CA2109816A1 - Novel amidoalkyl- and imidoalkyl-piperazines - Google Patents
Novel amidoalkyl- and imidoalkyl-piperazinesInfo
- Publication number
- CA2109816A1 CA2109816A1 CA002109816A CA2109816A CA2109816A1 CA 2109816 A1 CA2109816 A1 CA 2109816A1 CA 002109816 A CA002109816 A CA 002109816A CA 2109816 A CA2109816 A CA 2109816A CA 2109816 A1 CA2109816 A1 CA 2109816A1
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- hydrogen atom
- general formula
- carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
- C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
Compounds of general formula (I) wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is an NO2 group or a group NR7R8 wherein R7 and R8 are the same or different and each is hydrogen or alkyl, R5 is hydrogen, halogen or CF3, R6 is halogen, or CF3, W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group, an alkoxy group, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, processes and intermediates for their preparation, pharmaceutical preparation containing them and the use of the compounds in the treatment of mental disturbances.
Description
W093J21179 2 1 ~ 9 ~ 1 S PCT/SE93/~29~
Novel~ aml oalkyl- and imidoalkvl-PiPerazines Field of the invention The present invention relates to novel, 1-ary1-4(~-amido-~-alkyl and ~-imido-1-alkyl)piperazines, intermediates and processes for their preparation, pharmaceutical compositlons containing the piperazines and to the use of said compounds in therapy.
The object of the present invention is to provide novel compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety, depression and manic-depressive psychosis.
Prior art 2Q Buspirone is a known substance that has been recently tested in a variety of central nervous system diseases including depression. It has affinity for both SHTlA
receptors and for D2 receptors.
Glennon and colleagues (Glennon RA, Naiman NA, Lyon RA, ;, Titeler M: Journal of Medicinal Chemustry, 1988, 31, 1968-1971) describe some aryl piperazine derivatives, including NAN190 [=1-(2-methoxyphenyl)-4-(4-~2-phthalimido)butyl)piperazine] that bind to SHTlA
receptors as labelled by ~3H)-8-hydroxyDPAT. In another report, the same group (Raghuparthi RK, Rydelek-Fitzgerald L, Teitler M, Glennon RA: Journal of Medicical Chemistry 1991, 34, 2633-2638) describe some analogs of the SHTlA agonist NAN190 that have affinity at SHTlA
receptors, as well as some binding affinity at al receptors. Further synthetic work in a related area is also described (Glennon RA, Naiman NA, Pierson ME, Smith ~:
WOs3/2117s 2 1 ~ 3 8 1 6 PCT/SE93/0029~
JD, Ismaiel AM, Titeler M, Lyon RA: Journal of Medicinal Chemistry 1989, 32, 1921-1926).
Disclosure of the invention s According to the present invention it has been found that new compounds of the general formula fCH2~1 C\ ~ ~ R4 W I _~ C H 2]m N N~\ ~> I
[ R ] B ~¦-- R 5 n2 or pharmaceutically acceptable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 :~ and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and Z0 represents a hydrogen atom, a halogen atom, or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom or CF3, 25 W is an optionally substituted aromatic ring(s), a ~:
W~093/21179 21 ~ 9 ~1 ~ PCT/SE93/0029~
heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxv group having 1-3 carbon atoms, a phenyl group, or a pheno~y group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy `' group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B is a hydrogen atom or .~ and B together constitute a carbonyl group,
Novel~ aml oalkyl- and imidoalkvl-PiPerazines Field of the invention The present invention relates to novel, 1-ary1-4(~-amido-~-alkyl and ~-imido-1-alkyl)piperazines, intermediates and processes for their preparation, pharmaceutical compositlons containing the piperazines and to the use of said compounds in therapy.
The object of the present invention is to provide novel compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety, depression and manic-depressive psychosis.
Prior art 2Q Buspirone is a known substance that has been recently tested in a variety of central nervous system diseases including depression. It has affinity for both SHTlA
receptors and for D2 receptors.
Glennon and colleagues (Glennon RA, Naiman NA, Lyon RA, ;, Titeler M: Journal of Medicinal Chemustry, 1988, 31, 1968-1971) describe some aryl piperazine derivatives, including NAN190 [=1-(2-methoxyphenyl)-4-(4-~2-phthalimido)butyl)piperazine] that bind to SHTlA
receptors as labelled by ~3H)-8-hydroxyDPAT. In another report, the same group (Raghuparthi RK, Rydelek-Fitzgerald L, Teitler M, Glennon RA: Journal of Medicical Chemistry 1991, 34, 2633-2638) describe some analogs of the SHTlA agonist NAN190 that have affinity at SHTlA
receptors, as well as some binding affinity at al receptors. Further synthetic work in a related area is also described (Glennon RA, Naiman NA, Pierson ME, Smith ~:
WOs3/2117s 2 1 ~ 3 8 1 6 PCT/SE93/0029~
JD, Ismaiel AM, Titeler M, Lyon RA: Journal of Medicinal Chemistry 1989, 32, 1921-1926).
Disclosure of the invention s According to the present invention it has been found that new compounds of the general formula fCH2~1 C\ ~ ~ R4 W I _~ C H 2]m N N~\ ~> I
[ R ] B ~¦-- R 5 n2 or pharmaceutically acceptable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 :~ and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and Z0 represents a hydrogen atom, a halogen atom, or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom or CF3, 25 W is an optionally substituted aromatic ring(s), a ~:
W~093/21179 21 ~ 9 ~1 ~ PCT/SE93/0029~
heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxv group having 1-3 carbon atoms, a phenyl group, or a pheno~y group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy `' group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B is a hydrogen atom or .~ and B together constitute a carbonyl group,
2) when W is a carbocyclic ring~s) or a heterocyclic ring ~: then :~ R, m, R4, R5, and R6 are as defined above, 3S n1 is 0 or 1, n2 is 0 or 1, A and B are hydrogen atoms or O93/21179 PCT/SE93/0029~
2 1 0 9 ~ I b~ 4 A and B together constitute a carbonyl group,
2 1 0 9 ~ I b~ 4 A and B together constitute a carbonyl group,
3) when w is an optionally substituted methylene group then ~, m, R4, R5, and R6 are as defined above, n1 and n2 are 1 or n1 is 1 and n2 is 0 or n1 is 0 and n2 is 1, A and B together constitute a carbonyl group, exhibit an affinity for D2 and 5HTlA receptors. ThiS
effect makes it possible to use the compounds defined above in the treatment of mental disturbances e.g.
psychosis, schizophrenia and depression.
An aromatic ring(s) in the definition above is preferably phenyl or naphthyl and is mono- or disubstituted, wherein the substituents are preferably chosen from the following: a hydrogen atom, a halogen atom, a hydroxy group, CF3, an alkyl group(s) having 1-3 carbon atoms, or an alkoxy group(s~ having 1-3 carbon atoms.
Heterocyclic ring in the definition above is preferably furyl, thienyl, pyrrolyl, pyridyl, or indolyl.
A carbocyclic ring(s) in the definition above is preferably mono, bi, or polycyclic rings having 3-12 carbon atoms.
The substituents on the carbocyclic ring(s) in the definition abo~e are preferably a hydrogen atom or an alkyl group having 1-3 carbon atoms.
The substituent on the methylene group in the definition above is preferably a hydrogen atom or an alkyl group having 1-4 carbon atoms.
WO 93/21179 2 1 0 ~ PCI`/SE93/002 Halogen in the definition above is preferably a chlorine, bromine, or fluorine atom.
A preferred group of compounds are those of the general formula C ~ ~=X R 4 ~N [CH2]m N~~N~ Ia o R6 ; or pharmaceutically acceptable salts thereof, wherein Rl is situated in the 3- or 4-position and represents a hydrogen atom, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon : atoms, NO2, COCH3, or NR2R3 wherein R2 and R3 are the ~a~e or different and each represents a hydrogen atom or an alkyl group having 1-6 carbon atoms, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and rep:resents an N02 group or a group NR7R8 wherein R7 and R8 are the same or different and each represen~s a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta, or para position of the ring and represents a hydrogen atom, a halogen atom, or CF3, ' WO93/~1179 PCT/SE93/0029~
21~S ~1; 6 R6 is situated in the ortho, meta, or para position of the ring and represents a halogen atom or CF3 W is preferably chosen from the following groups:
the substituents preferably being a " ^~ ~ halogen atom, a hydroxy group, or a i r~r methoxy group, mcst preferred are ~ bromine, hydroxy, or methoxy in the ortho and/or meta positions. t 1S b j;j ~
:~ , :
2S ;V
' :
V ~ L
~
vi ~
:~:
:~
WO93/2l179 21 0 9 g 1 ~ PCT/SE93/0029~
vii Q~
viii ' Q ' -O <
i X ~ the substituents being a halogen atom or ~ a methoxy group 3~
Xi \ ¢
When W is chosen from one of the groups i-xi, then WO93/21179 ~1 O~i~1 S PCT/SE93/0029 m is preferably 4-6, R4 is preferably NH2, most preferred R4 is NH2 in the meta or para positions, R5 is preferably hydrogen or halogen, particularly preferred are compounds where R5 is hydrogen, chlorine, or bromine, most preferred R5 are hydrogen or chlorine in the meta or para positions, R6 is preferably CF3 or halogen, further preferred are compounds where R6 is CF3 or chlorine, most preferred R6 are CF3 or chlorine in the meta position.
When W is i-x, then R is preferably H. -When W is i, then n1 is preferably 0 and n2 is preferably 0 or 1,most preferred n2 is 0, A is preferably hydrogen, methoxy, or hydroxy in the ortho position.
When W is ii, then n1 is preferably 0.
When W is iii-vii, then n1 is preferably 0, A is preferably a hydrogen atom or an alkyl group with 1-3 carbon atoms, and B is preferably a hydrogen atom.
When W is viii, then n1 and n2 are preferably 0 and A and B preferably constitute a carbonyl group.
~' `:
WO93/21179 PCT/SE93/0029~
9 2IO9~1~
When W is ix, then nl and n2 are pref erably 1 and A and B preferably constitute a carbonyl group.
When W is x, then n1 and n2 are preferably 0 and A and B preferably constitute a carbonyl group.
Most preferred are the following compounds o Il [~C N--ICH234--N ~N~NH2 and O
Cl 11 N--~ C H 2]4--N~N~ N H z and :.
WO 93f21179 PCI/SEg3/0029 2109~16 O F
~ F
and N~_~ N~--NH2 and o Sr<~ ? F
~H ~F
~ 15 ~, and ~`
N N~ N~Z
F
-;~
WO 93/21179 2 1 0 9 ~1 6 PCI/SE93/0029~
~\ N N~NH2 and N
~=o ~ NH~
Cl and ~ ,/ ~NH
N~ F F
~: ~ 25 ~:"
~: and ~;; 3 0 WO93/21179 PCT/SE93/0029~
2iO981~ 12 N N~--NH2 r ~,F
F
NH F
0~
and O
~ ~ O N J ~ Cl ~ N H2 Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids ' are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic, malic, mandelic acid, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4`-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ~; benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These are readily prepared by methods known in the art.
::
W~ O ~3/21179 21 0 9 8 1 (~ PCr/SE93/0029 Preparat ion The compounds of the general formula I
f 2~1 \ ~ ~ R4 C --A l [ C H 2 ] m N N ~R 5 ¦F~H]n2 R6 wherein R is a hydrogen atom or a phenyl group, s m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 : 10 and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom, or CF3, W is an optionally substituted aromatic ring(s),~ a ; 20 heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy W~O 93/21179 2 1 ~ 9 8 1 ~ PCI /SE93/0029~;
1~
group ha~lng 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, nl is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of . diastereomers, provided that lj when W is an optionally substituted aromatic ring(s) then : R, m, R4, R5, and R6 are as defined above, :~ nl is 0 or 1, -~ n2 is 0 or 1~
A is a hydrogen atom, a halogen atom, CF3, a hydroxy : group, an alkyl g~oup having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group and B is a hydrogen atom or A and B together constitute a carbonyl group, : . ~
2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, m, R4, R5, and R6 are as defined above, nl is 0 or 1, n2 is O or 1, A and B are hydrogen atoms or A and B together constitute a carbonyl group, , :: 35 3) when W is an optionally substituted methylene group ~; then ~: R, m, R4, R5, and R6 are as defined above, WO93/21179 21 0 9 8 1 ~ PCT/SE93/0029 nl and n2 are l or nl is l and n2 is 0 or nl is 0 and n2 is l, A and B together constitute a carbonyl group, are prepared by any of the following alternative methods.
