is brought to reflux for 20 h ~ith 0.75 9 (6.5 x 10 3 mole3 of 2-chLoropyrimidine and 0O56 9 of ~odium bicarbonate in 25 ml of ethanol.
:
The m;xture is evaporated under vacuum and the residue taken up with methylene chloride and ~ater. The : ' i 4~
organic phase is dried, filtered and evapora~ed.
Atter chromatographic purification of the re-sidual oil, a solid product melting at 76C is obtained.
Example 2. 2-{[2-{4-t~ist4-fluorophenyl~methyl]-l~
piperidyl}ethyl~a~ino}-4(1H)-pyrimidinone.
2.1. 2-{4-l~is(4-fluorophenyl)~ethyl]-1-piperidyl}ethane-ni~rile.
A mixture of 28.7 9 (0~1 mole) of 4-~bist4-fluoro-phenyl)methyl~piperidine, 11.7 9 (û.11 mole) of sodium carbonate, ~.3 ml (0.1 mole) of 2-chloroethanenitrile and a fe~ crystaLs of sodiu~ ;odide in 150 ml of methyl isobutyl ketone is heated to reflux for 4 h.
The reaction mi~ture is evaporated and the resi-due taken up ~;th methylen~ chloride ~nd ~ater, The organic phase i5 dr;ed, filtered and evaporated.
The residual oil crystallizes in isopropyL ether.
(M.p. 114-116C).
2.2. 2-{4-~9ist4-fluorophenyl)~ethyl~ piperidyl}-ethanamine.
20 ~ 11.0 g t3.4 x 10 2 mole) of the above product~
dis~olved in 150 ml of ethanol saturated ~ith ~mmonia, is hydro9enated at ROOC in the presence of Raney nickel under a hydrog~n pressure of 60 bars.
~ hen the absorpt;on of hydrogen is complete, the catalyst ;s filtered of~ ~nd the residue evaporated to dryness.
The residual oil is distilled. (8.p~ 180C
:
' ':
~3~`5~
under 0.05 mm of mercury).
~.3~ 2-[[2-~4-C~;s(4-fluorophenyl)methyl~-1-piperidyL}-ethyllamino}-4~1H)-pyrimidinone.
2 9 (1.4 x 10 2 mole) of S-methyLthiouracil and 4.6 g ~1.4 x 10 ~ mols) of 2-{4-~bis(4-fLuorophenyL)-~ethyl~ piperidyl~ethanamine in 75 ml of toluene is heated under reflux for 48 h under an ~rgon atmopshere.
The solvent is evaporated off and the residual oil purified by chromatography on a sil;ca column.
The hydrochloride is prepare~ in isopropanol.
(M.p. 234-237C).
E~an~Le 3. 2-{~2-{4-C8is(4-fluorophenyl)methylene3-1-piperidyl}ethyl]methylamino}-4(1H)-pyrim;dinone.
3.1. 4-C~is(4-fluorophenyl)methylene]-N-methyl-1-piperi-dineethanamine.
14.3 9 (0.05 mole) of 4-~bist4-fluorophenyl)-~ethylene]p;peridine and 9.5 9 (0.025 mo~e) of 2-bromo-N-~ethyl-N-(triphenylmethyl)ethanamine dissolved in 7~ ml of toluene are heated to reflux.
~hen the reaction is complete, the mi~ture is cool~d and the precipitate filtered off. The filtrate is ~vaporated and the residua~ oil taken up ~ith 250 ml of N HCl. The ~ixture is heated to 50C for 1 h and left standing overnight, and the precipitate is filtered off. The f;ltrate is extracted ~ith ether and the aqueous phase is then alkalini~ed w;th sodium hydroxide and extr~cted with methylene chloride. The org~nie 131..~S~Z
_ g _ phase is washed ~ith water~ dried, filtered and evaporated.
A product is obtained in the form of an o;l, ~h;ch is used in the crude state for the next stage of 5 the synthesis.
3.2. 2-{~2-{4-t~is~4-fluorophenyl~methylene]-1-piperi-dyl}ethyllmethylamino~-4t1H)-pyrim;dinone.
