GB2255976A - Piperazine derivatives - Google Patents

Piperazine derivatives Download PDF

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GB2255976A
GB2255976A GB9215425A GB9215425A GB2255976A GB 2255976 A GB2255976 A GB 2255976A GB 9215425 A GB9215425 A GB 9215425A GB 9215425 A GB9215425 A GB 9215425A GB 2255976 A GB2255976 A GB 2255976A
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aryl
formula
alkyl
acid
hydrogen
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GB9215425D0 (en
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Ian Anthony Cliffe
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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Priority claimed from GB898909209A external-priority patent/GB8909209D0/en
Priority claimed from GB898924323A external-priority patent/GB8924323D0/en
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    • 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
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    • C07D295/08—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 bound oxygen or sulfur atoms
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    • 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
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    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/16—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 acylated on ring nitrogen atoms
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Abstract

Piperazine derivatives of formula <CHEM> and their pharmaceutically acceptable acid addition salts are disclosed. In the formula n is 1 or 2, R is hydrogen or lower alkyl, R<1> is an aryl or nitrogen containing heteroaryl radical, R<2> is hydrogen or lower alkyl, R<3> is aryl, C4-8 alkyl or aryl(lower)alkyl and X is a functionalised group of specified meaning. The compounds exhibit activity as 5-HT1A antagonists and can be used, into alia, for the treatment of CNS disorders, such as anxiety.