A) Reaction of a compound of the general formula II
~[CH2]n1--C~
W N [ C H 2]m--X
~ I H~A
LR ~
n2 wherein R, m, W, A, B, nl and n2 are as defined above and X is a suitable leaving group such as halogen, arylsulfonate or alkylsulfonate, with a compound of the general formula III
~ ~ 4 H - NN ~ R5 lll wherein R4, R5 and R6 are as defined above in a suitable : solvent,~such as an alcohol, DMF, acetonitrile or DMSO in : the presence of a base such as triethylamine, sodium : hydroxide, or potassium carbonate and a catalyt.ic amount of a sodium or potassium halide, such as KI at ambient or higher temperature for a prolonged time.
W~093/21179 2 1 ~ 9 8 1 6 l6 PCT/SE93/0029~
B`) Conversion of a compound of the general formula IV
[CH2]n1 C~ /--\ /~
~C Hl--A N--[ C H Z]m--N N ~ IV
nz wherein R, m, R5, R6, W, A, B, n1 and n2 are as defined above and Y is situated in the meta or para position and represents a group which can be transformed to a group R41, where R41 is situated in the meta or para position of the ring and represents a group NR7R8, wherein R7 and : 10 R8 are as defined above, by a suitable hydrolytic, reductive, electrochemical or other known processes.
Compounds of the formula IV can be prepared according to Method A~ Such a group Y may be chosen from easily clea~ed amides, carbamates, imines, benzylic amines or ~`` }5 other suitably protected amino groups. Such groups can be : trifluoroacetamido, formamido, t-butoxycarbonylamino, or N-benæylamino.
.~.
In addition, Y can be a group such as nitro, azido, hydroxyamino, hydrazono, amido or imino, which can be transformed to R41 by known reductive processes.
:
;:~
WO93J21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
C) Reaction of a compound of the general formula V
~tCH2]n 1 C~ O
W N rC H2]m- 1 V
iC H~A
LR ~ ~
n2 wherein R, m, W, A, B, nl and n2 are as defined above and S Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III
~ ~ R4 H - N N ~ R5 lll wherein R4, R5 and R6 are as defined above in the presence of a suitable reducing agent such as sodium , cyanoborohydride or lithium aluminium hydride in a direct : or stepwise manner.
D) Reaction of a compound of the general formula VI
O
[C H2]n1 C ~ T
W
\ V I
[CI H~A
~ ~: n 2 `
~:
W~93/21179 2 ~ 81 6 PCT/SE93/0029 wherein w, nl, n2, and A are as defined above, and T
independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula VII
~ ~ R 4 H 2 N--[ C H 2 ] m N~~N ~ R 5 V I I
wherein m, R4, R5 and R6 are as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time.
E) Reaction of a compound of the general formula VIII
i ]n,~--C~ /--\ /=XR4 N--tcH2]m--N ~N~R5 [~C ~--A
"2 :~ whexein R, m, R4, W, A, B, nl and n2 are as defined above and R5 is H,halogen, or CF3 with a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such as chloroform or dioxane.
:~
WO93/21179 21 ~ 9 81 ~ PCT/SE93/~29~
19 , . .
F) Reaction of a compound of the general formula IX
~cH2]n1 C~
W N--M IX
CH ~A
I
R '12 i wherein W, nl and n2 are as defined above, A and B
together represent a carbonyl group, and M represents a suitable alkali metal such as sodium or potassium, with a compound of the general formula X
~}~
X [C H2]m N N ~ R5 X
:
wherein X, R4, R~ and R6 are as defined above in a suitable solvent such as DMF, acetonitrile, or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate at ambient or higher temperature for a prolonged time.
,Intermediates A compound of the general formula II
,~ ` .
WO93/21179 PCT/SE93/0029~
21 99 81 ~ 20 ~[CH2]n 1--C
\ I [CH2]m--X I I
CH--A
I
R
n2 wherein R, m, W, A, B, nl, n2 and X are as defined above, can be prepared by reacting a compound of the general formula VI
~5 /~CH2]n 1 C~T
V
~CH~A
LR ~
n2 .
:: wherein W, nl, n2, and A are as defined above, and T
~ independently or together with A represents a suitable :: 25 derivative of an aliphatic, cycloaliphatic, aromatic or ~' heterocyclic acid or acid derivative, such as a halide, :; an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula , :
XI
H2N tC H2]m - O H Xl wherein m is as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time, and subsequently H reacting the intermediate of the general formula XII
~: ' W093/21179 2l 2 ~ 0 9 8 I 6 PCT/SE93/0029 o /[CH2]n --C
W l [CH2]m--OH Xll ~ H~ A E3 lR J
~2 wherein R, m, W, A, B, nl and n2 are as defined above,~
with a suitable halogenating agent such as thionyl chloride, phosgene, oxalyl chloride, or phosphorous tribromide, or with a suitable sulfonating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.
A compound of the general formula III
H--N N~2 R 5 R
~ wherein R41, R5 and R6 are as defined abo~e can be :~ prepared from a compound of the general formula XIII
~ Y
H--N N ~ ~
--/ ~R5 Xlll R
: 6 O
WO93/21179 ~ I ~ 9 ~ 1 G 22 PCT/SEs3/00295 wherein Y, R5 and R6 are as defined above in analogy with method B.
A compound of the general formula XIII
~ Y
H--N N ~_~ X l l I
wherein R5 and R6 are as defined above and Y is N02 can be prepared by reacting a compound of the general formula XIV
t,Y
~R5 XIV
wherein R5 and R6 are as defined above, Y is N02 and U is a halogen, with piperazine or a suitably monosubstituted piperazine, where the substituent is easily removeable, ~:; such as a benzyl or an ethoxycarbonyl group, or by reacting a compound of the general formula XV
H z N~ XV
~: 30 ~`
WO93/21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
wherein R5 and R6 are as defined above and Y is NO2, with a compound of the general formula XVI
~CH2cH2x V--N XV I
wherein X is as defined above and V is hydroyen or an easily removable group such as benzyl or ethoxycarbonyl.
A compound of the general formula x ~ ~ R4 X - ~C H2~m N ~ ~ 5 X
wherein X, m, R4, R5 and R6 are as defined above, can be ~: 20 prepared b~ reacting a compound of the general formula XVII
X [C H2~m - X XVII
.
'~ wherein X and m are as defined above, with a compound of the general formula III
3 0 /~ R 4 H--N N~R5 111 R
: ~ 35 . ~
W~93~21179 21 ~ 9 S 1 ~ PCT/SE93/0029~
wherein R4, R5 and R6 are as defined above, under - suitable reaction conditions analogous to method A.
Pharmaceutical formulations According to the present invention the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide~
lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between O.l and 99 ~ by weight of the preparation, more specifically between 0.5 and 20 ~ by weight for prepar~ations intended for injectioil and between 0.2 and 50 % by weight for preparations suitable for oral administration.
To produce pharmaceutical formulations containing a compound of the formula I in the form of dosage units for oral application the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gel~tine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet can be coated with a polymer well known in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in W~93/21179 2 I 0 9 ,~1 S PCT/SE93/0029~
water. Dyestuffs may be added to these coatings in orde~
to readily disti~guiish between tablets containins different active substances or different amounts of the active compounds.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn, starch or amylopectin), cellulose derivatives o-gelatine. Also liquids or semisolids of the drug can bc filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 ~ by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol, and propyl~ne glycol. Optionally such li~uid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients well known in the art.
. .
Solutions for parenteral applications can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the acti~e substance preferably in a concentration of from about 0.5 ~ to about 10 ~ by weight. These solutions may also contain stabilizing WO93/21179 PCT/SE93/0029~
21 0 3 81 ~ 26 agents and/or buffering agents and may conveniently ~e ~:
provided in various dosage unit ampoules.
Suitable daily doses of the compounds of the invention in the therapeutic trëatment of humans are 50 - 500 mg by oral administration and up to lO0 mg via parenteral -~
administration.
It is especially preferred to admirister a compound of ~.
the formula ~
Il N - [C Hz] - N N ~ N H2 or ~ ;
~ F F
: 20 O 93~21179 21 a 9 81 ~ PCr/SE93/0029 EXAMPLES
Examx)le_ ~Method A) 1 (4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1-butvl)~iPerazine dihvdrochloride A mixture of 3.18 g (O.Oi mol~ of 4-amino-3-trifluoromethylphenylpiperazine, a catalytic amount of KI, 4.1 g ~O.03 mol) of potassium carbonate and 3.0 g (0.01 mol) of N-(4-bromo~utyl)phthalimide in 25 ml of DM~
was stirred at lOO'C overnight. After addition of 500 ml of water, the mixture was extracted with ether. The extract was washed with water and extracted with dilute hydrochloric acid. The water layer was separated, made alkaline with sodium hydroxide and again extracted with ether. The extract was dried (Na2SO4) and acidified with hydrogen chloride in ether. The yielded precipitate was filtered off and recrystallized from ethanol-ether.
Yield 3.0 g (58%).
M.p. 226-227 C.
In an analogous way the following compounds (2-12) were prepared:
ExamDle 2 1-L4-Amino-3-trifluoromethYlDhenYl)-4-(3-~hthalimido~
~ro~yl)~i~erazine dihydrochloride.
M.p. 167-169'C.
WO93/21179 21 OYXl fi 28 PCr/SE93/0029~ ~;
~xaml?le 3 ~ ' ~ ~9= ~ fl_oromethvl~henvl)-4-~5-(3-methoxvphthalimido)~ ntYll~i~erazine oxalate ~-M.p. 114-118 C.
Exam~?le 4 1- (4-Amino-3-trifl oromethYlPhenyl) -4- F4- (4-~hlorophthalimido)-l-bu-~llpi~erazine dihYdrochloride.
M.p . 203-204 C .
Exam~le 5 1-~4-Amino-3-~rifluoro~thylphenyl)-4-(5-phthalimido-1-Pentyl)piPerazine trihvdrochloride.
M.p. 109-113-C.
.: .
~xamDle 6 ~
~ .
1-~4-Amino-3~5-dichlc-oPhenyl)-4 - ( 4 -Dhthalimido-l - ~
butYl)piP erazine ~.
M.p. 116-ll9 C. -2xamD1e 7 1-(4-Amino-3-trifluoromethYl~henyl)-4 - ~ 3-(1,8- -~
na~hthalimido)-l-~ropYl lpiperazine ~-M.p. 156-158-C. ~
~:
W093/21179 21 0 9 .~1 ~ P~/SE93/~29~
Example 8 1-(4-Amino-3 -tri f luoromethvlPhenyl ) -4 - ~ 4 - ( 3, 3 -dimethvlqlutarimido)-l-butvllpiperazine dihYdrochloride M.p. 235-236 C.
Examplè 9 1-(4-Amino-3-trifluoromethvl~henYl)-4-f4-(3,3-tetrameth~leneqlutarimido~ -l-butYllpiperazine dihvdrochloride M.p. 243-245 C.
Exam~le 10 1- ( 4 -Amino-3 -tri f luoromethYlPhenYl ) -4 - ~ 5 - ( 3 - ~ :
~henvlalutarimido) -1-PentYl l Pierazine hYdrochloride M . p . 13 6 -140 C .
~:xamDle 11 1- (3-Amino-4-chloroDhènvl) -4- ~5- (2-furanecarboxamido) -1-~entYl 1 Pi~)erazine oxalate M.p. 165-170-C.