1 9 (2.~ x 10 3 mole) of the above amine, dis-solved in S0 ~l of toluene, is heated to reflux under 1n argon for 48 h with 0.5 g (2.9 x 10 3 mole) of S-(methyl)-thiourac;l~ The solution i5 evaporated to dryness ~nd the residual oil puritied by chromatography on a silica column. A product melting at 164-165C ;s ob~ained.
: Example 4. 1-{2-lMethyl-(2-pyrimidinyl)amino]ethyl}-~, ~-di-phenyl-4-piperidinemethanol.
4.1. 1-C2-(Methyla~ino)ethyl]-~-diphenyl-4-piperi-d;nemethanol.
A m;xture of 26.7 9 (0.1 mole) of ~ diphenyl-piperidinemethanoL, 38 ~ (0.1 mole) of N-methyl-N-tri-20~- tyl-2-bromoethanamine and 8.4 9 (0.1 ~ole) of sodium : : bicarbonate in 400 ~l of methyl isobutyl ketone is heated to reflux for:48 h. ~he mixture is then filtered ~hile .
boilin~ and the filtrate left to stand, the precipitate ~obtained is filtered oft and dried.
25: M.p. 202-205~C.
: The precipitate is taken up ~i~h 300 ml of N HCl and stirred for 4 h at room:temperature. The mixture is :: :
~ :
~31~5~
filtered and the prec;pitate ~ashed with water.
The filtrate ;s alka~;nized ~;th concentrated sodium hydroxide and extract~d ~ith methylene chloride.
The organic phase ;s ~ashed ~;th water, dr;ed, filtered S and evaporated~ A product ~elting at 168-170C is obtained.
4.2. 1-C2-~Me~hyl-(2-pyrimidinyl)amino~ethyl}-~,a-di-phenyl-4-p;peridinemethanol.
4.9 9 tO.015 mole~ of 1-C2-(nethyLam;no)ethyl-N,~-diphenyl-4-piperidinemethanol, 1.7 g (0.015 mole~ of 2-chloropyri~idine and 1.3 9 of sodium bicarbonate in 75 ml of ethanol are brought to refLux under an argon atmosphere~ Refluxing is maintained for 24 h and the mixture is cooled and filtered. ~he filtrate is eYapora-1S ted~ the res;due taken up with ether and the organic phase ~ashed uith wa~er, dried, f;ltered and e~aporated.
The hydrochloride ;s prepared in ethanol.
M.p. 211-212C.
E~an~l- S. 4-(~iphenylmethylene)-N-methyi-N-(2-pyrimi-dinyl~ pip~ridineeth-namine.
: : The hydrochloride of Example 4 is taken up in 100 ml of bN hydrochloric acid and ehe ~ixture is brought ~ to reflux frJr 2 h. The solut;on is coo~ed and poured : into ice. The mixture is alkalinized ~ith sodium hy-droxide and extracted ~i~h methylene chloride. The organic phase is ~ashed ~ith water, dried, filtered and : evaporated. A product melting at ~8-100C is obtained.
Example 6. 2-~2-{4-tBis(b-fluorophenyl)hydroxyme~hyl]-1-piperidyl}~thyL~methylamino'3-4tlH)-pyrimidinone.
6.1. ~ Bist4-fluorophenyL)-1-{2-[(methyl)(triphenyL-methyl)amino~e~hyl}-4-piperidinemethanol.
S The product is prepared ~sing the process des-cribed in 4.1.~ s~arting ~;~h 22~0 9 ~0.072 mole) of ~,a-bis(4-fluorophenyl)-4-piperidinemethanoL, 27.6 9 tO.072 mole) of 2-bromo-N-methyl-N-(tr;phenyLmethyl)-ethanamine, 6.7 9 of sodium bicarbonate and 200 ml of methyl isobutyl ketone.
M.p. 100C.
6.2. ~,-Bist4-fluorophenyl)-1-~2-(methylamino)ethylJ-4-piperid;neTethanol.
The hydrolysis is carried out as in 4.1~, s~art-15 ing ~ith 41 9 tO.068 mole) of the above productO
M.p. 146-148C.