Description

PIPERAZINE DERIVATIVES This invention relates to piperazine derivatives.
The novel piperazine derivatives of the present invention are acids of the formula
where n is one of the integers 1 or 2, R is hydrogen or lower alkyl, R1 is an aryl or nitrogen containing heteroaryl radical, and 3 R3 is an aryl radical, an alkyl radical containing 4 to 8 carbon atoms or an aryl (lower) alkyl radical The acids of formula (I) are useful for preparing amides of formula (II)
where n, R, R1 and R3 are as defined above R5 is hydrogen or lower alkyl and R9 is hydrogen, an alkyl group of 1 to 8 carbon atoms other than a tertiary alkyl group, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl or 8-azaspiro[4.5]deca-7,9-dione-8-yl- (lower)alkyl [with the proviso that when R3 is aryl or aralkyl, R9 is not a phenyl group substituted in the ortho position by halogen, nitro, trifluoroalkyl, cyano, sulphonic acid, sulphonamido, carboxy, carbalkoxy, carboxylanilino or a 4-carboxylamino 9 benzosulphonamido group and that when R is hydrogen, alkyl, aryl or aryl(lower)alkyl R5 is hydrogen or a primary or secondary lower alkyl group] or R5 and R9 together with the nitrogen atom to which they are attached represent an azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl with the further proviso that n is 1 when R5 and R9 are both hydrogen or both methyl and R3 is aryl.
The amides of formula II are described and claimed in our copending UK Application No 9008925.1 (Publication No. 2230781A) of which the present application is a divisional. As explained in our copending application the- amides act on the central nervous system by binding to 5-HT receptors and hence can be used as medicaments for treating humans and other mammals.
The term lower as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of lower alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl and isopentyl.
3 When R3 is an alkyl group of 4 to 8 carbon atoms it may be a straight or branched chain group; a preferred example is tert.-butyl. Preferably R3 is an aryl radical.
When used herein - aryl means an aromatic radical having 6 to 12 carbon atoms (eg phenyl, naphthyl) which optionally may be substituted by one or more substituents commonly used in medicinal chemistry, eg substituents such as lower alkoxy, halogen, trifluoromethyl, nitro, carbalkoxy, carboxamido, cyano, amino, (lower)alkylamino and di(lower)alkylamino.
Examples of aryl(lower)alkyl and aryl(lower)alkoxy include, for example, benzyl and benzyloxy in which the phenyl group may be substituted as defined above.
When used herein "nitrogen containing heteroaryl radical means an aromatic ring containing one or more nitrogen atoms as heteroatoms (eg pyridinyl, pyrimidinyl or pyrazinyl) which may optionally be substituted by one or more lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Preferably the heteroaryl radical is monocyclic.
Preferred compounds of formula (II) are:those in which n is 1; those in which R1 is aryl particularly an optionally substituted phenyl such as o-methoxyphenyl; those in which R is hydrogen; those in which R3 is aryl particularly optionally substituted phenyl.
An amide of formula (II) may be prepared by acylating an amine of formula NHR5R9 (III) NHR R where R5 and R9 are as defined above with an acid of formula (I) as defined above or with an acylating derivative thereof. Examples of acylating derivatives include the acid halides (eg acid chlorides), azides, anhydrides, imidazolides (eg obtained from carbonyldiimidazole), activated esters or O-acyl ureas obtained from a carbodiimide such as a dialkylcarbodiimide particularly dicyclohexylcarbodiimide. Preferably the amine is acylated with the acid in presence of a coupling agent such as l,l -carbonyldiimidazole, isobutylchloroformate or diphenylphosphinyl chloride.
The acids of formula (I) may be prepared by methods known in the art. For example certain acids may be prepared by Michael reaction of an acid of formula CH2=CR3COOH (IV) and a piperazine of formula
in a method similar to the Michael reaction described in our copending Application No 9008925.1 for the preparation of the final products. The acids of formula (IV) are known or may be prepared by methods known in the art.
An alternative method for preparing the acids of formula (I) comprises hydrolysing a nitrile of formula
The nitrile of formula (VI) may be prepared by known methods such as reacting an unsaturated nitrile of formula CH2=CR3CN with a piperazine of formula (V) under Michael conditions or reacting a ketone of formula
with p-toluenesulphonylisocyanide.
The following Examples illustrate the invention.
EXAMPLE 1 a-l-[4-(2-Methoxyphenyl)piperazinyl)methyl}benzene- acetic acid l-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo The solid was triturated with acetone (3 x 100 ml) to give a first crop of product (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallised over 1 month. The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the product (9.01 g) as white crystals, m.p. 160-163 .
(Found: C, 68.4; H, 7.2; N, 7.9.
C20H24N203.0.5H2O requires C, 68.8; H, 7.2; N, 8.0%.) EXAMPLE 2 2-{1-[4-(2-Methoxyphenyl)piperazinyl]methyl}-3-benzene- propanoic acid 2-(Phenylmethyl)propenoic acid (Mannich and Ganz, Chem. Ber., 1922, 55, 3486) (2.00 g, 12.35 mmol) and 1-(2-methoxyphenyl)piperazine (2.37 g, 12.35 mmol) in propanol (25 ml) were boiled under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo.
The residue was triturated with acetone and ether to give the product (0.80 g) as a colourless powder, m.p.
155-158 .
(Found: C, 71.6; H, 7.4; N, 7.6.
C21H26N203 requires C, 71.2; H, 7.3; N, 7.9%.)

Claims (5)

  1. CLAIMS 1. An acid of the formula
    where n is one of the integers 1 or 2, R is hydrogen or lower alkyl, R1is an aryl or nitrogen containing heteroaryl radical, and R is an aryl radical, an alkyl radical containing 4 to 8 carbon atoms or an aryl(lower)alkyl radical.
  2. 2. a-l-[4-(2-Methoxyphenyl)piperazinyl)methyli benzene-acetic acid.
  3. 3. 2-{1-[4-(2-Methoxyphenyl)piperazinyl]methyl}-3- benzene-propanoic acid.
  4. 4. A process for preparing an acid as claimed in claim 1 which comprises carrying out a Michael reaction of an acid of formula 3 CH2=CR COOH (IV) (where R3 is as defined in claim 1) and a piperazine of formula
    (where R and R1 are as defined in claim 1)
  5. 5. A process for preparing an acid as claimed in claim 1 which comprises hydrolysing a nitrile of formula (VI)
    (where n, R, R1 and R3 are as defined in claim 1).
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