~':-.' ~xam~le 12 ~:.
. ".
1-(4-Amino-3-trifluoromethYlPhen~1)-4-(4- :~
cyclohexanecarboxamido-l-butYl)PiPerazine .. ~:
:,~
M.p. 127-128-C. -.
71 0~ 81 ~ 30 :~
~xam~le 13 (Method s) ~ -1-(4-Amino-3-trifluoromethylphen~l~=4-~4-phthalimido-1-butvl?Pi~erazine acetate. ~ :
The product from example 38, (9.53 g, 20 mmol), dissolved ~
in 100 ml ethanol and 50 ml acetic acid was hydrogenated :
with Pd/C (1.0 g) as catalyst for 5 h. The mixture was filtered, the solvent evaporated and the residue :
crystallized from diisopropylether and ethanol to yield 10.0 g of the title product. , -M.p. 101-103-C.
-' In an analogous way the following compounds (examples 14-24) were prepared:
Exam~le 14 : .
1-(4-Amino-3-trifluoromethYl~henYl)-4-(6-~hthalimido-1- ~:
hexvl~piperazine acetate M.p. 125-127-C.
~xiIm~le 15 ~~
1-(4-Amino-3-trifluoromethvlPhenvl)-4-(8-~hthalimido~
:
octYl)~i~erazine aceta~te -M.p. 94-96 C.
ExamDle_16 1-(3-Amino-4-c Yll= ~ hthalimido-l-bUtYlL~
~i~erazine acetate. :
M.p. 159-162-C.
W~93/21179 2 1 0 9 ~ 1 6 PCT/SE93/0029~
Exam~le 17 1-(3-Amino-4-chloro~henyl)-4-(5-~hthalimido-1-Dentvl)-i_L"~
:-M.p. 149-150-C.
~xam~le 18 1-(4-Amino-3-methvl~heny1)-4-(4-~hthalimido-1-butyl)- :
~iPerazine acetate.
M.p. 123-126-C. ~:~
Exam~le 19 1-(3-Amino-4-chloro~henvl)-4-~4-(3,3-tetramethYlene-alutarimido~-l-butYllpiPerazine -~
M.p. 133-136-C. ;
:`.''~
~xamPle 20 ~-~
~, 1-(4-Amino-3-trifluoromethvlPhenvl!-4-[6-(3-Phenox~-benzamido~ hexvl~ erazine acetate M.p. 128-131-C.
ExamDle 21 ~0 1-(4-Amino-3-trifluoromethvlPhenvl)~4-~6-cYclohexane carb,oxamido-l-hexYl)piperazine dihydrochlor de M.p. 112-115-C.
WO 93/21179 PCl/SE93/0029~
210981(~ 32 ~xam~le 22 1-(4-Amino-3-trifluoromethvlPhenvl)-4-(4-adamantane-carboxamido-l-butyl)pi~erazine dihvdrochloride M.p. 123-125-C.
~xamDle 23 ;
1-(4-Amino-3-trifluoromethYlPhenYl!-4-l4-adamantane-acetamido-l-butvl)~i~erazine ~.
M.p. 115-116-C.
Example 24 1-(4-Amino-3-trifluoromethvl~henYl)-4-(6-adamantane-carboxamido~l-hexvl)~iperazine lH NMR (CDC13) d 7.00 (s, 1 H), 6.96 (dd, 1 H), 6.70 (d, 1 H), 5.57 (bs, 1 H), 3.26 (bs, 2 H), 3.24 (m, 2 H), 3.08 (m, 4 H), 2.61 (m, 4 H), 2.39 (m, 2 H), 2.04 (bs, 3 H), 1.84 (bs, 6 H), 1.71 (bs, 6H), 1.52 (m, 4 H), 1.34 (m,
effect makes it possible to use the compounds defined above in the treatment of mental disturbances e.g.
psychosis, schizophrenia and depression.
An aromatic ring(s) in the definition above is preferably phenyl or naphthyl and is mono- or disubstituted, wherein the substituents are preferably chosen from the following: a hydrogen atom, a halogen atom, a hydroxy group, CF3, an alkyl group(s) having 1-3 carbon atoms, or an alkoxy group(s~ having 1-3 carbon atoms.
Heterocyclic ring in the definition above is preferably furyl, thienyl, pyrrolyl, pyridyl, or indolyl.
A carbocyclic ring(s) in the definition above is preferably mono, bi, or polycyclic rings having 3-12 carbon atoms.
The substituents on the carbocyclic ring(s) in the definition abo~e are preferably a hydrogen atom or an alkyl group having 1-3 carbon atoms.
The substituent on the methylene group in the definition above is preferably a hydrogen atom or an alkyl group having 1-4 carbon atoms.
WO 93/21179 2 1 0 ~ PCI`/SE93/002 Halogen in the definition above is preferably a chlorine, bromine, or fluorine atom.
A preferred group of compounds are those of the general formula C ~ ~=X R 4 ~N [CH2]m N~~N~ Ia o R6 ; or pharmaceutically acceptable salts thereof, wherein Rl is situated in the 3- or 4-position and represents a hydrogen atom, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon : atoms, NO2, COCH3, or NR2R3 wherein R2 and R3 are the ~a~e or different and each represents a hydrogen atom or an alkyl group having 1-6 carbon atoms, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and rep:resents an N02 group or a group NR7R8 wherein R7 and R8 are the same or different and each represen~s a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta, or para position of the ring and represents a hydrogen atom, a halogen atom, or CF3, ' WO93/~1179 PCT/SE93/0029~
21~S ~1; 6 R6 is situated in the ortho, meta, or para position of the ring and represents a halogen atom or CF3 W is preferably chosen from the following groups:
the substituents preferably being a " ^~ ~ halogen atom, a hydroxy group, or a i r~r methoxy group, mcst preferred are ~ bromine, hydroxy, or methoxy in the ortho and/or meta positions. t 1S b j;j ~
:~ , :
2S ;V
' :
V ~ L
~
vi ~
:~:
:~
WO93/2l179 21 0 9 g 1 ~ PCT/SE93/0029~
vii Q~
viii ' Q ' -O <
i X ~ the substituents being a halogen atom or ~ a methoxy group 3~
Xi \ ¢
When W is chosen from one of the groups i-xi, then WO93/21179 ~1 O~i~1 S PCT/SE93/0029 m is preferably 4-6, R4 is preferably NH2, most preferred R4 is NH2 in the meta or para positions, R5 is preferably hydrogen or halogen, particularly preferred are compounds where R5 is hydrogen, chlorine, or bromine, most preferred R5 are hydrogen or chlorine in the meta or para positions, R6 is preferably CF3 or halogen, further preferred are compounds where R6 is CF3 or chlorine, most preferred R6 are CF3 or chlorine in the meta position.
When W is i-x, then R is preferably H. -When W is i, then n1 is preferably 0 and n2 is preferably 0 or 1,most preferred n2 is 0, A is preferably hydrogen, methoxy, or hydroxy in the ortho position.
When W is ii, then n1 is preferably 0.
When W is iii-vii, then n1 is preferably 0, A is preferably a hydrogen atom or an alkyl group with 1-3 carbon atoms, and B is preferably a hydrogen atom.
When W is viii, then n1 and n2 are preferably 0 and A and B preferably constitute a carbonyl group.
~' `:
WO93/21179 PCT/SE93/0029~
9 2IO9~1~
When W is ix, then nl and n2 are pref erably 1 and A and B preferably constitute a carbonyl group.
When W is x, then n1 and n2 are preferably 0 and A and B preferably constitute a carbonyl group.
Most preferred are the following compounds o Il [~C N--ICH234--N ~N~NH2 and O
Cl 11 N--~ C H 2]4--N~N~ N H z and :.
WO 93f21179 PCI/SEg3/0029 2109~16 O F
~ F
and N~_~ N~--NH2 and o Sr<~ ? F
~H ~F
~ 15 ~, and ~`
N N~ N~Z
F
-;~
WO 93/21179 2 1 0 9 ~1 6 PCI/SE93/0029~
~\ N N~NH2 and N
~=o ~ NH~
Cl and ~ ,/ ~NH
N~ F F
~: ~ 25 ~:"
~: and ~;; 3 0 WO93/21179 PCT/SE93/0029~
2iO981~ 12 N N~--NH2 r ~,F
F
NH F
0~
and O
~ ~ O N J ~ Cl ~ N H2 Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids ' are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic, malic, mandelic acid, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4`-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ~; benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These are readily prepared by methods known in the art.
::
W~ O ~3/21179 21 0 9 8 1 (~ PCr/SE93/0029 Preparat ion The compounds of the general formula I
f 2~1 \ ~ ~ R4 C --A l [ C H 2 ] m N N ~R 5 ¦F~H]n2 R6 wherein R is a hydrogen atom or a phenyl group, s m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 : 10 and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom, or CF3, W is an optionally substituted aromatic ring(s),~ a ; 20 heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy W~O 93/21179 2 1 ~ 9 8 1 ~ PCI /SE93/0029~;
1~
group ha~lng 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, nl is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of . diastereomers, provided that lj when W is an optionally substituted aromatic ring(s) then : R, m, R4, R5, and R6 are as defined above, :~ nl is 0 or 1, -~ n2 is 0 or 1~
A is a hydrogen atom, a halogen atom, CF3, a hydroxy : group, an alkyl g~oup having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group and B is a hydrogen atom or A and B together constitute a carbonyl group, : . ~
2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, m, R4, R5, and R6 are as defined above, nl is 0 or 1, n2 is O or 1, A and B are hydrogen atoms or A and B together constitute a carbonyl group, , :: 35 3) when W is an optionally substituted methylene group ~; then ~: R, m, R4, R5, and R6 are as defined above, WO93/21179 21 0 9 8 1 ~ PCT/SE93/0029 nl and n2 are l or nl is l and n2 is 0 or nl is 0 and n2 is l, A and B together constitute a carbonyl group, are prepared by any of the following alternative methods.
A) Reaction of a compound of the general formula II
~[CH2]n1--C~
W N [ C H 2]m--X
~ I H~A
LR ~
n2 wherein R, m, W, A, B, nl and n2 are as defined above and X is a suitable leaving group such as halogen, arylsulfonate or alkylsulfonate, with a compound of the general formula III
~ ~ 4 H - NN ~ R5 lll wherein R4, R5 and R6 are as defined above in a suitable : solvent,~such as an alcohol, DMF, acetonitrile or DMSO in : the presence of a base such as triethylamine, sodium : hydroxide, or potassium carbonate and a catalyt.ic amount of a sodium or potassium halide, such as KI at ambient or higher temperature for a prolonged time.
W~093/21179 2 1 ~ 9 8 1 6 l6 PCT/SE93/0029~
B`) Conversion of a compound of the general formula IV
[CH2]n1 C~ /--\ /~
~C Hl--A N--[ C H Z]m--N N ~ IV
nz wherein R, m, R5, R6, W, A, B, n1 and n2 are as defined above and Y is situated in the meta or para position and represents a group which can be transformed to a group R41, where R41 is situated in the meta or para position of the ring and represents a group NR7R8, wherein R7 and : 10 R8 are as defined above, by a suitable hydrolytic, reductive, electrochemical or other known processes.
Compounds of the formula IV can be prepared according to Method A~ Such a group Y may be chosen from easily clea~ed amides, carbamates, imines, benzylic amines or ~`` }5 other suitably protected amino groups. Such groups can be : trifluoroacetamido, formamido, t-butoxycarbonylamino, or N-benæylamino.
.~.
In addition, Y can be a group such as nitro, azido, hydroxyamino, hydrazono, amido or imino, which can be transformed to R41 by known reductive processes.