6.3. 2-~2~4-C~ist4-fluorophenyl)hydroxymethylJ-1-piperidyl~ethyl]methylamino~-4t1H)-pyrimidinoneO
The product is prepared as described in 3.~., Z0 starting ~ith 7 9 (0.02 mole) of the above product and 2.8 9 (0.02 ~ole) of S-~methyl)thiouracil in 100 ml of toluene.
M.p. 166-167C~.
:~
The compound~ o~ the ;nvention possess an anti-seroeonin activity (in respect of the 5HTZ eype receptors3.
~ his activity was de~on~trated l'in vîtro" by the S displac~ment of ligands bound specificaLLy tD sero-toninergic receptors ~SBS binding t~st), and "in vivo"
by antagonism of ~h~ ~ffec~s of serotonin at the peri-pheral level (OES tes~) and at rentral level ~AHT test).
595 Test: the compounds of the invention were subjected to a test of displace~ent of ~he binding of spiroperidol to the serotoninergic ~5-HT2) receptors of ra~ cerebral sortex.
For this testO rat brains are removed and th~
cortex is dissected out and homogenized at 0C in 10 volumes of a mixture containing, per litre, 50 millimoles of Tris/HC~ buffer at pH 7.4, 120 millimole~ of sodium chlor;de and 5 millimoles of potassium chloride. The ho~ogeneous mix~ure 15 centrifuged at 40,000 x g for 10 ~in, and the peLlet is ~hen recovered t~ice, ~ashed by suspending ie in the same buffer ~ix~ure, homogenized : ag6in ~nd centr;tuged. LastLy, the fin~l pellet is diluted in the same butfe~r mi~ture in the proportian of ~: 100 m~ of vet tissue for 1 ~l of buffer.
The tissue is then subjec~ed eO a prior 10-min Z5:~ incubation at 37C in the presence of 10 misromoles~l of pargyline, and then to a 20-min incubation at 3?S in the presence of ~3H~spiroperidol ~specific activity:
:
' ' ~3~. ~i4 25.6 Ci per millimole) at a concentration of 0.3 nano-mole/l and test compourid at concentrations ranging from 0.0001 to 100 micr~moles/L.
1-ml aliquots are removed and filtered under vacuu~, and the filters are ~ashed t~ice ~ith 5 ml of coLd buffer and dried. The radioactivity is measured in toluene ;n the presenc~ of 5 g/l of 2,5-diphenyLoxazole ~PP0) and 0.1 9/~ of 1,4-~is~5-phenyl-2-oxazolyl)benzene ( POPOP ) .
To assess the ac~ivity of the compounds, the curve is plotted for the percentage ;nhibition of the specific binding of ~3H~spiroperidol as a function of the concentration of displacing drug. The 1Cso concen-tration, ~he concentration between 50X o~ ~he specific binding, is determined graphicallyr The specific binding is defined as ~he binding dispLaced by 100 micromo~les/l of 5~HT.
The ICsa concentrat;ons of the compounds of the invention lie for the most part between 1 and 50 : 20 nano~oles/l.
OES Tests the antiserotoninergic activi~y o~ the com-.
pounds of the invention ~as aLso de~onstrated by their effect on serotonin-induLed oedema in rats, according to th~ method described by Maling et al, JO Pharmacol. Exp~
Therap., 191 (2), 300-310 t1974).
The animals are CD strain male rats tCh. River, France~ ~eighing lZ0 to 150 9, tas~ed for 18 h and t?~ 4 distributed in randomized sets.
The co~pounds, dissolved or suspended in T~een 80 at a concentration of 196, are administered orally in the proportion ot 0.5 ml for 100 9 of body-weight, 1 h before the sub-plantar injection of 1 ~9 of serotonin (dissolved in s~eril~ physiolo~ical s~line~ in a volu~e of 0.1 ml~ into one of the hind le~s. The volume of oede~a i5 measured 1 h after the injection of serotonin by means of an Ugo ~asile mercury plethysometer.
The AD40 (dose ~hich decreases by 40X the volume of the oedema, relative to the sontrol animals~ is deter~ined graphically.