:
;:~
WO93J21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
C) Reaction of a compound of the general formula V
~tCH2]n 1 C~ O
W N rC H2]m- 1 V
iC H~A
LR ~ ~
n2 wherein R, m, W, A, B, nl and n2 are as defined above and S Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III
~ ~ R4 H - N N ~ R5 lll wherein R4, R5 and R6 are as defined above in the presence of a suitable reducing agent such as sodium , cyanoborohydride or lithium aluminium hydride in a direct : or stepwise manner.
D) Reaction of a compound of the general formula VI
O
[C H2]n1 C ~ T
W
\ V I
[CI H~A
~ ~: n 2 `
~:
W~93/21179 2 ~ 81 6 PCT/SE93/0029 wherein w, nl, n2, and A are as defined above, and T
independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula VII
~ ~ R 4 H 2 N--[ C H 2 ] m N~~N ~ R 5 V I I
wherein m, R4, R5 and R6 are as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time.
E) Reaction of a compound of the general formula VIII
i ]n,~--C~ /--\ /=XR4 N--tcH2]m--N ~N~R5 [~C ~--A
"2 :~ whexein R, m, R4, W, A, B, nl and n2 are as defined above and R5 is H,halogen, or CF3 with a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such as chloroform or dioxane.
:~
WO93/21179 21 ~ 9 81 ~ PCT/SE93/~29~
19 , . .
F) Reaction of a compound of the general formula IX
~cH2]n1 C~
W N--M IX
CH ~A
I
R '12 i wherein W, nl and n2 are as defined above, A and B
together represent a carbonyl group, and M represents a suitable alkali metal such as sodium or potassium, with a compound of the general formula X
~}~
X [C H2]m N N ~ R5 X
:
wherein X, R4, R~ and R6 are as defined above in a suitable solvent such as DMF, acetonitrile, or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate at ambient or higher temperature for a prolonged time.
,Intermediates A compound of the general formula II
,~ ` .
WO93/21179 PCT/SE93/0029~
21 99 81 ~ 20 ~[CH2]n 1--C
\ I [CH2]m--X I I
CH--A
I
R
n2 wherein R, m, W, A, B, nl, n2 and X are as defined above, can be prepared by reacting a compound of the general formula VI
~5 /~CH2]n 1 C~T
V
~CH~A
LR ~
n2 .
:: wherein W, nl, n2, and A are as defined above, and T
~ independently or together with A represents a suitable :: 25 derivative of an aliphatic, cycloaliphatic, aromatic or ~' heterocyclic acid or acid derivative, such as a halide, :; an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula , :
XI
H2N tC H2]m - O H Xl wherein m is as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time, and subsequently H reacting the intermediate of the general formula XII
~: ' W093/21179 2l 2 ~ 0 9 8 I 6 PCT/SE93/0029 o /[CH2]n --C
W l [CH2]m--OH Xll ~ H~ A E3 lR J
~2 wherein R, m, W, A, B, nl and n2 are as defined above,~
with a suitable halogenating agent such as thionyl chloride, phosgene, oxalyl chloride, or phosphorous tribromide, or with a suitable sulfonating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.
A compound of the general formula III
H--N N~2 R 5 R
~ wherein R41, R5 and R6 are as defined abo~e can be :~ prepared from a compound of the general formula XIII
~ Y
H--N N ~ ~
--/ ~R5 Xlll R
: 6 O
WO93/21179 ~ I ~ 9 ~ 1 G 22 PCT/SEs3/00295 wherein Y, R5 and R6 are as defined above in analogy with method B.
A compound of the general formula XIII
~ Y
H--N N ~_~ X l l I
wherein R5 and R6 are as defined above and Y is N02 can be prepared by reacting a compound of the general formula XIV
t,Y
~R5 XIV
wherein R5 and R6 are as defined above, Y is N02 and U is a halogen, with piperazine or a suitably monosubstituted piperazine, where the substituent is easily removeable, ~:; such as a benzyl or an ethoxycarbonyl group, or by reacting a compound of the general formula XV
H z N~ XV
~: 30 ~`
WO93/21179 2 1 0 3 8 1 ~ PCT/SE93/0029~
wherein R5 and R6 are as defined above and Y is NO2, with a compound of the general formula XVI
~CH2cH2x V--N XV I
wherein X is as defined above and V is hydroyen or an easily removable group such as benzyl or ethoxycarbonyl.
A compound of the general formula x ~ ~ R4 X - ~C H2~m N ~ ~ 5 X
wherein X, m, R4, R5 and R6 are as defined above, can be ~: 20 prepared b~ reacting a compound of the general formula XVII
X [C H2~m - X XVII
.
'~ wherein X and m are as defined above, with a compound of the general formula III
3 0 /~ R 4 H--N N~R5 111 R
: ~ 35 . ~
W~93~21179 21 ~ 9 S 1 ~ PCT/SE93/0029~
wherein R4, R5 and R6 are as defined above, under - suitable reaction conditions analogous to method A.
Pharmaceutical formulations According to the present invention the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide~
lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between O.l and 99 ~ by weight of the preparation, more specifically between 0.5 and 20 ~ by weight for prepar~ations intended for injectioil and between 0.2 and 50 % by weight for preparations suitable for oral administration.
To produce pharmaceutical formulations containing a compound of the formula I in the form of dosage units for oral application the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gel~tine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet can be coated with a polymer well known in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in W~93/21179 2 I 0 9 ,~1 S PCT/SE93/0029~
water. Dyestuffs may be added to these coatings in orde~
to readily disti~guiish between tablets containins different active substances or different amounts of the active compounds.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn, starch or amylopectin), cellulose derivatives o-gelatine. Also liquids or semisolids of the drug can bc filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 ~ by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol, and propyl~ne glycol. Optionally such li~uid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients well known in the art.
. .
Solutions for parenteral applications can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the acti~e substance preferably in a concentration of from about 0.5 ~ to about 10 ~ by weight. These solutions may also contain stabilizing WO93/21179 PCT/SE93/0029~
21 0 3 81 ~ 26 agents and/or buffering agents and may conveniently ~e ~:
provided in various dosage unit ampoules.
Suitable daily doses of the compounds of the invention in the therapeutic trëatment of humans are 50 - 500 mg by oral administration and up to lO0 mg via parenteral -~
administration.
It is especially preferred to admirister a compound of ~.
the formula ~
Il N - [C Hz] - N N ~ N H2 or ~ ;
~ F F
: 20 O 93~21179 21 a 9 81 ~ PCr/SE93/0029 EXAMPLES
Examx)le_ ~Method A) 1 (4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1-butvl)~iPerazine dihvdrochloride A mixture of 3.18 g (O.Oi mol~ of 4-amino-3-trifluoromethylphenylpiperazine, a catalytic amount of KI, 4.1 g ~O.03 mol) of potassium carbonate and 3.0 g (0.01 mol) of N-(4-bromo~utyl)phthalimide in 25 ml of DM~
was stirred at lOO'C overnight. After addition of 500 ml of water, the mixture was extracted with ether. The extract was washed with water and extracted with dilute hydrochloric acid. The water layer was separated, made alkaline with sodium hydroxide and again extracted with ether. The extract was dried (Na2SO4) and acidified with hydrogen chloride in ether. The yielded precipitate was filtered off and recrystallized from ethanol-ether.
Yield 3.0 g (58%).
M.p. 226-227 C.
In an analogous way the following compounds (2-12) were prepared:
ExamDle 2 1-L4-Amino-3-trifluoromethYlDhenYl)-4-(3-~hthalimido~
~ro~yl)~i~erazine dihydrochloride.
M.p. 167-169'C.
WO93/21179 21 OYXl fi 28 PCr/SE93/0029~ ~;
~xaml?le 3 ~ ' ~ ~9= ~ fl_oromethvl~henvl)-4-~5-(3-methoxvphthalimido)~ ntYll~i~erazine oxalate ~-M.p. 114-118 C.
Exam~?le 4 1- (4-Amino-3-trifl oromethYlPhenyl) -4- F4- (4-~hlorophthalimido)-l-bu-~llpi~erazine dihYdrochloride.
M.p . 203-204 C .
Exam~le 5 1-~4-Amino-3-~rifluoro~thylphenyl)-4-(5-phthalimido-1-Pentyl)piPerazine trihvdrochloride.
M.p. 109-113-C.
.: .
~xamDle 6 ~
~ .
1-~4-Amino-3~5-dichlc-oPhenyl)-4 - ( 4 -Dhthalimido-l - ~
butYl)piP erazine ~.
M.p. 116-ll9 C. -2xamD1e 7 1-(4-Amino-3-trifluoromethYl~henyl)-4 - ~ 3-(1,8- -~
na~hthalimido)-l-~ropYl lpiperazine ~-M.p. 156-158-C. ~
~:
W093/21179 21 0 9 .~1 ~ P~/SE93/~29~
Example 8 1-(4-Amino-3 -tri f luoromethvlPhenyl ) -4 - ~ 4 - ( 3, 3 -dimethvlqlutarimido)-l-butvllpiperazine dihYdrochloride M.p. 235-236 C.
Examplè 9 1-(4-Amino-3-trifluoromethvl~henYl)-4-f4-(3,3-tetrameth~leneqlutarimido~ -l-butYllpiperazine dihvdrochloride M.p. 243-245 C.
Exam~le 10 1- ( 4 -Amino-3 -tri f luoromethYlPhenYl ) -4 - ~ 5 - ( 3 - ~ :
~henvlalutarimido) -1-PentYl l Pierazine hYdrochloride M . p . 13 6 -140 C .
~:xamDle 11 1- (3-Amino-4-chloroDhènvl) -4- ~5- (2-furanecarboxamido) -1-~entYl 1 Pi~)erazine oxalate M.p. 165-170-C.
~':-.' ~xam~le 12 ~:.
. ".
1-(4-Amino-3-trifluoromethYlPhen~1)-4-(4- :~
cyclohexanecarboxamido-l-butYl)PiPerazine .. ~:
:,~
M.p. 127-128-C. -.
71 0~ 81 ~ 30 :~
~xam~le 13 (Method s) ~ -1-(4-Amino-3-trifluoromethylphen~l~=4-~4-phthalimido-1-butvl?Pi~erazine acetate. ~ :
The product from example 38, (9.53 g, 20 mmol), dissolved ~
in 100 ml ethanol and 50 ml acetic acid was hydrogenated :
with Pd/C (1.0 g) as catalyst for 5 h. The mixture was filtered, the solvent evaporated and the residue :
crystallized from diisopropylether and ethanol to yield 10.0 g of the title product. , -M.p. 101-103-C.
-' In an analogous way the following compounds (examples 14-24) were prepared:
Exam~le 14 : .
1-(4-Amino-3-trifluoromethYl~henYl)-4-(6-~hthalimido-1- ~:
hexvl~piperazine acetate M.p. 125-127-C.
~xiIm~le 15 ~~
1-(4-Amino-3-trifluoromethvlPhenvl)-4-(8-~hthalimido~
:
octYl)~i~erazine aceta~te -M.p. 94-96 C.
ExamDle_16 1-(3-Amino-4-c Yll= ~ hthalimido-l-bUtYlL~
~i~erazine acetate. :
M.p. 159-162-C.
W~93/21179 2 1 0 9 ~ 1 6 PCT/SE93/0029~
Exam~le 17 1-(3-Amino-4-chloro~henyl)-4-(5-~hthalimido-1-Dentvl)-i_L"~
:-M.p. 149-150-C.
~xam~le 18 1-(4-Amino-3-methvl~heny1)-4-(4-~hthalimido-1-butyl)- :
~iPerazine acetate.
M.p. 123-126-C. ~:~
Exam~le 19 1-(3-Amino-4-chloro~henvl)-4-~4-(3,3-tetramethYlene-alutarimido~-l-butYllpiPerazine -~
M.p. 133-136-C. ;
:`.''~
~xamPle 20 ~-~
~, 1-(4-Amino-3-trifluoromethvlPhenvl!-4-[6-(3-Phenox~-benzamido~ hexvl~ erazine acetate M.p. 128-131-C.
ExamDle 21 ~0 1-(4-Amino-3-trifluoromethvlPhenvl)~4-~6-cYclohexane carb,oxamido-l-hexYl)piperazine dihydrochlor de M.p. 112-115-C.
WO 93/21179 PCl/SE93/0029~
210981(~ 32 ~xam~le 22 1-(4-Amino-3-trifluoromethvlPhenvl)-4-(4-adamantane-carboxamido-l-butyl)pi~erazine dihvdrochloride M.p. 123-125-C.
~xamDle 23 ;
1-(4-Amino-3-trifluoromethYlPhenYl!-4-l4-adamantane-acetamido-l-butvl)~i~erazine ~.
M.p. 115-116-C.
Example 24 1-(4-Amino-3-trifluoromethvl~henYl)-4-(6-adamantane-carboxamido~l-hexvl)~iperazine lH NMR (CDC13) d 7.00 (s, 1 H), 6.96 (dd, 1 H), 6.70 (d, 1 H), 5.57 (bs, 1 H), 3.26 (bs, 2 H), 3.24 (m, 2 H), 3.08 (m, 4 H), 2.61 (m, 4 H), 2.39 (m, 2 H), 2.04 (bs, 3 H), 1.84 (bs, 6 H), 1.71 (bs, 6H), 1.52 (m, 4 H), 1.34 (m,
4 H).
~xamole 25_l b5b~Li~L~
-- .
1-(4-Amino-2-trifluoromethvlPhenvl)-4-~4-~hthalimido-1-butyl)~i~erazine dihYdrochloride.
To a mixture of 1-(4-nitro-2-trifluoromethylphenyl)-4-(4-phthalimido-l-butyl)-piperazine (7.8 g, 0.01 mol) in 200 ml ethanol and 60 ml water, 11.2 g of sodium dithionite was added in portions while stirring and heating at lOO C. The mixture was heated under reflux for 1 h and the ethanol was evaporated. The residual water solution WO93/21179 2 1 0 9 S 1 ~ PCT~SE93/0029~
was made basic with NaOH and extracted with ether. The extract was washed with water, dried and the ether was evaporated. The yielded oil was dissolved in 100 ml dry ether and the dihydrochloride was precipitated by the addition of hydrogen chloride in ether. The salt was recrystallized from ethanol-ether to give 2.3 g (44 ~) of ~-the target compound.
M.p. 243 -244 C. --~
~xa~Dle 26 (~ethod s) 1-(4-DiethYlamino-3-trifluoromethYlPhenvl)-4-(4 ~hthalimido-1-butvl)-~i~erazine The product from Example 13 (1.0 g, 2 mmol), dissolved in ~-
~xamole 25_l b5b~Li~L~
-- .
1-(4-Amino-2-trifluoromethvlPhenvl)-4-~4-~hthalimido-1-butyl)~i~erazine dihYdrochloride.
To a mixture of 1-(4-nitro-2-trifluoromethylphenyl)-4-(4-phthalimido-l-butyl)-piperazine (7.8 g, 0.01 mol) in 200 ml ethanol and 60 ml water, 11.2 g of sodium dithionite was added in portions while stirring and heating at lOO C. The mixture was heated under reflux for 1 h and the ethanol was evaporated. The residual water solution WO93/21179 2 1 0 9 S 1 ~ PCT~SE93/0029~
was made basic with NaOH and extracted with ether. The extract was washed with water, dried and the ether was evaporated. The yielded oil was dissolved in 100 ml dry ether and the dihydrochloride was precipitated by the addition of hydrogen chloride in ether. The salt was recrystallized from ethanol-ether to give 2.3 g (44 ~) of ~-the target compound.
M.p. 243 -244 C. --~
~xa~Dle 26 (~ethod s) 1-(4-DiethYlamino-3-trifluoromethYlPhenvl)-4-(4 ~hthalimido-1-butvl)-~i~erazine The product from Example 13 (1.0 g, 2 mmol), dissolved in ~-
5 ml acetic acid, was added to a mixture of sodium .-borohydride (304 mg, 8 mmol) and 20 ml toluene. The --mixture was heated for 6 h at 80 C, cooled and added to ~ -50 ml water and 50 ml ether and made alkaline with 2 M
sodium hydroxide. The organic phase was dried and evaporated. The residue was recrystallized from hexane to yield 440 mg of the target product.
M.p. 70 - 71-C.
Examole 27 (Method B) -1-(4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1 butYl)-~i~erazine. -~
4-~4-Acetamino-3-trifluoromethylphenyl)-1-(4-phthalimido-1- butyl)-piperazine (4.9 mg, 0.01 mmol), dissolved in 2 ml ethanol and 0.2 ml 2 M hydrochloric acid, was heated for 5 h at 80 C. The solvent was removed and the residue was shown by gas chromatography to be identical with the product in example 1.
:
. :"
)93/21179 21 (~ I 6 34 PCr/SE93/0029~
Exam~le 28 (Method C) :
4-(4-Amino-3~trifluoromethylPhenvl)-1-(4-Phthalimido-l-butYl)-piperazine -~
S
To a refluxing solution of 4-phthalimido-1-butanal (0.713 -g 3.25 mmol) and N-(4-amino-3-trifluoromethylphenyl)-piperazine (0.804 g, 3.25 mmol) in CHCl3 (10 ml) was added dropwise 98% formic acid in ^HCl3 (10 ml) n 20 lQ min. The solution was heated under reflux for 2 h. The solvent was removed and the residue purified b~
chromatography and shown ~ thin laver chromatography and gas chromatography to be identical to the product in example 1.
Example 29 (Method D) 1_14-Amino-3-trifluoromethvlPhenYl)-4-~4-~hthalimido-1-but~l)pi~erazine 4-(4-Amino-3-trifluoromethylphenyl)-1-(4-aminobutyl)-pipera zine(32 mg, 0.1 mmol) and phthalic anhydride (30 mg, 0.2 mmol) dissolved in 1 ml acetic acid were stirred at 75 C for 3 hours. The solvent was removed and the residue was shown by gas chromatography and thin layer chromatography to be identical with the product in example 1.
~xamDle 30 (Method D) 1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(5-bromo-2,3-dimethoxYbenzamido)-1-butvll~i~erazine dioxalate , .
The product from example 1 (3.3 ~, 6.4 mmol) was dissolved in 60 ml ethanol, made alkaline with 2 M NaOH, `
and the base was heated with hydrazine hydrate (2.0 ml) at 75C for 3.5 h. After cooling, the solution was WO93/21179 2 1 0 9 8 1 6 PCT/SE93/0029~ ~
acidified with 27 ml ~ M HCl and evaporated. The residue was dissolved in 75 ml H2O and 75 ml ether. The aqueous ;~
phase was made alkaline and extracted with chloroform. ~
The solvent was evaporated to yield crude 1-(4- ~-aminobutyl)-4-(4-amino-3-trifluoromethylphenyl)-piper azine. A solution o~ 5-bromo-2,3-dimethoxybenzoic acid (O.52 g, 2.0 mmol) in 10 ml ~oluene, thionylchloride (2 ml, 23 mmol), and a few drops of DMF was heated at 60C --for 3 h. The solvent was evaporated and the residue was dissolved in 15 ml of dichloromethane and evaporated again. The residual acyl chloride was dissolved in 15 ml, dichloromethane and a solution of the crude amin from above (O.51 g, 1.6 mmol) and triethylamine (O.45 g, 3.2 mmol) in 10 ml dichloromethane was added with cooling.
After stirring overnight the solvent was evaporated and -the residue was partitioned between dil. HCl and ether.
The organic phase was extracted with water and the combined water phases were made alkaline and extracted repeatedly with chloroform. Drying (Na2SO4) and evaporation gave 0.57 g of the product as an oil. The ~-base was dissolved in aceton and treated with oxalic acid -affording O.9S g of the title product.
M.p. 174-175-C. ~`
In an analogous way the following compounds (examples 31-34) were prepared~
~xamole 31 1-(4~Amino-3-trifluoromethvlPhenvl)-4-(4-benzamido-1- -butvl)~iperazine M.p. 117-120-C. ;~
.. . :
WO93/21179 21 09 81 ~ 36 PCT/SEg3/0029 xam~le 32 1-(4-Amino-3-trifluoromethvl~henYl)-4-~5-(5-bromo-2,3=
dimethoxvbenzamido)-1-~entvll~iperazine dioxalate S ~, M.p. 151-154-C.
~xample 33 10 1-(4-Amino-3-trifluoromethYlPhenY1)-4-~4-(2-norbornanecarboxamido)-1-butYll~i~erazine hYdrochloride M.p. 77-80 C.
15 Example 34 (R,endo)-1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(2-norbor anecarboxamido)-l-but~llPiPerazine hYdrochloride M.p. 142-146-C.
~xamDle 35 (Method E) 1-(4-Amino-S-bromo-3-trifluoromethYlPhenvl)-4-(4-2S ~hthalimido-1-butvl)~i~erazine oxalate The product in Example 13 (1.0 g, 2 mmol) was dissolved in 20 ml dioxane and 5 ml methanol. Bromine (350 mg, 2.2 ~mol) dissolved in 3 ml dioxane was added and the mixture stirred at ambient temperature for 5 hours, the solvent evaporated, the residue made alkaline with 2 M aqueous NaOH and extracted with methylene chloride. The solvent was removed and the residue dissolved in diisopropyl ether and a precipitate of the title compound was obtained with oxalic acid dissolved in ethanol.
M.p. 172-175-C.
WO93/21179 21 0 9 81 6 PCT/SE93/0029~
Exam~le 36 (intermediatei com~ound ~I~
N-(5-Bromo~entyl)-3-methoxvphthalimide 3-Methoxyphthalic anhydride (3.0 g, 16.8 mmol) and 5-amino-l-pentanol(1.7 g, 16.8 mmol) were mixed and heated to 120C for 2 h. After cooling phosphorus tribromide (3.5 g, 13 mmol) was added and the mixture heated to 110C for 2 h and poured into ice, extracted with ethyl acetate and the organic phase was separated, dried and the solvent evaporated. The residue was crystallized fro~
ethyl acetate/hexane.
M.p. 65-67 C.
Example 37 (intermediate comDound ~I ) N-(5-Tosvloxv~entvl~-5-bromo-2,3-dimethoxYbenzamide A solution of 5-bromo-2,3-dimethoxybenzoic acid (l.56 g, -
sodium hydroxide. The organic phase was dried and evaporated. The residue was recrystallized from hexane to yield 440 mg of the target product.
M.p. 70 - 71-C.
Examole 27 (Method B) -1-(4-Amino-3-trifluoromethvl~henvl)-4-(4-Phthalimido-1 butYl)-~i~erazine. -~
4-~4-Acetamino-3-trifluoromethylphenyl)-1-(4-phthalimido-1- butyl)-piperazine (4.9 mg, 0.01 mmol), dissolved in 2 ml ethanol and 0.2 ml 2 M hydrochloric acid, was heated for 5 h at 80 C. The solvent was removed and the residue was shown by gas chromatography to be identical with the product in example 1.
:
. :"
)93/21179 21 (~ I 6 34 PCr/SE93/0029~
Exam~le 28 (Method C) :
4-(4-Amino-3~trifluoromethylPhenvl)-1-(4-Phthalimido-l-butYl)-piperazine -~
S
To a refluxing solution of 4-phthalimido-1-butanal (0.713 -g 3.25 mmol) and N-(4-amino-3-trifluoromethylphenyl)-piperazine (0.804 g, 3.25 mmol) in CHCl3 (10 ml) was added dropwise 98% formic acid in ^HCl3 (10 ml) n 20 lQ min. The solution was heated under reflux for 2 h. The solvent was removed and the residue purified b~
chromatography and shown ~ thin laver chromatography and gas chromatography to be identical to the product in example 1.