The AD40 Of the compounds of the invention, de-termined orally~ is bet~een 0.1 and 2 mg/ky~
AHT Test: the antiserotoninerg;c activity of the com-pounds was studied in respect of ~heir effect on the antagonism of "head-t~itches" induced by L-5-hydroxy-trypeophan (L-S-HTP) in m;se, according to the ~ethod described by Corne ~t al, ~r~ J. Pharmacol., 20V 106-120 ~196~).
The oice (CD1 m~les, tharles River France;
18-22 9 ot body~eight~ receive the test product~ at : inçreasing doses, or the solvent, intraperiton~a~ly or orally, si~ultaneously ti.p. ad~;ni~tration) or 60 minu-tes before (oral administration) a subcutaneous injection of L~5-HTP at a dose of 250 ~g/kg. Forty-fiv~ minutes after this inject;on sf 5-HTP, the number of t~itches is -~1.3~ Z
counted, for each mouse, for l minute.
For each treatment, the mean number of twitches, as well as the percentage variation relative to the control batch, are calculated.
From the dose-response curve, the ~50 (50% active dose or dose which decreases by 50~ the mean number of twitches relative to the control animals) is determined by the graphic method of Miller and Tainter ~Proc. Soc. Exp.
Biol. Med., (1944), 57, 261).
The ADso values of the ompounds of the invention are generally from n . 05 to 2 mg/kg in~rape~itoneally and 0.1 to 4 mg/kg orally.
:: :
::
:: :
. ~
~3~
Append i x 1 .
R~ (CRz)n~N~ 4 ( I ) R' :
, : : :
: ~ ::
;: ~
:: : ~: :
, ; ' ` ' . ' ~.3~5'~
Acpendi~ 2 R ~ NH R ~ -(CH2)n-Rs R2 X(CH2)n'Rs ~ l R2 ~II) R~ (III) . R ~ N-(CH2)n-~
: / :2-chloropyrimidine-/ ~r / 2-methylthio-4-pyrimidinone ~3 -(CH2)n-N~R4 ; ~ R2 N
~ (I)
S The product is prepared ~sing the process des-cribed in 4.1.~ s~arting ~;~h 22~0 9 ~0.072 mole) of ~,a-bis(4-fluorophenyl)-4-piperidinemethanoL, 27.6 9 tO.072 mole) of 2-bromo-N-methyl-N-(tr;phenyLmethyl)-ethanamine, 6.7 9 of sodium bicarbonate and 200 ml of methyl isobutyl ketone.
M.p. 100C.
6.2. ~,-Bist4-fluorophenyl)-1-~2-(methylamino)ethylJ-4-piperid;neTethanol.
The hydrolysis is carried out as in 4.1~, s~art-15 ing ~ith 41 9 tO.068 mole) of the above productO
M.p. 146-148C.
6.3. 2-~2~4-C~ist4-fluorophenyl)hydroxymethylJ-1-piperidyl~ethyl]methylamino~-4t1H)-pyrimidinoneO
The product is prepared as described in 3.~., Z0 starting ~ith 7 9 (0.02 mole) of the above product and 2.8 9 (0.02 ~ole) of S-~methyl)thiouracil in 100 ml of toluene.
M.p. 166-167C~.
:~
The compound~ o~ the ;nvention possess an anti-seroeonin activity (in respect of the 5HTZ eype receptors3.
~ his activity was de~on~trated l'in vîtro" by the S displac~ment of ligands bound specificaLLy tD sero-toninergic receptors ~SBS binding t~st), and "in vivo"
by antagonism of ~h~ ~ffec~s of serotonin at the peri-pheral level (OES tes~) and at rentral level ~AHT test).
595 Test: the compounds of the invention were subjected to a test of displace~ent of ~he binding of spiroperidol to the serotoninergic ~5-HT2) receptors of ra~ cerebral sortex.
For this testO rat brains are removed and th~
cortex is dissected out and homogenized at 0C in 10 volumes of a mixture containing, per litre, 50 millimoles of Tris/HC~ buffer at pH 7.4, 120 millimole~ of sodium chlor;de and 5 millimoles of potassium chloride. The ho~ogeneous mix~ure 15 centrifuged at 40,000 x g for 10 ~in, and the peLlet is ~hen recovered t~ice, ~ashed by suspending ie in the same buffer ~ix~ure, homogenized : ag6in ~nd centr;tuged. LastLy, the fin~l pellet is diluted in the same butfe~r mi~ture in the proportian of ~: 100 m~ of vet tissue for 1 ~l of buffer.