Example 29 (Method D) 1_14-Amino-3-trifluoromethvlPhenYl)-4-~4-~hthalimido-1-but~l)pi~erazine 4-(4-Amino-3-trifluoromethylphenyl)-1-(4-aminobutyl)-pipera zine(32 mg, 0.1 mmol) and phthalic anhydride (30 mg, 0.2 mmol) dissolved in 1 ml acetic acid were stirred at 75 C for 3 hours. The solvent was removed and the residue was shown by gas chromatography and thin layer chromatography to be identical with the product in example 1.
~xamDle 30 (Method D) 1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(5-bromo-2,3-dimethoxYbenzamido)-1-butvll~i~erazine dioxalate , .
The product from example 1 (3.3 ~, 6.4 mmol) was dissolved in 60 ml ethanol, made alkaline with 2 M NaOH, `
and the base was heated with hydrazine hydrate (2.0 ml) at 75C for 3.5 h. After cooling, the solution was WO93/21179 2 1 0 9 8 1 6 PCT/SE93/0029~ ~
acidified with 27 ml ~ M HCl and evaporated. The residue was dissolved in 75 ml H2O and 75 ml ether. The aqueous ;~
phase was made alkaline and extracted with chloroform. ~
The solvent was evaporated to yield crude 1-(4- ~-aminobutyl)-4-(4-amino-3-trifluoromethylphenyl)-piper azine. A solution o~ 5-bromo-2,3-dimethoxybenzoic acid (O.52 g, 2.0 mmol) in 10 ml ~oluene, thionylchloride (2 ml, 23 mmol), and a few drops of DMF was heated at 60C --for 3 h. The solvent was evaporated and the residue was dissolved in 15 ml of dichloromethane and evaporated again. The residual acyl chloride was dissolved in 15 ml, dichloromethane and a solution of the crude amin from above (O.51 g, 1.6 mmol) and triethylamine (O.45 g, 3.2 mmol) in 10 ml dichloromethane was added with cooling.
After stirring overnight the solvent was evaporated and -the residue was partitioned between dil. HCl and ether.
The organic phase was extracted with water and the combined water phases were made alkaline and extracted repeatedly with chloroform. Drying (Na2SO4) and evaporation gave 0.57 g of the product as an oil. The ~-base was dissolved in aceton and treated with oxalic acid -affording O.9S g of the title product.
M.p. 174-175-C. ~`
In an analogous way the following compounds (examples 31-34) were prepared~
~xamole 31 1-(4~Amino-3-trifluoromethvlPhenvl)-4-(4-benzamido-1- -butvl)~iperazine M.p. 117-120-C. ;~
.. . :
WO93/21179 21 09 81 ~ 36 PCT/SEg3/0029 xam~le 32 1-(4-Amino-3-trifluoromethvl~henYl)-4-~5-(5-bromo-2,3=
dimethoxvbenzamido)-1-~entvll~iperazine dioxalate S ~, M.p. 151-154-C.
~xample 33 10 1-(4-Amino-3-trifluoromethYlPhenY1)-4-~4-(2-norbornanecarboxamido)-1-butYll~i~erazine hYdrochloride M.p. 77-80 C.
15 Example 34 (R,endo)-1-(4-Amino-3-trifluoromethYlPhenvl)-4-~4-(2-norbor anecarboxamido)-l-but~llPiPerazine hYdrochloride M.p. 142-146-C.
~xamDle 35 (Method E) 1-(4-Amino-S-bromo-3-trifluoromethYlPhenvl)-4-(4-2S ~hthalimido-1-butvl)~i~erazine oxalate The product in Example 13 (1.0 g, 2 mmol) was dissolved in 20 ml dioxane and 5 ml methanol. Bromine (350 mg, 2.2 ~mol) dissolved in 3 ml dioxane was added and the mixture stirred at ambient temperature for 5 hours, the solvent evaporated, the residue made alkaline with 2 M aqueous NaOH and extracted with methylene chloride. The solvent was removed and the residue dissolved in diisopropyl ether and a precipitate of the title compound was obtained with oxalic acid dissolved in ethanol.
M.p. 172-175-C.
WO93/21179 21 0 9 81 6 PCT/SE93/0029~
Exam~le 36 (intermediatei com~ound ~I~
N-(5-Bromo~entyl)-3-methoxvphthalimide 3-Methoxyphthalic anhydride (3.0 g, 16.8 mmol) and 5-amino-l-pentanol(1.7 g, 16.8 mmol) were mixed and heated to 120C for 2 h. After cooling phosphorus tribromide (3.5 g, 13 mmol) was added and the mixture heated to 110C for 2 h and poured into ice, extracted with ethyl acetate and the organic phase was separated, dried and the solvent evaporated. The residue was crystallized fro~
ethyl acetate/hexane.
M.p. 65-67 C.
Example 37 (intermediate comDound ~I ) N-(5-Tosvloxv~entvl~-5-bromo-2,3-dimethoxYbenzamide A solution of 5-bromo-2,3-dimethoxybenzoic acid (l.56 g, -
6.0 mmol) in 25 ml toluene, thionyl chloride (6 ml, 70 mmol), and a few drops of DMF was heated at 60C for 3 h.
The solvent was evaporated, and the residue dissolved in 20 ml dichloromethane and evaporated again. The residual acid chloride was dissolved in 20 ml dichloromethane and -added to a solution of ~-aminopentanol (l.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml dichloromethane at -35 C and the temperature allowed to rise to O C in 4 h. The solution was washed with dilute HCl, the organic phase separated, and the solvent removed to yield 2.2 g of a crude oil. This oil was dissolved in 20 ml dichloromethane, triethylamine (4 ml, 28 mmol) and tosylchloride (l.33 g, 7 mmol) were added, and the mixture was stirred at ambient temperature overnight.
Ethyl ether (lO0 ml) was added and the organic phase washed with sodium carbonate solution and water. After drying, the organic solvent was evaporated to yield 2.7 g (5.5 mmol) of the title product as an oil.
.
WO93/21179 2 1 ~ 9 ~1 ~ 38 Pcr/sF93/oo29~
1H NMR(CDCL3) d 7.9 (bs, 1 H), 7.81 (d, 1 H), 7.77 (d, 2 H), 7.34 (d, 2 H), 7.13 (d, 1 H), 4.03 (t, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.42 (q, 2 H), 2.44 (s, 3 H), 1.73-1.40 (m, 6 H).
Example 38 (intermediate com~ound IV) 1-(4-Nitro-3-trifluoromethYlphen~1)-4-(~hthalimido-1-butvl~piperazlne '' ~he compound from example 39 (8.5 g, 30 mmol), 4-1 -~romobutylphthalimide (1'.1 g, 40 mmol), potassium carbonate (S.0 g, 36 mmol) and a catalytic amount of potassium iodide were warmed to 90 C in 80 ml DMF for 6 h. The mixture was poured into 500 ml water and extracted ~-with methylene chloride. The organic phase was dried, the ~-solvent evaporated and the resid~e triturated with ethanol/diisopropyl ether to yield a yellow, crystalline product.
M.p. 152-154-C.
ExamDle 39 (intermed~ate compound XIII) . -..
1-(4-Nitro-3-trifluoromethvl~henvl)PiPerazine A mixture of 22,4 g (0.1 mol) of 4-nitro-3-trifluoro-methyl-1-chlorobenzene, 50,0 g (0.58 mol) of anhydrous piperazine and a catalytical amount of KI in 80 ml of 1-propanol was stirred and heated at lOO C overnight. After cooling, 1 1 of ice-water was added with stirring. The yielded precipitate was filtered off, washed with water and dried.
Yield 26.6 g (94%). M.p. 81-83-C.
W~093/21179 2 1 ~ 9 8 1 ~ PCT/SE93/00295 Example 4 0 ( interme~liate comDound XI~I ) 4 -Amino - 2, 6 -di chloroPhenvlPiPeraz ine 2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol~, dissolved in 100 ml methanol and 10 ml 2 M HCl, was hydrogenated with platinum on carbon as catalyst at NTP in 8 h. The catalyst was filtered off and the solvent removed. The residue was dissolved in ether and made alkaline to yield 5.1 g (29 mmol) of a grey crystalline powder. This product was reacted with bis-(2-chloroethyl)amine hydrochloride (5.4 g, 30 mmol) with heating to lOO C in -n-butanol with 3xl g sodium carbonate (30 mmol) for 26 h.
The solvent was evaporated, the residue taken up in ether and made alkaline to yield 3.4 g (48 %) of product as an ~-~
oil. -lH NMR(CDCL3) d 6.82 (s, 2 H), 4.10 (s, 2 H), 3.02 (m, 8 H~, 1.82 (s, 1 H).
Pharmaceutical ~re~arations The following examples illustrate suitable pharmaceutical compositions to be used in the method of the invention.
For the preparation of tablets the following compositions can be made. -Com~osition 1 Compound according to Example 1 50 g --30Lactose 85 g Potato starch 40 g ~ ~
Polyvinylpyrrolidone 5 g ~-Microcrystalline cellulose 18 g Magnesium stearate 2 g ~---21(~9~1~ 40 Com~osition 2 Co~pound according to Example 1 100 g Lactose 90 g Potato starch 50 g Polyvinylpyrrolidone 5 g Microcrystalline cellulose 23 g r~
Magnesium stearate 2 g -. .
From the above compositions 1 000 tablets can be made, containing S0 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. hydroxypropyl methyl cellulose in an organic solvent or using water.
Pharmacoloqv It is generally accepted that drugs that bind to dopamine D2 receptors and are antagonists at these receptors will be clinically effective as antipsychotic agents (for example in schizophrenia). It is also believed that a serotoninergic (5HTlA) receptor affinity as an agonist can be a useful property by reducing the incidence of extrapyramidal side effects and by increasing the efficacy of the substance in psychoses. These substances by having a certain ratio of D2 and 5HTlA binding will retain an antipsychotic effect at the same time as having a reduced incidence of side effects and improved efficacy.
Table 1 illustrates the binding affinities (Ki values, nM) of several iof the compounds at dopamine (D2 ) and serotonin ( 5HTlA) receptors and the ratios D2/5HTlA.
The pharmacological methods are described below.
WO 93/21179 2 1 D 9 81 S PCl/SE93/0029~i D2 Receptor Bindin~ Assav .. .
Tissue preparation: The rats are decapitated and the striata dissected out on ice. The tissue is homogenized at O C in 20 ml 0.05 M Tris-HCl buffer pH 7.7, using a sranson s30 sonifier. The homogenate is centrifuged at 4 C for 10 minutes at 48000 g, in a Sorvall RC-5B ;
Refrigerated Superspeed Centrifuge. The pellet is resuspended and recentrifuged. The final pellet is resuspended in incubation buffer (0.05 M Tris-HCl pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaC12, 1 mM MgCl2 and 10 ~M pargylin), to a final :-concentration of 2.5 mg wet weight/0.5 ml. The homogenate is preincubated for 10 min at 37 C.
Receptor binding assay: Various concentrations of the test compound, the radioligand (lnM 3H-Raclopride) and the homogenate are incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 ~M (+)-Butaclamol~ The incubation is terminated by rapid filtration through glass fiber paper (Whatman GF/B) and subsequent washing with cold -~
incubation buffer, using a cell harvester equipment. The radioactivity of the filters is measured in a Packard 2200CA liquid scintillation counter. Data is analyzed by non-linear regression using the LIGAND program, and -~
presented as Ki values.
.:
5-HTl~ Rece~tor bindina Assa~ -~
Tissue preparation. Cerebral cortex + hippocampus from each rat was dissected and homogenized in 15 ml ice-cold 50mM Tris-HCl buffer 4.0 mM CaC12 and 5.7 mM ascorbic acid, pH 7.5 with an Ultra-Turrax (Janke & Kunkel, Staufen, FRG) for ten s. After centrifugation for 12.5 -min at 17,000 rpm (39,800 x g in a Beckman centrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA),
The solvent was evaporated, and the residue dissolved in 20 ml dichloromethane and evaporated again. The residual acid chloride was dissolved in 20 ml dichloromethane and -added to a solution of ~-aminopentanol (l.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml dichloromethane at -35 C and the temperature allowed to rise to O C in 4 h. The solution was washed with dilute HCl, the organic phase separated, and the solvent removed to yield 2.2 g of a crude oil. This oil was dissolved in 20 ml dichloromethane, triethylamine (4 ml, 28 mmol) and tosylchloride (l.33 g, 7 mmol) were added, and the mixture was stirred at ambient temperature overnight.
Ethyl ether (lO0 ml) was added and the organic phase washed with sodium carbonate solution and water. After drying, the organic solvent was evaporated to yield 2.7 g (5.5 mmol) of the title product as an oil.
.
WO93/21179 2 1 ~ 9 ~1 ~ 38 Pcr/sF93/oo29~
1H NMR(CDCL3) d 7.9 (bs, 1 H), 7.81 (d, 1 H), 7.77 (d, 2 H), 7.34 (d, 2 H), 7.13 (d, 1 H), 4.03 (t, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.42 (q, 2 H), 2.44 (s, 3 H), 1.73-1.40 (m, 6 H).
Example 38 (intermediate com~ound IV) 1-(4-Nitro-3-trifluoromethYlphen~1)-4-(~hthalimido-1-butvl~piperazlne '' ~he compound from example 39 (8.5 g, 30 mmol), 4-1 -~romobutylphthalimide (1'.1 g, 40 mmol), potassium carbonate (S.0 g, 36 mmol) and a catalytic amount of potassium iodide were warmed to 90 C in 80 ml DMF for 6 h. The mixture was poured into 500 ml water and extracted ~-with methylene chloride. The organic phase was dried, the ~-solvent evaporated and the resid~e triturated with ethanol/diisopropyl ether to yield a yellow, crystalline product.
M.p. 152-154-C.
ExamDle 39 (intermed~ate compound XIII) . -..
1-(4-Nitro-3-trifluoromethvl~henvl)PiPerazine A mixture of 22,4 g (0.1 mol) of 4-nitro-3-trifluoro-methyl-1-chlorobenzene, 50,0 g (0.58 mol) of anhydrous piperazine and a catalytical amount of KI in 80 ml of 1-propanol was stirred and heated at lOO C overnight. After cooling, 1 1 of ice-water was added with stirring. The yielded precipitate was filtered off, washed with water and dried.
Yield 26.6 g (94%). M.p. 81-83-C.
W~093/21179 2 1 ~ 9 8 1 ~ PCT/SE93/00295 Example 4 0 ( interme~liate comDound XI~I ) 4 -Amino - 2, 6 -di chloroPhenvlPiPeraz ine 2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol~, dissolved in 100 ml methanol and 10 ml 2 M HCl, was hydrogenated with platinum on carbon as catalyst at NTP in 8 h. The catalyst was filtered off and the solvent removed. The residue was dissolved in ether and made alkaline to yield 5.1 g (29 mmol) of a grey crystalline powder. This product was reacted with bis-(2-chloroethyl)amine hydrochloride (5.4 g, 30 mmol) with heating to lOO C in -n-butanol with 3xl g sodium carbonate (30 mmol) for 26 h.
The solvent was evaporated, the residue taken up in ether and made alkaline to yield 3.4 g (48 %) of product as an ~-~
oil. -lH NMR(CDCL3) d 6.82 (s, 2 H), 4.10 (s, 2 H), 3.02 (m, 8 H~, 1.82 (s, 1 H).
Pharmaceutical ~re~arations The following examples illustrate suitable pharmaceutical compositions to be used in the method of the invention.
For the preparation of tablets the following compositions can be made. -Com~osition 1 Compound according to Example 1 50 g --30Lactose 85 g Potato starch 40 g ~ ~
Polyvinylpyrrolidone 5 g ~-Microcrystalline cellulose 18 g Magnesium stearate 2 g ~---21(~9~1~ 40 Com~osition 2 Co~pound according to Example 1 100 g Lactose 90 g Potato starch 50 g Polyvinylpyrrolidone 5 g Microcrystalline cellulose 23 g r~
Magnesium stearate 2 g -. .
From the above compositions 1 000 tablets can be made, containing S0 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. hydroxypropyl methyl cellulose in an organic solvent or using water.
Pharmacoloqv It is generally accepted that drugs that bind to dopamine D2 receptors and are antagonists at these receptors will be clinically effective as antipsychotic agents (for example in schizophrenia). It is also believed that a serotoninergic (5HTlA) receptor affinity as an agonist can be a useful property by reducing the incidence of extrapyramidal side effects and by increasing the efficacy of the substance in psychoses. These substances by having a certain ratio of D2 and 5HTlA binding will retain an antipsychotic effect at the same time as having a reduced incidence of side effects and improved efficacy.
Table 1 illustrates the binding affinities (Ki values, nM) of several iof the compounds at dopamine (D2 ) and serotonin ( 5HTlA) receptors and the ratios D2/5HTlA.
The pharmacological methods are described below.
WO 93/21179 2 1 D 9 81 S PCl/SE93/0029~i D2 Receptor Bindin~ Assav .. .
Tissue preparation: The rats are decapitated and the striata dissected out on ice. The tissue is homogenized at O C in 20 ml 0.05 M Tris-HCl buffer pH 7.7, using a sranson s30 sonifier. The homogenate is centrifuged at 4 C for 10 minutes at 48000 g, in a Sorvall RC-5B ;
Refrigerated Superspeed Centrifuge. The pellet is resuspended and recentrifuged. The final pellet is resuspended in incubation buffer (0.05 M Tris-HCl pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaC12, 1 mM MgCl2 and 10 ~M pargylin), to a final :-concentration of 2.5 mg wet weight/0.5 ml. The homogenate is preincubated for 10 min at 37 C.
Receptor binding assay: Various concentrations of the test compound, the radioligand (lnM 3H-Raclopride) and the homogenate are incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 ~M (+)-Butaclamol~ The incubation is terminated by rapid filtration through glass fiber paper (Whatman GF/B) and subsequent washing with cold -~
incubation buffer, using a cell harvester equipment. The radioactivity of the filters is measured in a Packard 2200CA liquid scintillation counter. Data is analyzed by non-linear regression using the LIGAND program, and -~
presented as Ki values.
.:
5-HTl~ Rece~tor bindina Assa~ -~
Tissue preparation. Cerebral cortex + hippocampus from each rat was dissected and homogenized in 15 ml ice-cold 50mM Tris-HCl buffer 4.0 mM CaC12 and 5.7 mM ascorbic acid, pH 7.5 with an Ultra-Turrax (Janke & Kunkel, Staufen, FRG) for ten s. After centrifugation for 12.5 -min at 17,000 rpm (39,800 x g in a Beckman centrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA),
7~ ~1 0 9 81 6 42 PCT/SE93/00295 the pellets were resuspended in the same buffer and homogenization and centrifugation repeated. To each pellet 5 ml ice-cold 0.32 M sucrose were added and homogenized for 5 sec. These samples were kept frozen at -70 C. When used they were diluted with the buffer to 8 mg tissue/ml and homogenized for 10 sec. The tissue homogenates were incubated for ten min at 37 C and then supplied with 10 ~M pargyline followed by reincubation for 10 min. The binding assay follow~d that described by Peroutka, J. Neurochem. 47, 529-540, (1986). The incubation mixture (2 mi) contained 3H-8-oH-DPAT (0.25 tQ 8 nM), 5 mg ml tissue homogenate in 50 mM Tris-HCl buffer containing 4.0 mM CaC12 and 5.7 mM ascorbic acid, pH 7.5. Six different concentrations of 3H-8-oH-DPAT were analyzed. Binding experiments were started by the addition of tissue homogeT :e and .ollowed by incubation at 37 C for ten min. ~ ~ incubation mixtures were filtered through Whatman GF/B glass filters with a Brandel Cell Harvester (Gaithersburgh, MD, USA). The filters were washed twice with 5 ml ice-cold 50 mM Tris-HCl buffer, pH 7.S, and counted with S ml Ultima GoldTM
(Packard) in a Beckman LS 3801 scintillation counter. `
Non-specific binding was measured by the addition of 10 ~M S-~T to the reaction mixture. The binding data were processed by non-linear least squares computer analysis ~Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980).
Data were presented as Ki values (nM).
WO 93/2117g ~ 1 0 9 ~ 1 ~ PCr/SE93/00295 CO
.- O O O j O ~, 1-- ¦ co C~l ~" O j C~l ~
~ In I ,.
.C 0 ~ C" N Cl) , 0 t~ ~ I .' I ~
_ r ~, O
~) ¦ I I z z : L ~
~ o~,~Z ~t ¦ o=t~ O--~ O=t~ 0=~
C o o . o o o ¦ O O O j o 3 ~ 3 b a: I I I I I , I
O I a, C ~ Z
(Packard) in a Beckman LS 3801 scintillation counter. `
Non-specific binding was measured by the addition of 10 ~M S-~T to the reaction mixture. The binding data were processed by non-linear least squares computer analysis ~Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980).
Data were presented as Ki values (nM).
WO 93/2117g ~ 1 0 9 ~ 1 ~ PCr/SE93/00295 CO
.- O O O j O ~, 1-- ¦ co C~l ~" O j C~l ~
~ In I ,.
.C 0 ~ C" N Cl) , 0 t~ ~ I .' I ~
_ r ~, O
~) ¦ I I z z : L ~
~ o~,~Z ~t ¦ o=t~ O--~ O=t~ 0=~
C o o . o o o ¦ O O O j o 3 ~ 3 b a: I I I I I , I
O I a, C ~ Z
Claims (13)
1. A compound of the general formula I
or pharmaceutically accetable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and represents an hydrogen atom, a halogen atom or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom or CF3, W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B is a hydrogen atom or A and B together constitute a carbonyl group, 2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A and B are hydrogen atoms or A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then R, m, R4, R5, and R6 are as defined above, n1 and n2 are 1 or n1 is 1 and n2 is 0 or n1 is 0 and n2 is 1, A and B together constitute a carbonyl group,
or pharmaceutically accetable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is situated in the meta or para position of the ring and represents an NO2-group or a group NR7R8 wherein R7 and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and represents an hydrogen atom, a halogen atom or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom or CF3, W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B is a hydrogen atom or A and B together constitute a carbonyl group, 2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, m, R4, R5, and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A and B are hydrogen atoms or A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then R, m, R4, R5, and R6 are as defined above, n1 and n2 are 1 or n1 is 1 and n2 is 0 or n1 is 0 and n2 is 1, A and B together constitute a carbonyl group,
2. A compound according to claim 1 having the formula or or or or or or or or
3. A process for the preparation of a compound of the general formula I as defined in claim 1, characterized by A) reaction of a compound of the general formula II
II
wherein R, m, W, A, B, n1 and n2 are as defined in claim 1 and X is a leaving group with a compound of the general formula III
III
wherein R4, R5 and R6 are as defined in claim 1, or B) conversion of a compound of the general formula IV
IV
wherein R, m, R5, R6, W, A, B, n1 and n2 are as defined in claim 1 and Y is situated in the meta or para position and represents a group which can be transformed to a group R41, where R41 is situated in the meta or para position of the ring and represents a group NR7R8 as defined in claim 1, or C) reaction of a compound of the general formula V
V
wherein R, m, W, A, B, n1 and n2 are as defined in claim 1 and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III
III
wherein R4, R5 and R6 are as defined in claim 1, or D) reaction of a compound of the general formula VI
VI
wherein W, n1, n2, and A are as defined in claim 1, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative with a compound of the general formula VII
VII
wherein m, R4, R5 and R6 are as defined in claim 1, or E) reaction of a compound of the general formula VIII
VIII
wherein R, m, R4, W, A, B, n1 and n2 are as defined in claim 1 and R5 is H,halogen, or CF3 with a suitable halogenating reagent or F) reaction of a compound of the general formula IX
IX
wherein W, n1 and n2 are as defined in claim 1, A and s together represent a carbonyl group, and M represents an alkali metal with a compound of the general formula X
X
wherein X, R4, R5 and R6 are as defined in claim 1, whereafter, if so desired the compound obtained by any of the processes A)-F) is converted to a pharmaceutically acceptable salt thereof.