The tissue is then subjec~ed eO a prior 10-min Z5:~ incubation at 37C in the presence of 10 misromoles~l of pargyline, and then to a 20-min incubation at 3?S in the presence of ~3H~spiroperidol ~specific activity:
:
' ' ~3~. ~i4 25.6 Ci per millimole) at a concentration of 0.3 nano-mole/l and test compourid at concentrations ranging from 0.0001 to 100 micr~moles/L.
1-ml aliquots are removed and filtered under vacuu~, and the filters are ~ashed t~ice ~ith 5 ml of coLd buffer and dried. The radioactivity is measured in toluene ;n the presenc~ of 5 g/l of 2,5-diphenyLoxazole ~PP0) and 0.1 9/~ of 1,4-~is~5-phenyl-2-oxazolyl)benzene ( POPOP ) .
To assess the ac~ivity of the compounds, the curve is plotted for the percentage ;nhibition of the specific binding of ~3H~spiroperidol as a function of the concentration of displacing drug. The 1Cso concen-tration, ~he concentration between 50X o~ ~he specific binding, is determined graphicallyr The specific binding is defined as ~he binding dispLaced by 100 micromo~les/l of 5~HT.
The ICsa concentrat;ons of the compounds of the invention lie for the most part between 1 and 50 : 20 nano~oles/l.
OES Tests the antiserotoninergic activi~y o~ the com-.
pounds of the invention ~as aLso de~onstrated by their effect on serotonin-induLed oedema in rats, according to th~ method described by Maling et al, JO Pharmacol. Exp~
Therap., 191 (2), 300-310 t1974).
The animals are CD strain male rats tCh. River, France~ ~eighing lZ0 to 150 9, tas~ed for 18 h and t?~ 4 distributed in randomized sets.
The co~pounds, dissolved or suspended in T~een 80 at a concentration of 196, are administered orally in the proportion ot 0.5 ml for 100 9 of body-weight, 1 h before the sub-plantar injection of 1 ~9 of serotonin (dissolved in s~eril~ physiolo~ical s~line~ in a volu~e of 0.1 ml~ into one of the hind le~s. The volume of oede~a i5 measured 1 h after the injection of serotonin by means of an Ugo ~asile mercury plethysometer.
The AD40 (dose ~hich decreases by 40X the volume of the oedema, relative to the sontrol animals~ is deter~ined graphically.
The AD40 Of the compounds of the invention, de-termined orally~ is bet~een 0.1 and 2 mg/ky~
AHT Test: the antiserotoninerg;c activity of the com-pounds was studied in respect of ~heir effect on the antagonism of "head-t~itches" induced by L-5-hydroxy-trypeophan (L-S-HTP) in m;se, according to the ~ethod described by Corne ~t al, ~r~ J. Pharmacol., 20V 106-120 ~196~).
The oice (CD1 m~les, tharles River France;
18-22 9 ot body~eight~ receive the test product~ at : inçreasing doses, or the solvent, intraperiton~a~ly or orally, si~ultaneously ti.p. ad~;ni~tration) or 60 minu-tes before (oral administration) a subcutaneous injection of L~5-HTP at a dose of 250 ~g/kg. Forty-fiv~ minutes after this inject;on sf 5-HTP, the number of t~itches is -~1.3~ Z
counted, for each mouse, for l minute.
For each treatment, the mean number of twitches, as well as the percentage variation relative to the control batch, are calculated.
From the dose-response curve, the ~50 (50% active dose or dose which decreases by 50~ the mean number of twitches relative to the control animals) is determined by the graphic method of Miller and Tainter ~Proc. Soc. Exp.
Biol. Med., (1944), 57, 261).
The ADso values of the ompounds of the invention are generally from n . 05 to 2 mg/kg in~rape~itoneally and 0.1 to 4 mg/kg orally.