II
wherein R, m, W, A, B, n1 and n2 are as defined in claim 1 and X is a leaving group with a compound of the general formula III
III
wherein R4, R5 and R6 are as defined in claim 1, or B) conversion of a compound of the general formula IV
IV
wherein R, m, R5, R6, W, A, B, n1 and n2 are as defined in claim 1 and Y is situated in the meta or para position and represents a group which can be transformed to a group R41, where R41 is situated in the meta or para position of the ring and represents a group NR7R8 as defined in claim 1, or C) reaction of a compound of the general formula V
V
wherein R, m, W, A, B, n1 and n2 are as defined in claim 1 and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III
III
wherein R4, R5 and R6 are as defined in claim 1, or D) reaction of a compound of the general formula VI
VI
wherein W, n1, n2, and A are as defined in claim 1, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative with a compound of the general formula VII
VII
wherein m, R4, R5 and R6 are as defined in claim 1, or E) reaction of a compound of the general formula VIII
VIII
wherein R, m, R4, W, A, B, n1 and n2 are as defined in claim 1 and R5 is H,halogen, or CF3 with a suitable halogenating reagent or F) reaction of a compound of the general formula IX
IX
wherein W, n1 and n2 are as defined in claim 1, A and s together represent a carbonyl group, and M represents an alkali metal with a compound of the general formula X
X
wherein X, R4, R5 and R6 are as defined in claim 1, whereafter, if so desired the compound obtained by any of the processes A)-F) is converted to a pharmaceutically acceptable salt thereof.
4. A process according to claim 3 characterized in that compound according to claim 2 is prepared.
5. A compound of the formula II
II
R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, w is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R and m, are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B i S a hydrogen atom or A and s together constitute a carbonyl group, 2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, and m, are as defined above, n1 is 0 or 1, n2 is 0 or 1, A and s are hydrogen atoms or A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then R, and m, are as defined above, n1 and n2 are 1 or n1 is 1 and n2 is 0 or n1 is 0 and n2 is 1, A and B together constitute a carbonyl group.
II
R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, w is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then R and m, are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B i S a hydrogen atom or A and s together constitute a carbonyl group, 2) when W is a carbocyclic ring(s) or a heterocyclic ring then R, and m, are as defined above, n1 is 0 or 1, n2 is 0 or 1, A and s are hydrogen atoms or A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then R, and m, are as defined above, n1 and n2 are 1 or n1 is 1 and n2 is 0 or n1 is 0 and n2 is 1, A and B together constitute a carbonyl group.
6. A compound of the formula III1 III1 wherein R41 is situated in the meta or para position of the ring and represents a group NR7R8 wherein R7 and R8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R5 is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF3, R6 is situated in the ortho, meta or para position and represents a halogen atom or CF3.
7. A pharmaceutical preparation comprising as active ingredient a compound according to any of claims 1-2.
8. A pharmaceutical preparation according to claim 7 in dosage unit form.
9. A pharmaceutical preparation according to claims 8-9 comprising the active ingredient in association with a pharmaceutically acceptable carrier.
10. A compound according to any of claims 1-2 for use as a therapeutically active substance.
11. Use of a compound according to any of claims 1-2 for the preparation of medicaments with effect against mental disturbances.
12. A method for the treatment of mental disturbances in mammals, including man, characterized by the administration to a host in need of such treatment of an effective amount of a compound according to any of claims 1-2.
13. Compounds and processes and intermediates, for their preparation, pharmaceutical compositions containing them, and their use in the treatment of mental disturbances as claimed in claim 1-12 inclusive and substantially as described.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9201138A SE9201138D0 (en) | 1992-04-09 | 1992-04-09 | NOVEL PHTHALIMIDOALKYL PIPERAZINES |
| SE9201138-6 | 1992-04-09 | ||
| CN93118820A CN1099752A (en) | 1992-04-09 | 1993-08-31 | Novel amidoalkyl- and imidoalkyl-piperazines |
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|---|---|
| CA2109816A1 true CA2109816A1 (en) | 1993-10-28 |
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| CA002109816A Abandoned CA2109816A1 (en) | 1992-04-09 | 1993-04-06 | Novel amidoalkyl- and imidoalkyl-piperazines |
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|---|---|
| EP (1) | EP0594813A1 (en) |
| JP (1) | JPH06508378A (en) |
| CN (1) | CN1099752A (en) |
| AU (1) | AU665825B2 (en) |
| BG (1) | BG98281A (en) |
| CA (1) | CA2109816A1 (en) |
| CZ (1) | CZ270193A3 (en) |
| FI (1) | FI935494A0 (en) |
| HU (1) | HUT68891A (en) |
| NO (2) | NO934426D0 (en) |
| SE (1) | SE9201138D0 (en) |
| SI (1) | SI9300191A (en) |
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| WO (1) | WO1993021179A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1266582B1 (en) * | 1993-07-30 | 1997-01-09 | Recordati Chem Pharm | (DI) AZACYLO-HEXANIC AND DIAZACYLO-HEPTANIC DERIVATIVES |
| US5395835A (en) * | 1994-03-24 | 1995-03-07 | Warner-Lambert Company | Naphthalamides as central nervous system agents |
| GB9411099D0 (en) * | 1994-06-03 | 1994-07-27 | Wyeth John & Brother Ltd | Piperazine derivatives |
| FR2742149B1 (en) * | 1995-12-11 | 1998-02-13 | Inst Nat Sante Rech Med | NOVEL 2-NAPHTAMIDE DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS |
| US5703235A (en) * | 1996-03-21 | 1997-12-30 | Neurogen Corporation | N-Aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands |
| US5763609A (en) | 1996-03-21 | 1998-06-09 | Neurogen Corporation | Certain pyrrolo pyridine-3-carboxamides; a new class of gaba brain receptor ligands |
| RU2179554C2 (en) * | 1996-04-05 | 2002-02-20 | Сосьете Де Консей Де Решерш Э Д'Аппликасьон Сьентифик (С.К.Р.А.С.) | Derivatives of piperazine, compounds, pharmaceutical composition |
| HU227543B1 (en) | 2001-09-28 | 2011-08-29 | Richter Gedeon Nyrt | N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them |
| HUP0103987A3 (en) * | 2001-09-28 | 2004-11-29 | Richter Gedeon Vegyeszet | Phenylpiperazinylalkyl carboxylic acid amid derivatives, process for their preparation, pharmaceutical compositions containing them and their intermediates |
| CN1665503A (en) * | 2002-07-04 | 2005-09-07 | 施瓦茨制药有限公司 | Utilization of heteroarene carboxamide as dopamine-D3 ligands for the treatment of cns diseases |
| CN1948298B (en) * | 2006-11-09 | 2010-09-01 | 东南大学 | Dopamine D3 acceptor portion agonist and its application |
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|---|---|---|---|---|
| US3398151A (en) * | 1966-02-01 | 1968-08-20 | Mead Johnson & Co | Azaspirodecanediones and azaspiroundecanediones |
| US3488352A (en) * | 1966-10-11 | 1970-01-06 | Shulton Inc | Basically substituted alkoxy anthranilamides,their corresponding 2-nitro compounds and derivatives thereof |
| US3505338A (en) * | 1966-11-25 | 1970-04-07 | American Cyanamid Co | Thiophenecarbonylalkylene-diamines |
| FR1537901A (en) * | 1967-07-19 | 1968-08-30 | Bruneau & Cie Lab | Amide derivatives of halogeno and nitro benzoic acids and their preparation |
| US3558777A (en) * | 1968-06-21 | 1971-01-26 | Mead Johnson & Co | Pharmacologic processes and compositions containing azaspirodecanediones and azaspiroundecanediones |
| US3465080A (en) * | 1968-10-07 | 1969-09-02 | American Cyanamid Co | Therapeutic compositions containing morpholinoalkylene - indoles and methods of administering such in the treatment of depression |
| JPS504650B2 (en) * | 1971-09-03 | 1975-02-22 | ||
| US3940397A (en) * | 1974-11-13 | 1976-02-24 | E. R. Squibb & Sons, Inc. | 2-[(Substituted-piperazinyl)alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones |
| NL8005133A (en) * | 1980-09-12 | 1982-04-01 | Duphar Int Res | PHENYLPIPERAZINE DERIVATIVES WITH ANTIAGRESSIVE ACTION. |
| US4361565A (en) * | 1981-12-28 | 1982-11-30 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines |
| DE3529872A1 (en) * | 1985-08-21 | 1987-02-26 | Kali Chemie Pharma Gmbh | NEW TETRAOXY CONNECTIONS |
| US4892943A (en) * | 1985-10-16 | 1990-01-09 | American Home Products Corporation | Fused bicyclic imides with psychotropic activity |
| IL90279A (en) * | 1988-05-24 | 1995-03-30 | American Home Prod | Piperazinyl carboxamide derivatives, their preparation and pharmaceutical com¦ositions containing them |
| DE68918832T2 (en) * | 1988-12-28 | 1995-02-09 | Suntory Ltd | Benzoxazepine derivatives. |
| US4939137A (en) * | 1989-06-28 | 1990-07-03 | Ortho Pharmaceutical Corporation | Ring-fused thienopyrimidinedione derivatives |
| AU658134B2 (en) * | 1989-12-28 | 1995-04-06 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
| US5143923B1 (en) * | 1991-04-29 | 1993-11-02 | Hoechst-Roussel Pharmaceuticals Incorporated | Benzoisothiazole-and benzisoxazole-3-carboxamides |
| IT1251144B (en) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | BENZIMIDAZOLONE DERIVATIVES |
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1992
- 1992-04-09 SE SE9201138A patent/SE9201138D0/en unknown
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1993
- 1993-04-06 CA CA002109816A patent/CA2109816A1/en not_active Abandoned
- 1993-04-06 JP JP5518225A patent/JPH06508378A/en active Pending
- 1993-04-06 EP EP93909109A patent/EP0594813A1/en not_active Withdrawn
- 1993-04-06 AU AU39643/93A patent/AU665825B2/en not_active Ceased
- 1993-04-06 HU HU9303520A patent/HUT68891A/en unknown
- 1993-04-06 WO PCT/SE1993/000295 patent/WO1993021179A1/en not_active Application Discontinuation
- 1993-04-06 CZ CZ932701A patent/CZ270193A3/en unknown
- 1993-04-06 SK SK1389-93A patent/SK138993A3/en unknown
- 1993-04-09 SI SI9300191A patent/SI9300191A/en unknown
- 1993-08-31 CN CN93118820A patent/CN1099752A/en active Pending
- 1993-12-06 NO NO934426D patent/NO934426D0/en unknown
- 1993-12-06 NO NO934426A patent/NO180794C/en unknown
- 1993-12-08 FI FI935494A patent/FI935494A0/en not_active Application Discontinuation
- 1993-12-08 BG BG98281A patent/BG98281A/en unknown
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|---|---|
| NO934426L (en) | 1993-12-06 |
| AU665825B2 (en) | 1996-01-18 |
| NO180794B (en) | 1997-03-17 |
| SE9201138D0 (en) | 1992-04-09 |
| NO934426D0 (en) | 1993-12-06 |
| EP0594813A1 (en) | 1994-05-04 |
| AU3964393A (en) | 1993-11-18 |
| NO180794C (en) | 1997-06-25 |
| FI935494A (en) | 1993-12-08 |
| SI9300191A (en) | 1993-12-31 |
| BG98281A (en) | 1994-09-30 |
| HUT68891A (en) | 1995-08-28 |
| SK138993A3 (en) | 1994-11-09 |
| FI935494A0 (en) | 1993-12-08 |
| JPH06508378A (en) | 1994-09-22 |
| WO1993021179A1 (en) | 1993-10-28 |
| CZ270193A3 (en) | 1994-08-17 |
| CN1099752A (en) | 1995-03-08 |
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