:: :
::
:: :
. ~
~3~
Append i x 1 .
R~ (CRz)n~N~ 4 ( I ) R' :
, : : :
: ~ ::
;: ~
:: : ~: :
, ; ' ` ' . ' ~.3~5'~
Acpendi~ 2 R ~ NH R ~ -(CH2)n-Rs R2 X(CH2)n'Rs ~ l R2 ~II) R~ (III) . R ~ N-(CH2)n-~
: / :2-chloropyrimidine-/ ~r / 2-methylthio-4-pyrimidinone ~3 -(CH2)n-N~R4 ; ~ R2 N
~ (I)
Claims (13)
1. A compound which is a piperidine derivative of formula (I) (I) in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R', which id identical to R, is hydrogen or a halogen, either R1 id H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R', which id identical to R, is hydrogen or a halogen, either R1 id H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1 in which n is 2.
3. A compound according to claim 1 in which R and R' are fluorine.
4. A compound according to claim 1 in which R' is in the 4-position.
5. A compound according to claim 1 in which R3 is methyl.
6. A process for preparing a compound as defined in claim 1 which comprises reacting a compound of formula (IV):
(IV) in which n, R, R', R1, R2 and R3 are as defined in claim 1 with either 2-chloropyrimidine or 2-methylthio-4-pyrimidinone in a protic or aprotic solvent.
(IV) in which n, R, R', R1, R2 and R3 are as defined in claim 1 with either 2-chloropyrimidine or 2-methylthio-4-pyrimidinone in a protic or aprotic solvent.
7. A process according to claim 6 in which a compound of formula (III) (III) in which R, R', R1 and R2 are as defined in claim 1 and R5 is cyano and n' is 1, 2 or 3 or R5 is phthalimido or NR3Trit, in which R3 is hydrogen or (C1-4)alkyl and Trit is triphenylmethyl, and n' is 2, 3 or 4, is hydrogenated in the presence of Raney nickel if R5 is cyano, or hydrolysed in the presence of hydrazine if R5 is phthalimido or in the presence of hydrochloric acid if R5 is NR3Trit, to obtain the compound of formula (IV).
8. A process according to claim 7 in which the compound of formula (III) is prepared by reacting a compound of formula (II) (II) in which R, R', R1 and R2 are as defined in claim 1 with a compound of formula X-(CH2)n'-R5, in which X is a labile group and n' and R5 are as defined in claim 7.
9. A process for preparing a compound as defined in claim 1 in which R1 and R2 together denote a bond which comprises subjecting a corresponding compound of formula (I), in which R1 is OH and R2 is H, to dehydration in a strong acid medium.
10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable excipient.
11. Use of a compound of formula (I) as defined in claim 1 as a therapeutic agent for humans or animals.
12. Use of a compound of formula (I) as defined in claim 1 for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihistaminic compound.
13. Use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of migraine, anxiety, depression, obesity, inflammation, asthma, an allergy, vascular or gastrointestinal spasms, hypertension or platelet aggregation or of a condition requiring an antiemetic or antihistaminic compound.
ABSTRACT
A compound which is a piperidine derivative of formula (I) (I) in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R1, which is identical to R, is hydrogen or a halogen, either R1 is H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
ABSTRACT
A compound which is a piperidine derivative of formula (I) (I) in which:
n is 1, 2, 3 or 4, R is hydrogen or a halogen, R1, which is identical to R, is hydrogen or a halogen, either R1 is H or OH and R2 is H, or R1 and R2 together denote a bond, R3 is hydrogen or (C1-4) alkyl, and R4 is H or OH, including tautomeric forms thereof, or a pharmaceutically acceptable acid addition salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8710408A FR2618436B1 (en) | 1987-07-23 | 1987-07-23 | PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR87.10408 | 1987-07-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1305482C true CA1305482C (en) | 1992-07-21 |
Family
ID=9353448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000572857A Expired - Fee Related CA1305482C (en) | 1987-07-23 | 1988-07-22 | Piperidine derivatives, their preparation and their application in therapy |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4853387A (en) |
| EP (1) | EP0301936B1 (en) |
| JP (1) | JPS6440479A (en) |
| KR (1) | KR890002103A (en) |
| AT (1) | ATE83482T1 (en) |
| AU (1) | AU600378B2 (en) |
| CA (1) | CA1305482C (en) |
| DE (1) | DE3876711T2 (en) |
| DK (1) | DK412888A (en) |
| FI (1) | FI883483A (en) |
| FR (1) | FR2618436B1 (en) |
| HU (1) | HU198476B (en) |
| IL (1) | IL87175A (en) |
| NO (1) | NO170580C (en) |
| NZ (1) | NZ225525A (en) |
| PT (1) | PT88088B (en) |
| ZA (1) | ZA885369B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2667317B1 (en) * | 1990-10-02 | 1992-12-04 | Synthelabo | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2678271B1 (en) * | 1991-06-27 | 1995-01-13 | Synthelabo | PYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2678268B1 (en) * | 1991-06-27 | 1993-09-03 | Synthelabo | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| EP0522914A1 (en) * | 1991-06-27 | 1993-01-13 | Synthelabo | 2-Piperidinylpyrimidin-4-carboxamide derivatives, their preparation and their application in therapy |
| ATE124942T1 (en) * | 1991-06-27 | 1995-07-15 | Synthelabo | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS. |
| DE69300162T2 (en) * | 1992-07-03 | 1995-11-02 | Synthelabo | 2-Amino-N - [[[4- (aminocarbonyl) pyrimidin-2-yl] amino] alkyl] pyrimidine-4-carboxamide derivatives, their preparation and their use in therapeutics. |
| FR2696744B1 (en) * | 1992-10-12 | 1994-12-30 | Logeais Labor Jacques | 2-Pyrrolidone derivatives, their preparation process and their therapeutic applications. |
| WO2011137012A1 (en) * | 2010-04-27 | 2011-11-03 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
| WO2019005883A1 (en) * | 2017-06-26 | 2019-01-03 | University Of Virginia Patent Foundation | Compositions and uses thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4617393A (en) * | 1985-07-19 | 1986-10-14 | American Home Products Corporation | 5-substituted-6-aminopyrimidines, composition and uses as cardiotonic agents for increasing cardiac contractility |
| FR2620121B1 (en) * | 1987-09-09 | 1990-01-05 | Synthelabo | ((PYRIMIDINYL-2) -AMINOALKYL) -1 PIPERIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
-
1987
- 1987-07-23 FR FR8710408A patent/FR2618436B1/en not_active Expired
-
1988
- 1988-07-12 DE DE8888401809T patent/DE3876711T2/en not_active Expired - Fee Related
- 1988-07-12 AT AT88401809T patent/ATE83482T1/en not_active IP Right Cessation
- 1988-07-12 EP EP88401809A patent/EP0301936B1/en not_active Expired - Lifetime
- 1988-07-21 IL IL87175A patent/IL87175A/en unknown
- 1988-07-22 PT PT88088A patent/PT88088B/en not_active IP Right Cessation
- 1988-07-22 KR KR1019880009228A patent/KR890002103A/en not_active Application Discontinuation
- 1988-07-22 AU AU19717/88A patent/AU600378B2/en not_active Ceased
- 1988-07-22 US US07/223,076 patent/US4853387A/en not_active Expired - Fee Related
- 1988-07-22 NO NO883262A patent/NO170580C/en unknown
- 1988-07-22 NZ NZ225525A patent/NZ225525A/en unknown
- 1988-07-22 JP JP63184458A patent/JPS6440479A/en active Pending
- 1988-07-22 ZA ZA885369A patent/ZA885369B/en unknown
- 1988-07-22 CA CA000572857A patent/CA1305482C/en not_active Expired - Fee Related
- 1988-07-22 DK DK412888A patent/DK412888A/en not_active Application Discontinuation
- 1988-07-22 HU HU883882A patent/HU198476B/en not_active IP Right Cessation
- 1988-07-22 FI FI883483A patent/FI883483A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2618436B1 (en) | 1989-10-27 |
| PT88088B (en) | 1995-03-01 |
| HU198476B (en) | 1989-10-30 |
| NO883262L (en) | 1989-01-24 |
| AU600378B2 (en) | 1990-08-09 |
| NO883262D0 (en) | 1988-07-22 |
| ZA885369B (en) | 1989-03-29 |
| FR2618436A1 (en) | 1989-01-27 |
| NO170580C (en) | 1992-11-04 |
| EP0301936B1 (en) | 1992-12-16 |
| KR890002103A (en) | 1989-04-08 |
| US4853387A (en) | 1989-08-01 |
| PT88088A (en) | 1989-06-30 |
| ATE83482T1 (en) | 1993-01-15 |
| DE3876711D1 (en) | 1993-01-28 |
| IL87175A (en) | 1993-04-04 |
| NO170580B (en) | 1992-07-27 |
| DK412888D0 (en) | 1988-07-22 |
| NZ225525A (en) | 1990-05-28 |
| FI883483A0 (en) | 1988-07-22 |
| FI883483A (en) | 1989-01-24 |
| DE3876711T2 (en) | 1993-07-01 |
| DK412888A (en) | 1989-01-24 |
| JPS6440479A (en) | 1989-02-10 |
| HUT47269A (en) | 1989-02-28 |
| IL87175A0 (en) | 1988-12-30 |
| AU1971788A (en) | 1989-01-27 |
| EP0301936A1 (en) | 1989-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1428820B1 (en) | Non-imidazole alkylamines as histamine H-3-receptor ligands and their therapeutic applications | |
| EP0100200B1 (en) | 2-substituted 4-amino-6,7-dimethoxyquinolines | |
| AU2004281214B2 (en) | Derivatives of N-``phenyl(piperidine-2-yl) methyl benzamide, preparation method thereof and applications of same in therapeutics | |
| Janssens et al. | New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines | |
| RU2167152C2 (en) | N-substituted azaheterocyclic carboxylic acids or their pharmaceutically acceptable salts, method of their synthesis, pharmaceutical composition based on thereof and method of inhibition of neurogenic inflammation | |
| RU2125566C1 (en) | Piperazine derivatives, methods of their synthesis | |
| US4891376A (en) | 1-((2-Pyrimidinyl)aminoalkyl)piperidines, their preparation and their application in therapy | |
| IE900997L (en) | New 4-fluorobenzoic derivatives, processes for preparing¹them and pharmaceutical compositions containing them | |
| CA1175432A (en) | N-oxacyclyl-alkylpiperidine derivatives, process for their preparation, pharmaceutical products containing them, and their use | |
| JPH06340620A (en) | New amino piperidine and amino pyrrolidine and aminoperhydroazepin compound | |
| HU191643B (en) | Process for preparing new n-phenyl-n'-cycloalkyl-alkanoyl-piperazine derivatives | |
| JPH0673038A (en) | Biphenyl derivatives, medicinal compositions containing these compounds and their preparation | |
| CA1305482C (en) | Piperidine derivatives, their preparation and their application in therapy | |
| EP0275696A1 (en) | Piperidine derivatives | |
| KR970008313B1 (en) | 4-phenyl-4-£n-(phenyl)amido| piperidine derivatives and pharmaceutical compositions and method for employing such compounds | |
| EP0406739A2 (en) | Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the same | |
| US4529730A (en) | Piperidine derivatives, their preparation and pharmaceutical compositions containing them | |
| JPH08501287A (en) | Amide derivative | |
| EP0719773B1 (en) | Imidazolidinone derivative, acid-addition salt thereof, and remedy for senile dementia | |
| DK149133B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 2- (4- (DIPHENYLMETHYL) - L-PIPERIDINYL) - ACETIC ACIDS OR PHARMACEUTICAL ACCEPTABLE SALTS | |
| US4857536A (en) | Antihistaminic benzimidazole derivatives | |
| JPH03120271A (en) | Phenyl alkylamine derivative having anti-ischemic activity | |
| NZ205239A (en) | Nicotinamide 1-oxide derivatives and pharmaceutical compositions | |
| JP3012048B2 (en) | Piperazine derivative | |
| US4900738A (en) | N-heterocyclic-N-(4-piperidyl)amides and pharmaceutical compositions and their use as analgesics |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |