GB2230780A - Tertiary alkyl functionalised piperazine derivatives - Google Patents

Tertiary alkyl functionalised piperazine derivatives Download PDF

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GB2230780A
GB2230780A GB9008924A GB9008924A GB2230780A GB 2230780 A GB2230780 A GB 2230780A GB 9008924 A GB9008924 A GB 9008924A GB 9008924 A GB9008924 A GB 9008924A GB 2230780 A GB2230780 A GB 2230780A
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compound
carbon atoms
pharmaceutically acceptable
acceptable salt
alkyl
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GB2230780B (en
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Ian Anthony Cliffe
Magid Abdel-Megid Abou-Gharbia
John Patrick Yardley
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John Wyeth and Brother Ltd
Wyeth LLC
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John Wyeth and Brother Ltd
American Home Products Corp
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    • 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
    • C07D295/14—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
    • C07D295/145—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 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07D295/08—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
    • C07D295/084—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 with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 with the ring nitrogen atoms and the oxygen or sulfur 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
    • C07D295/125—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
    • C07D295/14—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
    • C07D295/145—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 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—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 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

Compounds of the formula <CHEM> in which R<1> is alkyl; R<2> and R<3> are alkyl or taken together they are polymethylene, R<2> and R<3> complete a 5-norbornen-2-yl moiety; X is -CO2-, -OCO-, -OCO2-, -N(R<7>)CO-, -NHNHCO-, -ON(R<7>)CO-, -CON(R<7>)-, -N(R<7>)CO2-, -OCON(R<7>)- or -N(R<7>)CON(R<8>)-, wherein R<7> and R<8> are, independently, hydrogen, alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are halo, alkyl, alkoxy, cyano, nitro or perhalomethyl; R<4> is hydrogen or alkyl; R<5> is hydrogen, alkyl, hydroxyalkyl, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are hydroxy, halo, alkyl, alkoxy, trifluoromethyl, nitro, cyano, carbalkoxy, carboxamido, amino, alkylamino, or dialkylamino; R<6> is phenyl, benzyl, 2-, 3-, or 4-pyridinyl, 2-pyrimidinyl or 2-pyrazinyl, any of which may be substituted by one or more hydroxy, halo, alkyl, alkoxy, trifluoromethyl, nitro, cyano, carbalkoxy, carboxamido, amino, alkylamino or dialkylamino; n is one of the integers 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof, with the proviso that when X is -CON(R<7>)- and R<7> is alkyl, R<6> is other than 2-pyrimidinyl, are antidepressant and/or anxiolytic agents.

Description

i 1 - 1 AHP-9500-F TERTIARY ALK This invention relates to novel tertiary
alkyl functional piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them.
The anxiolytic activity of buspirone and structurally related compounds has been attributed to their selective activity at a serotonin (5hydroxytyptamine; 5HT) subtype receptor designated the 5-HT1A receptor. U. S. Patent No. 4,202,898 discloses the treatment of anxiety and depression with a group of substituted phenylpiperazine derivatives. Among the compounds disclosed as useful for that purpose is 2,2-dimethyipropanoic acid (3-trifluoromethyithio phenyf-piperazino)ethyl ester (column 3, compound 21). The therapeutic value of 5-HT1A receptor agonists in treating multi-CNS disorders has recently been extended to compound structures such as umespirone which has high affinity for both the 5HTIA and D2 receptor binding sites (E.P. DE 3529872, 8719). US 4,797,489 by Abou-Gharbia et al discloses adainantyl- and fluorenylarylpilDerazines and -arylpiperidines which are useful for the treatment of CNS disorders.
In accordance with this invention there is provided a group of novel compounds which exhibit serotonin 5HT1A receptor affinity which characterizes them as antidepressant andlor anxioiytic agents. Some of the compounds of this invention exhibit both 5HT1A receptor affinity and dopamine D2 receptor binding which characterizes them as anxiolytic and/or antidepressant agents with elements of antipsychotic activity. The compounds of this invention are of the following structural formula:
R1 R 4 R5 R2-C-X - C --.CH-,)a-- N \--/ N- R6 AHP-9500-F in which and R1 is alkyl of 1 to 6 carbon atoms; R2 and R3 are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms or taken together with the carbon atom to which they are attached, R2 and R3 complete a 5norbornen-2-yl moiety; X is -C02-, -OCO-, -OC02-, -N(R7)CO-, -NHNHCO-, -ON(R7)CO-, -CON(R7)-, -N(R7)C02-, -OCON(R7)- or -N(R7)CON(R8)_; wherein R7 and R8 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, nitro or perhalomethyl; R4 is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is hydrogen, alkyl of 1 to 8 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are hydroxy, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, carbalkoxy of 2 to 7 carbon atoms, carboxamido, amino, alkylamino of 1 to 6 carbon atoms or dialkylamino of 2 to 12 carbon atoms; R 6 is phenyl, benzyi, 2-, 3-, or 4-pyridinyl, 2-pyrimidinyl or 2pyrazinyl; any of which may be substituted by one or more hydroxy, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trif luo rom ethyl, nitro, cyano, carbalkoxy of 2 to 7 carbon atoms, carboxamido, amino, alkylamino of 1 to 6 carbon atoms or dialkylamino of 2 to 12 carbon atoms; 1 AHP-9500-F n is one of the integers 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof, with the proviso that when X is -CON(R7)- and R7 is alky], R6 is other than 2-pyrimidinyl.
The preferred compounds from the standpoint of production economics and activity profile are those of the formula:
RI R4 R5 R2-C,__X - C ---4CH2),- N N-R6 1 K R I is alkyl of 1 to 6 carbon atoms; is R2 and R3 are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 6 carbon atoms or taken together with the carbon atom to which they are attached, R2 and R3 complete a 5norbornen-2-yl moiety; X is -C02-, -OCO-, -OC02-, -N(R7)CO-, -NI-INHCO-, -ON(R7)CO-, -CON(R7)-, -N(R7)C02, -OCON(R7)- or -N(R7)CON(R8)-, wherein R7 and R8 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, nitro or perhalomethyl; R4 is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, phenyl, benzyi, p- hydro xyphe nyi, p-methoxypheny], omethoxyphenyl, p-chlorophenyl or p-fluorophenyl; R6 is phenyl, 2-alkylphenyl in which the alkyl substituent has 1 to 6 carbon atoms, 2-alkoxyphenyl in which the alkoxy substituent has 1 to 6 AHP-9500-F carbon atoms, 2-halophenyl, 2-cyanophenyl, 2-nitrophenyl, 2perhalomethylphenyl, benzyi, 2-, 3-, or 4-pyridinyf, 2pyrimidinyl or 2pyrazinyl; and n is one of the integers 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof, with the proviso that when X is -CON(R7)- and R7 is alkyl, RE; is other than 2-pyrimidinyl.
The halo substituent referred to in the preceding paragraph may be chloro, bromo-, fluoro- or lodo, the chforo-, bromo- and fluoro- substituents being preferred. For simplicity, the -lower alkyl and alkoxy groups containing 1 to 4 carbon atoms are preferred throughout the molecules. The pharmaceutically acceptable salts are produced conventionally from such acids as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene suifonic, acetic, citric, maleic, succinic acid and the like.
The compounds of this invention present chiral centers depending upon the substituent variations of R1, R2 and R3 and R4 and R5. The optical isomers generated at these positions may be separated and isolated or directly produced from reactants of known or related configurations, by conventional means.
Highly selective 5HT1A receptor binding has been observed with the compounds of this invention in which R5 is alkyl of 4 to 8 carbon atoms or an optionally substituted phenyl or benzyl moiety. These compounds demonstrate only poor relative binding to the D2 and al receptors. As such, their selective anxiolytic activity is clearly indicated.
The compounds of this invention are produced by various conventional methods from commercially available starting materials or reactants producible-by conventional techniques. Thus, for example, the desired" tertiary butyl ureas, carbamates, and carbonates can be prepared by reacting tert-alkylamine or tertalkylalcohol with the appropriate pipe razinylalkanol or pipe razi nylalkyla mine in the presence of phosgene or an appropriate phosgene equivalent such as 1 AHP-9500-F - 5 trichloromethyl chloroformate in a suitable solvent such as methylene chloride, e. g.
R1 1 NI-12 H3 R1 R2-C-N=C = 0 R4 \ HO (CH2-, N \-i N- R' R 4 R$ R 8 H N (CH2n- N N R 6 n R4 R5 0 CH -N N- R 6 o 2n R 3 Carbamates R 4 R5 0 (CH,- N N- R' N N 2 n H R R1 1 R2-C- 1 R3 Ureas Reaction of the above piperazinylalkylamine with a compound of formula R 2 - 0. CO-1. H a 1 13 R 1 (where Hal is halogen) gives a carbonate.
The desired esters may be prepared by esterification of the appropriately substituted piperazinylalkanoll eg with an acid halide in a suitable solvent such as CH 2 cl 2 in the presence of an acid acceptor such as trlethylamine.
AHP-9500-F CR3 c N The desired a-substituted carboxamides can be prepared by acylating a corresponding amine. In one example the appropriately substituted Nbenzylpiperazinylalkylamine is acylated by reaction with an acid halide in methylene chloride and in the presence of triethylamine to afford the Nbenzylcarboxamide intermediate, which is debenzylated to give an intermediate compound in which R 6 is hydrogen. This may be alkylated to the compound of th invention, eg by reaction with the appropriate arylo heteroarylhalide. An example of the process is illustrated below:
Ri 3 -5 1 /--\ --,.1 - CH17;7-IN \--/' N_/"C /1- k AHP-9500-F - 2 1 1^ i ^1 =2- Z4 c i Of course, the reverse esters, amides and carbamates are prepared in the same manner with the oppositely functional reactants. Thus the reverse carbonate may be prepared by reacting a piperazine isocyanate of formula R 4 R 5 OCN.C-(CH 2 -----N with an alcohol of formula.
/ 1 N-R 6 In one method for preparing the reverse amide (in which X is NR 7 CO-) an amine or the formula:
an -nc:e zi 'ne AHP-9500-P 8 - R4 \ R5 HCCC-- x- zln -N N-R6 or with any acylating derivative thereof. Examples of acylating derivatives include the acid halides (eg. acid chlorides), azides, anhydrides, imidazolides (eg obtained from carbonyidiimidazole), activated esters or 0-acyl ureas obtained from a carbodUmide such as a dialkylcarbodiimide particularly dicyclohexylcarbodiimide. Preferably the amine is acylated with the acid in presence of a coupling agent such as 1, 1'-carbonyidiimidazole, LU-butylchloroformate or diphenylphosphinyl chloride. The hydrazides and hydroxamates are produced in the same manner from the substituted hydrazine or substituted hydroxylamine and the desired carboxylic acid. A reverse ester of the invention (le a compound where X is -OCO-) may be prepared by esterification of the above acid with an alcohol of the formula:
R1 1 R- COH 1 M.
Esterification may be carried out by the general methods known in the art.
An alternative method of preparing the compounds of the invention comprises alkylation of a piperazine of the formula:
HN N-R6 \-i with an alkylating agent providing the group:
R' R4 RS R2-C.--- X- C (CH2)n- 1.5 The alkylating agent may be, for example, a compound of the formula:
MP9500-F R1 R4 RS R2-C,._ X- C (CH2)r Z where Z is a leaving group such as halogen or an alkyi- or aryl- sulphonyloxy group. Alternatively where n is 1 the alkylating agent may be an unsaturated compound of the formula:
RI 1 R2-C- X-CR5 = CH2 1 W and the compounds are reacted by means of a Michael reaction. The reaction may be carried out at elevated temperature in the presence of an alcohol.
The amides of the invention in which X is -NH-CO- may be prepared by an alternative method comprising reacting a nitrile of the formula:
R4 \ R6 L n 1.1 C - (CH2)-- N \--/ N-R6 with the tertiary alcohol of the formula:
RI 1 R- C-CM 1 W under acidic conditions as in the Ritter reaction.
A further method of preparing the reverse amides of the invention in which n is 1 comprises the desulphurisation of a sulphur containing compound of the n tormula:
AHP-9500-F S 1 11 /--\ R- xi-imrl,.,u-CHR-5-C-N N-R6 R1 M.
The desulphurisation may be carried out in the presence of a nickel catalyst. The sulphur containing compound may be prepared by a Willgerodt reaction, eg. an aryl alkyi ketone of the formula CH3CO-R-5 is reacted with sulphur and a piperazine of the formula:
HN \--/ N-R6 and the resulting thioamide is treated with a base and with an isocyanate of the formula:
R' 1 R2- C-NCO 1 W The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
is The following Examples illustrate, without limitation, the preparation of representation compounds of this invention.
MP-9500P - 11 Example 1
N-(1,1-Dimethylethyi)-N1-[4-[4-(2-metboxyphenyt)-1piperazinyllbutyi]urea To a suspension of tert-butylamine (0.4 g, 0.005 mol) in 50 mL of dry methylene chloride under a dry nitrogen atmosphere was added triethylamine (1.2 g, 0.01 mol). The resulting solution was refluxed for thirty minutes, and then trichloromethyl chforoformate (0.57 g, 0.002 mol) was added dropwise via syringe and the resulting suspension was refluxed for three hours. The reaction mixture was then allowed to cool to room temperature, and to the cold solution was added a solution of 2- [4- (2- methyoxyph e nyi)- 1 -pipe razinyi]butylam in e (1.5 g, 0.005 mol) in 15 mL of dry methylene chloride, followed by an additional two equivalents of triethylamine (1.2 g, 0.01 mol). The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted to 200 mL with methylene chloride, washed with 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium suffate, and concentrated on a rotary evaporator to a yellow oil. The desired product (TLC on silica gel using a 20% methanol in ethyl acetate solvent mixture, Rf=0.41) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt to afford 0.33 g of the title compound as a trihydroch lo ride, mp. = 167-169C.
is Elemental analysis for C201-134N402.31-IC1 CaVd: C, 50.90; H, 7.90; N, 11.87 Found: C, 51.04; H, 8.04; N, 11.75 Example 2
N-[4-[4-(2-Methoxyphenyl)-1-piperazinyllbutyi]-2,2di methyl propa na mide To a stirred solution of 4-(2-methoxyphenyl) - 1 -pipe razinylbutanamine (1.71 g, 0.006 mol) and triethylamine (0.8 g, 0.008 mol) in 50 mL of methylene chloride, pivaloy]. chloride (0.78 g, 0.006 mol) was added and stirring was continued overnight at room temperature. The methylene chloride solution was AHP-9500-F washed with water, dried over anhydrous M9S04, and evaporated under reduced pressure. The desired product was isolated by high pressure liquid chromatography (HPLC) on silica gel (using a gradient consisting of from 10% ethyl acetate in hexane to 10% methanol in ethyl acetate) and converted to the dihydrochloride salt (0.95 g, 38%), mp. = 191-1960C.
Elemental analysis for C20H33N302.21-IC1.112 H20 Caidd: C, 55.94; H, 8.22; N, 9.79 Found: C, 56.03; H, 8.24; N, 9.89 Example 3
2,2-Dimethylpropanoic acid 2-[4-(2-methoxyphenyi)-1- piperazinyi]ethyl ester Piraloyl chloride (15.0 g, 0.124 mol) and triethylamine (13.1 g, 0.13 mol) were stirred with 1-bromoethanol (15.5 g, 0.124 mol) in CH2C12 at room temperature. The desired product, 2-bromoethylpivalate was recovered for use in the following procedure.
To a stirred solultion of W(2-methoxyph enyl) pipe razin e (3.64 g, 0.019 mol) and triethylamine (6 g, 0.06 mol) in 80 mL of DMF was added 2bromoethylpivalate (4 g, 0.019 mol). The reaction mixture was stirred overnight at room temperature. The DMF was removed under reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The organic layer was washed with water, dried (anhydrous Na2S04) and evaporated. The desired product was separated by preparative HPLC and converted to the dihydrochloride salt, mp. = 193-1951>C.
Elemental analysis for C18)-128N203.21-IC1 CaVd: C, 54.96; H, 7.63; N, 7.12; Cl, 18.07 Found: C, 54.94; H, 7.52; N, 6.97; Cl, 17.69 AHP-9500-F 13 - Example 4
2,2-Dimethylpropanoic acid 3-[4-(2-methoxyphenyl)-1piperazinyi]propyl ester To a stirred solution of 3-[4-(2-methoxyphenyl)- 1 -pipe razinyl]propanol (4.76 g, 0.019 mol) and triethylamine (6 g, 0.06 mol) in 100 mL of methylene chloride was added pivaloyl chloride (2.28 g, 0.019 mol) and stirring was continued overnight at room temperature. The organic layer was washed with water, dried (anhydrous Na2S04) and evaporated. The title compound was isolated by preparative HPLC and converted to the dihydrochloride salt; mp. - 202-2040C.
Elemental analysis for C19H3ON203.21-IC1 Caic'd: C, 56.01; H, 7.86; N, 6.87 Found: C, 56.13; H, 8.09; N, 6.73 EXample 5
2,2-Dimethylpropanoic acid 3-[4-(2-chlorophenyi)-1piperazinyl]propyl ester The title compound was prepared following procedure of Example 4 with the exception that 3-[4-(2-chlorophenyi)-piperazine]propanol (4.89 g, 0.019 mol) was used instead of 3-[4 - (2-metho xyphe nyi) -pipe razi nyi] prop anot. The title compound was converted to the hydrochloride salt, mp. = 186-1880C.
Elemental analysis for Cl 8H27N202MC1 Calc!d: C, 57.06; H, 7.46; N, 7.46 Found: C, 57.73; H. 7.06; N, 7.13 MP-9500F 14 - Example 6
2,2- Di methyl pro pa noic acid 3-[4-(2-pyrimidinyl)-1piperazinyllpropyl ester Pivaloyl chloride (15.0 g, 0.124 mol) and triethylamine (13.1 g, 0.13 mol) were stirred with 1-bromopropanot (17.3 g, 0.124 mol) in CH2C12 at room temperature. The desired product, 3-bromopropylpivalate was recovered for use in the following procedure.
To a stirred solution of W(2-pyrimidinyl)piperazine dihydrochloride (4.25 g, 0.0179 mol) and triethylamine (6.06 g, 0.06 mol) in DMF was added 3bromopropyl pivalate (4.0 g, 0.0179 mol) and the solution was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in CH2C12. The CH2C12 extract was washed with water, dried (anhydrous Na2S04) and evaporated to afford 9.0 g of crude title compound. Purification by HPLC and conversion to the dihydrochloride with ethereal HCl yielded the product, mp. 1781800C.
Elemental analysis for Cl 6H26N402.2HCI.H20 Caic'd: C, 48.36; H, 7.55; N, 14.10 Found: C, 48.00; H, 7.08; N, 13.70 Example 7 (R)-N-[1-Methyi-2-[4-(2-methoxyphenyi)-1piperazinyllethyll trimethylacetamide To a chilled solution of t-butoxycarbonyl D--alanine (9.45 g, 0.05 mol) and 1-(2-methoxyphenyl)piperazine (9.6 g, 0.05 mol) in 125 mi- of CH2C12 was added diethyl cyandphosphonate (8.34 mL, 0.055 mol) in 50 mL of CH2C12 over 30 minutes followed by triethylamine (7.37 mL, 0.055 mol) in 50 mL of CH2C12 over 15 minutes. After 2.5 hour, the solution was washed with water (2 x 100 mL) and K2C03 (2 c 100 mL of 10% aqueous), dried over anhydrous K2C03 and evaporated to an oil. The crude 1 -(t-butoxycarbonyi-D-- a 1 a n y 1) - 4 - ( 2 - AHP-9500-F methoxyphenyi)piperazine was stirred in 200 mL of 4.5 N HCl in ethyl acetate for 1 hour at room temperature, diluted with 400 mL of anhydrous diethyl ether, filtered, washed and dried invacuo. The 1-(D--alanyi)-4-(2methoxyphenyi)piperazine dihydrochioride was stirred in 200 mL of anhydrous THF, treated with 225 mL of 1M BH3 in THF, and refluxed 3.5 hours. After cooling in ice, the reaction was quenched with 140 mL of 2N aqueous HCl and reflexed 18 hours. THF was removed on a RotovaporO, the aqueous solution was made basic with 6N sodium hydroxide and the amine was extracted into diethyl ether. The ether solution was dried over anhydrous K2C03, filtered and acidified with 4.5 N HCI in ethyl acetate. The salt was filtered, washed with diethyl ether, converted to the free base in 2 N NaOH and extracted into diethyl ether. After drying as above and evaporation, the (R)-1methyl-2-14-(2-methoxyphenyi)piperazinyl]ethylamine was obtained as an oil (11.8 g, 94.7% based on BoC-P_-alanine). A sample was converted to the tri hydrochloride sesquihydrate, mp. 219221OC; [alID25 = -26.4 c = 0.99 MeOH. 1 H NIVIR (DMSO-d& 8: 1.32 (d, 3H), 3.8 (s, 3H), 6.9-7.0 (m, 4H), IR was devoid of carbonyl peaks.
Elemental analysis for Cl 4H23N30.3HCL-1.5 H20) Calc'd: C, 43.59; H, 7.58; N, 10.89 Found: C, 43.47; H, 7.08; N, 10.57 (R) - [1 -m ethyl-2-[4- (2-m ethoxyphe nyl)- 1 -pipe razi ny llethylam in e (2.49 g, 0.01 mol) and trimethylacetic acid (2.04 g, 0.02 mol) in 25 mL of CH2C12 were chilled in ice and treated with diethylcyanophospho n ate (3.26 g, 3.1 mL, 0.02 mol) in 10 mL of CH2C12 over 15 minutes followed by Nmethy(morpho line (2.02 g, 2.2 mL, 0.02 mol) in 10 mL CH2C12 over 15 minutes and the reaction was followed by TLC. The reaction was essentially complete after 2 hours. After stirring overnight, the solution was washed with 2N NaOH (2 x 50 mL), and water (2 x 50 mL) and dried (anhydrous K2C03). The product was isolated using dry column chromatography on silica gel (300 g) and development with ethyl acetate. The fraction containing the product (Rf 0.54, uniplate, ethyl acetate) was evaporated to give 3.35 g (98% yield) as an oil which was dissolved in 150 mL anhydrous diethyl ether and precipitated with 4.5 N HCI in ethyl acetate, mp. 185-1880C.Recrystallization of a small sample from methanol and diethyl AHP-9500-F ether did not change the melting point. IR 1650 cm-1. 1 H NIVIR (DMSO d& 8: 1.1 (d, 12H), 3.7 (s, 3H), 7.0 (M, 4H), [alID25 = -11.67, c 1.03 MeOH Elemental analysis for Cl 9H31 N302.21-IC1 Caidd: C, 56.15; H, 8.18, N, 10.34; Cl, 17.45 Found: C, 55.76; H, 7.98; N, 9.98; Cl, 17.16; Example 8
N-2-(4-(2-Methoxyphenyi)-1-piperazine)ethyI 2,2dimethylpropanamide To a solution of 2-(4-(2-m ethoxyph enyl) -1 -pipe razi n e) ethyl amine (3.00 g, 0.0127 mol) in CH2C12 (80 mL) were added trimethylacetyl chloride (1.6 mL, 1.6 g, 0.013 mol) and triethylamine (2.0 mL, 2.8 gy 0. 027 mol) successively. The solution was stirred at room temperature for 24 hours. The solution was washed with H20 and then brine and was dried with M9S04 and upon evaporation of CH2C12 gave 4.25 g of crude product. Purification by flash chromatography (silica gel, hexane, EtOAc, MeOH) provided a pure sample of the free base, 1.19 g. An additional 2.29 g of slightly impure product was recovered. Treatment of the pure sample in EtOH with HOI gave the dihydrochloride of the title compound, 1.13 g, mp. 2432440C.
Elemental analysis for C18H29N302.21-IC1 CaVd: C, 55.10; H, 7.96, N, 10.71 Found: C, 54.78; H, 8.05; N, 10.56 Example 9
INI-(1 1 -Dimethylethyl)-4-(2-methoxyphenyi)-1 piperazineacetamide To a solution of t-butyl chforoacetamide (3.51 g, 0.0235 mol) in DMF (150- 200 mL) was added successively 1-(2-methoxyphenyi)piperazine hydrochloride (5.35 g, 0.0234 mol) and triethyl amine (6.85 mL, 4.97 g, 0. 0491 MP-9500F mol). The solution was stirred at 900C for 4 hours. The DIVIF was evaporated under reduced pressure, The residue was partitioned between CH2C12 and H20. The aqueous phase was extracted once with CH2C12. The combined organic phases were washed once with a small amount of H20 and dried with M9S04. Evaporation of the solvent gave the crude product (6.24 g) which was purified by flash chromatography (silica gel, EtOAc, hexane) to yield the free base (4.8 g). Treatment with HCI in EtOH gave the title compound as the dihydrochloride, mp. 1050C (3.97 g, 43%).
Elemental analysis for Cl 7H27N302.2HCI.H20 CaVd: C, 51.51; H, 7.88; N, 10.670 Found: C, 51.59; H, 8.16; N, 10.39 Example 10
N-(1,1-Dimethylethyi)-4-(2-pyrimidinyf)-1piperazinepropanamide To a suspension of t-butylamine hydrochloride (prepared by treatment of an Et20 solution of t-butylamine (2.7 mL, 1.9 g, 0.026 mol) with HCl) in a solution of 3-bromopropionic acid chloride (4.47 g, 0.0261 mol) with CH2C12 (145 mL) was added N,N-diisopropylethylamine (9.1 mL, 6.8 g, 0.052 mol) over 10-15 minutes at room temperature. The solution was stirred at room temperature for 2.5-3 hours. A few mUs of N,N-diisopropylethylamine were added until the solution became homogeneous. The solution was washed twice with dilute HCI and once with H20, dried with M9S04 and evaporated to provide 3.34 g of N-lert-butyl 3bromopropanamide and N-tert-butyl acrylamide (approximately 36%164% by weight). The reaction mixture was taken up in EtOH (200 mL), and to the solution of amides was added 1-(2pyrimidinyi)piperazine dihydrochloride (6.82 g, 0.0288 mol) and sodium acetate (4.72 g, 0.0575 mol). The mixture was refluxed for 8 days. The solvent was evaporated. The residue was partitioned between CH2C12 and aqueous Na2C03. The CH2C12 phase was washed with aqueous NaCI and dried with M9S04. Evaporation of the CH2C12 gave 5.61 of crude compound which was purified by HPLC to give 4.13 g of free base. Treatment in EtOH with HCI gave the title compound, 4.48 g (46%), mp 220-2220C.
AHP-9500-F Elemental analysis for Cl 5H25NS0.2HCI 112 H20 Caidd: C, 48.25; H, 7.55; N, 18.76 Found: C, 48.42; H, 7.45; N, 18.62 Example 11
2 2-Di methyl propanoic acid 2-[4-(2-pyrimidinyi)-1piperazinyllethyl ester Following the procedure of Example 3, with the exception that W(2pyrimidinyi)piperazine was substituted for W(2methoxyphenyl)piperazine, afforded the title compound which was converted to the dihydrochloride salt with ethereal HCI, mp. 185-1870C.
Elemental analysis for C151-124N402.21-IC1 Caidd: C, 49.32; H, 7.12; N, 15.34 Found: C, 38.24; H, 3.69; N, 37.87 Example 12
Tertiary-butyl 3-[1-[4-(2-methoxyphenyi)piperazinyl]1-2phenylpropanoate A stirred suspension of 2-chloro-1-methylpyridinium iodide (3.28 g, 12.8 mmol) in toluene (20 mL) was treated under an atmosphere of nitrogen with atropic acid (1.80 g, 12.2 mol) treated with tert-butanol (0.92 mL, 11.8 mmol), treated with triethylamine (3.6 mL, 25.8 mmol), heated under reflux for 2 hours, cooled to room temperature and treated with water (100 mL) and diethyl ether (100 mL). The layers were separated and the aqueous layer extracted with diethyl ether (50 mL). The organic phases were combined, washed with water (100 mL), dried (M9S04), evaporated Ln vacuo, and the residue purified by chromatography [silica; hexane-ethyl acetate (201)l to give tert-butyl 2-phenylpropenoate (1.32 g) as an oil.
AHP-9500-F A solution of tert-butyl 2-phenylpropenoate (1.28 g, 6.3 mmol) and 1- (2methoxyphenyl)piperazine (1.22 g; 6.4 mmol) in ethanol (10 mL) was maintained at room temperature for 3 days, evaporated invacuo, and the yellow oil purified by chromatography [silica; hexane-ethyl acetate (5:1)] to give the free base of the product (1.96 g) as colorless crystals, mp. 99-1010C.
A suspension of free base in hot methanol (20 mL) was acidified with ethereal hydrogen chloride. The resulting solution was cooled to cool temperature and the mixture evaporated invacuo. The crystals were triturated with diethyl ether to give the dihydrochloride salt of the product (1.56 g), mp. 190-1930C.
Elemental analysis for C24H32N203.21-IC1 CaVd: C, 61.4; H, 7.3; N, 6.0 Found: C, 61.3; H, 7.5; N, 6.0 Example 13
N-Tertiary-butyl 3-[4-(2-methoxyphenyl)piperazinyl]-2-phenyi- 1-5 propanamide 1-(2-Methoxyphenyi)piperazine (22.6 g, 0.118 mol) and atropic acid (17.4 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 m Q to give a first crop of 3-[4-(2methoxyphenyl)piperazinyll-2-phenylpropionic acid (13.8 g) as white crystals. The filtrate was evaporated jIlvacuo to give an oil which slowly crystallized over 1 month. The solid was triturated with acetone (200 mL) to give a second crop of the same hernihydrate product (9.01 g) as white crystals, mp. 160-1630C.
Elemental analysis for C20H24N203.112 H20 Caidd: C, 68.8; H, 7.2; N, 8.0 Found: C, 68.4; H, 7.2; N, 7.9 A stirred suspension of 3 -[4- (2- m ethoxy phenyl) pipe razi nyl]- 2phenylpropionic acid (5.05 g; 14.7 mmol) in dichloromethane (30 ml) was treated AHP-9500-F with 1,1-carbonyidiimidazole (2.67 g, 16.5 mmol) and, after 35 minutes, the resulting solution was treated with lprl-butylamine (1.9 mi, 18.2 mmol). After 18 hours, the mixture was evaporated invacuo and the residue purified by chromatography (silica, diethyl ether) to give the product (2. 80 g, 48%) as white crystals. A suspension of the solid in methanolisopropanol (2 mi + 6 mi) was acidified with ethereal hydrogen chloride to give a solution which was evaporated _in vacuo to give a solid. Trituration with diethyl ether gave the dihydrochloride salt of the product (3.30 g), mp. 230-2310C.
Elemental analysis for C24H33N302.211C1 Calc'd: C, 61.5; H, 7.5; N, 9.0 Found: C, 61.4; H, 7.5; N, 8.9 Example 14
N-Tertiary-butyl 2-[[4-(2-methoxyphenyl)piperazinyi]methyll-3phenylpropanamide 2-(Ph enyl methyl) prope noic acid (Mannich glai., Chem. Ber., 1922, U, 3486) (2.00 g, 12.35 mmol) and 1 -(2-methoxyphenyl) pipe razin e (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 diethyl ether to give 2- [[4- (2-m ethoxyph e nyl) pipe razinyll m ethyl]-3-ph e ny 1 propanoic acid (0.80 g) as a colorless powder, mp. 155-1580C.
Elemental analysis for C21 H26N203 Caidd: C, 71.2; H, 7.3; N, 7.9 Found: C, 71.6; H, 7.4; N. 7.6 The product of the preceding paragraph (1.60 g, 4.5 mmol) in dichloromethane was treated with 1,1'-carbonyidiimidazole (0.73 g, 4.5 mmol), stirred for one hour, treated with tertiary butylamine (0.66 g, 9. 0 mmol), stirred for eighteen hours, evaporated 1 vacug andthe residue was chromatographically purified (silica; diisopropyl ether gradient- to die-thyl ether). The product was AHP-9500-F dissolved in hot isopropanol and treated with ethereal HCI to obtain the title compound as the hydrochloride salt (0.43 g), mp. 127.5-1300C.
Elemental analysis for C25H35N302MC1.3M H20 CaVd: C, 65.4; H, 8.2; N, 9.2 Found: C, 65.1; H, 8.0; N, 8.9 Example 15
N-[2-[4-(2-Methoxyphenyi)-1-piperazinyl)ethylllmethylcyclohexanecarboxamide To a solution of 2-(4-(2-methoxyphenyl)-1 -piperazinyl) ethyl amine (1.49 g, 0.00633 mol) in CH2C12 (40 mL), 1-methylcyclohexylcarboxylic acid chloride (1.00 g, 0.00622 mol) and triethylamine (1.0 mL, 0.73 g, 0.0072 mol) were added and the mixture stirred at room temperature overnight. The solution was washed with water and dried with M9S04. Evaporation gave 2.28 g of crude material which was purified by HPLC to give the pure free base, 1.54 g. Treatment with HCI in COH gave the title compound as the dihydrochloride, 1.36 g (51%), mp. 1801970C.
Elemental analysis for C21H33N302.2 HCH/2 H20 Caidd: C, 57.13; H, 8.22; N, 9.52 Found: C, 57.40; H, 7.93; N, 9.39 Example 16
4-(2- Methoxyphenyl)-N-(1 -methyl cyclo hexyl)-1 piperazinepropanamide To a suspension of 1-methyl-cyclohexylamine hydrochloride (4.59 g, 0.0307 mol) in CH2C12 (150 mL) was added 3-bromopropionyl chloride (5.26 g, 0. 0307 mol). Diisopropyl ethyl amine (20.7 mL, 15.4 g, 0.119 mol) was added slowly. The mixture was ' stirred at room temperature overnight. The organic phase was filtered, washed and aqueous HCI, water, and dried with MGS04. Evaporation of the CH2C12 gave 5.03 g of a mixture of N-1methylcyclohexyi-2-bromo- AHP-9500-F propanamide and N-1-methylcyclohexyl acrylamide in a ratio of 1 to 3. This mixture (3.0 g, 0.016 mol) was taken up in EtOH (142 mL). To this solution was added 1-(2-methoxyphenyl)piperazine hydrochloride (4.34 g, 0. 0190 mol) and sodium acetate (1.58 g, 0.0193 mol). The mixture was refluxed two days. The EtOH was evaporated. The residue was partitioned between H20 and CH2Ci2. The CH2C12 phase dried with M9S04. Evaporation of CH2C12 gave crude product, 6.77 g. Purification by HPLC gave the pure free base, 2.38 g, which was treated with HCI in EtOH to give the title compound as the dihydrochloride, 2.53 g (37%, based on the amide mixture), mp. 198-2030C.
Elemental analysis for C21 H33N302.2HCl CaVd: C, 58.33; H, 8.16; N, 9.72 Found: C, 58.00; H, 8.39, N, 9.63 Example 17
4-(2- Pyri midi nyi)-N-(1 -methyl cycl o hexyl)- 1 piperazinepropanamide is The title compound was prepared from -1-(2-pyrimidyi)piperazine dihydrochloride (2.77 g, 0.0117 mol), sodium acetate (1.92 g, 0.0234 mol) and the mixture of 3-N-1-methylcyclohexyi-bromopropanamide and N-1methylcyclohexyl acrylamide (1.8 g, 0.0098 mol) in the manner described in Example 16 to give 1.36 g of the title compound as the dihydrochloride (32%, based on the amide mixture), mp. 204-2090C.
Elemental analysis for Cl BH29N50. 2 HCI - 312 H20 Caidd: C, 50.1; H, 7.94; N, 16.24 Found: C, 49.84; H, 7.97; N, 16.19 AHP-9500-F Example 18
N-[2-[4-(2-Methoxyphenyi)-1-piperazinyi]ethyi]-N'-(1methylcyclohexyl)urea is To a solution of oxalyl chloride (35 mL, 51 g, 0.40 mol) in CH2C12 (214 mL) at room temperature was added solid 1-methyi-l-cyclohexanecarboxylic acid (20.05 g,.1410 mol). The solution was stirred at room temperature overnight. The solvent and excess oxalyl chloride were evaporated. The residue was stripped with CH2C12 twice. The 1 -methyl- 1 cyclohexanecarboxylic acid chloride (20.00 g, 0.1425 mol) in Et20, (110 mL) was added to a stirred suspension of concentrated aqueous NH3 (31 mL) in Et20 300 mL at room temperature. The mixture was stirred at room temperature for 3-4 hours. The aqueous layer was acidified to pH 1-2 with 6 M HCl and brine was added. The Et20 layer was separated and washed once with aqueous NaCI, dried with M9S04 and evaporated to remove the Et20 to, give16.40 g of the desired carboxamide. To a solution of Br2 (3.7 mL, 11 g, 0.072 mol) in 20% KOH in H20 (197 mL) at OOC was added solid 1-methyl1cyclohexanecarboxamide (10.00 g, 0.07082 mol). The solution was stirred for 23 hours at 011C and then extracted with C20 twice. Drying with M9S04 and evaporation of the C20 gave 1 -methyi- 1 -cyclohexylisocyanate (5.84 g) as an oil which crystallized slowly.
To a solution of 2-(4-(2-methoxyphenyi)- 1 -piperazinyl) ethyl amine (2. 02 g, 0.00858 mol) in CH2C12 (50 mL) was added 1-methylcyclohexyl isocyanate (1.20 g, 0.00862 mol) and the mixture was stirred at room temperature overnight. The mixture was washed once with H20, dried with M9S04 and evaporated to give the crude product (3.53 g) which was purified by HPLC to give the free base, (2.04 g). Treatment with HCl in COH gave the title compound as the dihydrochloride (1.06 g, 26%), mp. 155- 1610C.
Elemental analysis for C21 H34N402. 21-IC1. 312 H20 CaIdd: C, 53.16; H, 8.29; N, 11.81 Found: C, 53.26; H, 8.24; N, 11.75 AHP-9500-F Example 19
INI-2-(4-(2-Pyri m Idiny 1) -1 -p iperaziny I) et h y I -l methylcycloh exylcarboxa mide The title compound was prepared from 2-(4-(2-pyrimidinyl)-1 - piperazinyl)ethyl amine (1.50 g, 0.00724 mol), 1methylcyclohexylcarboxylic acid chloride (1.16 g, 0.00722 mol) and triethylamine (1.1 mL, 0.80 g, 0.0079 mol) in the manner previously described to give 1.80 g (62%) of product, mp. 2122200C.
Elemental analysis for Cl 8H29N50. 2 HCI Caidd: C, 53.47; H, 7.73; N, 17.32 Found: C, 53.1; H, 7.77; N, 17.15 Example 20 (R)-N-[2-[4-(2-Methoxyphenyi)-1-piperazinyll-1-methylethyll1 -methyl cycl ohexane carboxamide To a chilled solution of t-butoxycarbonyl P-alaninc 0.05 mol) and 1 -(2-methoxyphe nyl) pipe razine (9.6 g, 0.05 mol) in 125 mL of CH2C12 was added diethyl cyanophosphonate (8.34 mL, 0.055 mol) in 50 mL of CH2C12 over 30 minutes followed by triethylamine (7.37 mL, 0.055 mol) in 50 mL of CH2C12 over minutes. After 2 112 hours, the solution was washed with water (2 x 100 mL) and K2C03 (2 x 100 mL of 10% aqueous), dried over anhydrous K2C03 and evaporated to an oil. The crude 1-(t-butoxycarbonyl-D--alanyi)-4-(2- methoxyphenyl)piperazine was stirred in 200 mL of 4.5 N HCl in ethyl acetate for 1 hour at room temperature, diluted with 400 mL of anhydrous diethyl ether, filtered, washed and dried invacuo. The 1-(D--alanyl)-4-(2-methoxyphenyi)piperazine dihydrochloride was stirred in 200 mL of anhydrous tetrahydrofuran, treated with 225 mL of 1M BH3 in tetrahydrofuran, and refluxed 3 112 hours. After cooling in ice, the reaction was quenched with 140 mL of 2N aqueous HCI and refluxed 18 hours The tetrahydrofuran was removed on a Rotovapor, the aqueous solution was made basic with 6N sodium hydroxide and the amine was extracted into diethyl ether. The AHP-9500-F diethyl ether solution was dried over anhydrous K2C03, filtered and acidified with 4.5 N HCl in ethyl acetate. The salt was filtered, washed with diethyl ether, converted to free base in 2 N NaOH and extracted into diethyl ether. After drying as above and evaporation, (R)-1-methyi-2-[4- (2-methoxyphenyl)-piperazinyllethylamine was obtained as an oil (11.8 g, 94.7% based on BOC-2--alanine). A sample was converted to the trihydrochloride sesquihydrate, mp. 219-221OC; faID25 = -26.4 c=0.99 MeOH. 1H NMR (DMSO-d6) 8: 1.32 (d, 3H), 3.8 (s, 3H), 6.9-7.0 (m, 4H). The IR curve was devoid of carbonyl peaks.
Elemental analysis for C14H23N30.3HCI-1.5 H20 Calc'd: C, 43.59; H, 7.58; N, 10.89 Found: C, 43.47; H, 7.08; N, 10.57 RH1 -Methyl -2[4-(2-methoxyphenyi) - 1 -piperazinyi]ethylamine (2.49 g, 0.01 mol) and 1-methylcyclohexane carboxylic acid (2.84 g, 0.02 mol) in 25 mL of CH2C12 were chilled in ice and treated with diethylcyanophosphon ate (3.26 g, 3.1 mL, 0.02 mol) in 10 mL of CH2C12 over 15 minutes followed by N-methyl morpholine (2.02 g, 2.2 mL, 0.02 mol) in 10 mL of CH2Ci2 over 15 minutes. After stirring overnight, the solution was washed with 2N NaOH (2 x 50 mL), water (2 x 50 mL) and dried (anhydrous K2C03). The product was isolated using dry column chromatography on silica gel (300 g) and development with ethyl acetate. The product (Rf 0.59 uniplate, ethyl acetate) was dissolved in 150 mL of diethyl ether and precipitated with 4.5 N HCl in ethyl acetate. Recrystallization from methanolldiethyl ether gave the pure title compound as the dihydrochloride, mp. 180-1850C, lct]25 -9.32 c = 1.09 MeOH.
Elemental analysis for C22H35N302. 21-IC1 CaVd: C, 59.18; H, 8.35; N, 9.41 Found: C, 58.90; H, 8.21; N, 9.04 AHP-9500-F Example 21 (R) -1 -Met h yl-N-[1 -met h yl-2-[4-(2-pyri midi ny l)] -1 piperazinyi]ethyllcyclohexane carboxamide In a manner analagous to Example 20 using t-butoxycarbonyl-D-alanine and 1 -benzylpiperazine, (R)-1 -methyl-2-[4-phenyl methyl- 1 - piperazinyllethyl amine was obtained as an oil. A sample was converted to the trihydrochloride, dihydrate, mp. 246-2480C.
Elemental analysis for Cl 4H23N3. 31-IC1. 2H20 Caidd: C, 44.39; H, 7.92; N, 11.09 Found: C, 44.43; H, 6.89; K 10.71 in a manner analagous to Example 20 using (R)-1-methyl-2-[4-phenyimethyl- 1 -piperazinyl]ethylamine and 1-methylcyclohexanecarboxylic acid, (R)1 - methyl-N-[1 -methyl-2-[[(4-ph eny [methyl- 1 -piperazinyilethyl]cyclo hexanecarboxamide was obtained after crystallization from methanol and diethyl ether, mp. 168-1700C, [(x]25 -8.85 c = 1.02 MeOH.
Elemental analysis for C22H35N30. 21-IC1. 1112 H20 Caidd: C, 57.75; H, 8.81; N, 9.18 Found: C, 57.73; H, 8.76; N, 9.19 The product from the preceding paragraph (6.91g, 0.0151 mol) and 10% palladium on carbon (1 g) were shaken in 95% ethanol (200 mL) on a Parr hydrogenation apparatus until hydrogen uptake stopped and TLC on a sample of base showed no starting material (20 hours). The catalyst was removed by filtration and the filtrate was evaporated to dryness. The solid together with 2-chloropyrimidine (1.81 g, 0.0158 mol), powdered anhydrous potassium carbonate (20.7 g, 0.15 mol) and triethylamine (1 mL) were stirred at 65-700C in dimethylformamide (100 mL) overnight. The solvent was removed on a Rotovapor and the residue was partitioned between water and dichloromethane. The organic layer was washed with water, dried over sodium sulfate and evaporated. The title compound crystallized from hexane. Yield 2.58 g 49.4%, mp. 96-980C, [(xl25 -22.9 c = 1.00 MeOH.
MP9500-F Elemental analysis for Cl 9H31N50 Caidd: C, 66.05; H, 9.04; N, 20.2 Found: C, 65.86; H, 9.43; N, 19.92 Example 22
N-(1,1-Dimethylethyl)-3-[4-(2-methoxyphenyi)-1piperazinyllpropanamide A solution of n-Lell-butylacrylamide (1.799 g, 14.2 mmol) and 1(2methoxyphenyi)piperazine (2.111 g, 11.0 mmol) in propanol (20 mL) was maintained at room temperture for 8 days, evaporated invacuo, and chromatographed [silica; ethanol-ethyl acetate (1:20)] to give the free base of the product as a yellow oil (2.52 g, 72%).
The oil was dissolved in propan-2-ol (10 mL) and the solution acidified with ethereal hydrogen chloride. The mixture was evaporated in vacuo and the precipitate washed with diethyl ether to give the product as the dihydrochloride quarter hydrate (2.36 g, mp. 245-2480C (dec).
Elemental analysis for C181-129N302.21-IC1.114 H20 Caidd: C, 54.5; H, 8.0; N, 10.6 Found: C, 54.9; H, 8.1; N, 10.5 Example 23
2,2- Di methyl propa no ic acid 2-(4-(2-methoxyphenyi)piperazin-l-yi)-1phenylethyl ester A solution of 2,2-dimethylpropanoic acid chloride (0.28 g, 2.34 mmoles) in dichforomethane (10 mL) was added dropwise to a stirred solution of 2- (4-(2methoxyphenyi)piperazin-l-yi)-1-phenylethanol dihydrochloride (0.90 g, 2.34 mmoles) and triethylamine (0.73 g, 7.2 mmoles) in dichloromethane (15.0 mL). The reaction mixture was stirred at room temperature over the weekend and a AHP-9500-F - 28 further quantity of the same acid chloride (0.14 g, 1.17 mmoles) and triethylamine (0.30 g, 1.17 mmoles) was added. The reaction mixture was stirred overnight, filtered, concentrated under reduced pressure and chromatographed on silica gel. Elution with hexane:ethyl acetate (2:1) afforded an oil which was dissolved in acetonitrile and acidified with ethereal hydrogen chloride to give colourless crystals of the title compound as the dihydrochloride (0.91 g), mp. 237.9-240.90C (dec).
Elemental analysis for C24H32N203.2HCl Caidd: C, 61.4; H, 7.3; N, 6.0 Found: C, 6 1. 1; H, 7.4, N, 6.3 Example 24
0-(2-(4-(2-Methoxyphenyl)piperazin-l-yi)ethyi)-N-(2-methyl2propyl)carbamate Tributyltin methoxide (0.05 m[, 0.20 mmoles) was added to a solution of 2(4-(2-methoxyphenyi)piperazin-1 -yi)-1 -phenyl-ethanol (1.50 g, 4.8 mmoles) and t-butyl isocyanate (0.52 g, 5.3 mmoles) in toluene (15.0 mL). The reaction mixture was stirred for two days at room temperature and then chromatographed on silica gel, gradient eluting with hexane:ethyl acetate (2:1 to 12) to afford a colourless low-melting solid (1.93 g) which solidified on standing. The crude product was dissolved in ethyl acetate and acidified with ethereal hydrogen chloride to afford a colourless powder of the title compound as the dihydrochloride (1.63 g), mp. 184.3-188.311C.
Elemental analysis for C24H33N,303.21-IC1 Caidd: C, 59.4; H, 7.5; N, 8.7 Found: C, 59.8; H, 7.5; N, 8.7 AHP-9500-F - 29 Example 25
N-Tert-butyi-2-methoxyphenyi-3-(4-(2-methoxyphenyi)piperazin-l-yl)propanamide A solution of potassium tert-butoxide (5.15 g, 46.0 mmols) in warm tertbutanol (21 m]) was added to a cooled (ice-methanol) suspension of 1(2-[2methoxyphenyi]-2-oxo)ethyl-4-(2-methoxyphenyl)piperazine dihydrochloride (5.00 gm, 12.11 mmols) and tosy 1 methyl isocyan ide (2. 60 g, 13.31 mmols) in dry dimethoxyethane (100 mL). The reaction mixture was slowly allowed to warm to room temperature over 2 hours. Acetic acid (0.80 g, 13.33 mmots) was added to the reaction mixture followed by the addition of ethyl acetate (200 mL). The precipitate formed was filtered off and the filtrate concentrated to about 50 mL under reduced pressure. The concentrate was dissolved in water and washed with ethyl acetate. The combined organic phases were washed with brine, water, dried (M9S04) and. concentrated to afford a brown oil. The crude product was chromatographed on silica gel and gradient eluted with hexane:ethyl acetate (32) to ethyl acetate, to afford a brown oil (3.30 g). A sample (1.0 g) of the oil was dissolved in diisopropylether and acidified with ethereal hydrogen chloride to afford off-white crystals which were recrystallized from diethyl-ether in methanol to give 2-(2-methoxyphenyi)-3(4-(2methoxyphenyi)-piperazin-l-yl)propanenitrile as a dihydrochloride quarterhydrate as colourless crystals (0.75 g), mp. 189-192cC.
Elemental analysis for C21H25N302.2HCI.1/4H20 CaCd: C, 58.9; H, 6.5; N, 9.8 Found: C, 58.7; H, 6.5; N, 9.5 Tert-butanol (1.20 g, 16.2 mmoles) was added to an ice-cooled solution of 2-(2-methoxyphenyl)-3-(4-(2-methoxyphenyi)piperazin-lyl)propanenitrile dihydrochloride (1.90 g, 5.41 mmoles) in methane sulphonic acid (10.0 mL) and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was poured onto ice and basified with a mixture of 2M sodium hydroxide and solid sodium hydroxide. The aqueous layer was washed with ethyl acetate (3 x 30 mL) and the combined organic phases washed with brine (30 mL), water (30 mL), dried (M9S04) and concentrated to afford a brown oil. The crude product was MP-9500F chromatographed on silica gel and gradient eluted with ethyl acetate:hexane (1:1 to 4:1) and finally ethyl acetate to give a brown oil (2.06 g) which solidified on standing. The crude product was dissolved in diethyl ether and acidified with ethereal hydrogen chloride to afford a powder which was triturated in diisopropylether and then recrystallised from a mixture of diisopropylether and ethanol to afford the title compound as a dihydrochloride hydrate (0.30 g), mp. 129.0-132.50C.
Elemental analysis for C2SH35N303.21-IC1.1---120 Caidd: C, 58.1; H, 7.6; N, 8.1 Found: C, 58.5; H, 7.9; N, 7.7 Example 26
N-Tert-butyl-3-[1-[4-(2-methoxy)phenyl]piperazinyl]2phenylpropionhydrazide A suspension of tert-butylhydrazine hydrochloride (0.63 g, 5.0 mmol) in dry tetrahydrofuran (20 mL) was treated with triethylamine (0.7 mL, 0.5 g, 5.0 mmol). To the suspension were added 3-[1 -14- (2-methoxy)phe nyi] pipe razinyl]2-phenylpropionic acid (1.70 g, ' 5.0 mmol) and N,N- dicyclohexylcarbodUmide (1.03 g, 5.0 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated javacuo and the residue was extracted with hot ethyl acetate (50 mL). The precipitate was filtered off and washed, and the filtrate was concentrated in vacuo. The product was chromatographed on silica with eiuant ethyl acetate:toluene, 1Alethyl acetate to give the title compound as the free base (0.79 g), which was dissolved in ethyl acetate (40 mL) to give a solution. This was acidified with ethereal h-drogen chloride (5 mL) to give a precipitate which was triturated with acetonitrile to give the title compound as the dihydrochloride trihydrate (0.56 g), mp. 208-2100C.
1,5 Elemental analysis for C24H34N402.MC1.3H20 Caidd: C, 53.6; H, 7.9; N, 10.49 Found: C, 53.7; H, 7.6; N, 10.2 AHP-9500-F - 31 Example 27
O-Tert-butyl-3-[1-(4-(2-methoxy)phenyi)piperazinyi)-2phenylpropionohydroxamate is A stirred suspension of 0-tert-butylhydroxylamine hydrochloride (628 mg, 5.0 mmol) in dry tetrahydrofuran (20 mL) was treated successively with triethylamine (1.4 m L, 1.02 g, 10 mmol), and 3-[1-[4(2methoxy)phenyi]piperazinyi]-2-phenylpropionic acid (1.70 g, 5 0 mmol). A solution of dicyclohexylcarbodflmide (1.03 g, 5.0 mmol) in dry tetrahydrofuran (5 mL) was added, and the mixture was stirred for 2 hours and was allowed to stand for 81 hours. The suspension was concentrated in vacuo and extracted with hot ethyl acetate (2 x 40 mL). The extracts were concentrated javacuo and the residue chromatographed on silica with eluant ethyl acetate:toluene 1:4/ethyl acetate to give the title compound as the free base (1.39 g). The product was dissolved in methanol (70 mL), and the solution was acidified with ethereal hydrogen chloride (5 mL), concentrated invacuo and the product triturated with acetonitrile to give the title compund as the dihydrochloride (512 mg), mp. 1880C (dec).
Elemental analysis for C24H33N303.2HCI.2H20 CaVd: C, 57.4; H, 7.4; N, 8.4 Found: C, 57.6; H, 7.4; N, 8.35 Example 28 (R)- and (S)-N-Tertlary butyl-3-[4-(2methoxy)phenyl]piperazin-l-yi]-2- phenylpropionamide A solution of di-p-toluoyl-L-tartaric acid monohydrate (4.67 g, 11.55 mmol) in acetonitrile (20 ml) was added in one portion to a solution of compound of Example 13, free base (4.57 g, 11.55 mmol) in acetonitrile (80 mi). The solution was concentrated javacuo to give a white crystalline residue, which was redissolved in boiling acetonitrile (100 mi). The solution was allowed to cool overnight. The bulk solution was filtered, and the remaining crystals were collected, to give the first enantiomer as its di-p-toluoyl-L-tartrate (4.63 g). During the collection of AHP-9500-F the first crop of crystals, crystallisation was observed in the filtrate, and a second crop of crystals was collected separately, to give the second enantiomer as its di-ptoluoyl-L-tartrate (2.86 g). The remaining filtrate was concentrated javacuo to give a foam (1.48 g). The di-ptoluoyl-L-tartrate of the first enantiomer was combined with the foam, and the mixture was recrystallised twice from the hot acetonitrile (100 mi) to give the (R) title compound as its di-p-toluoyi-Ltartrate (3.64 g), m.p. 13011-1450C (dec.).
Elemental analysis for C241-133N302'C20H1808.0.25 H20 Caidd: C, 67.2; H, 6.6; N, 5.3 Found: C, 67.0; H, 6.8; N, 5.3 The di-p-toluoyl-L-tartrate of the second enantiomer was combined with the two residues of recrystallisation of the di-p-toluoyl-L-tartrate of the first enantiomer, and the mixture was dissolved in chloroform (50 mi). The solution was washed with N aqueous sodium hydroxide (60 m]), and the aqueous phase was extracted with chloroform (50 mi). The combined chloroform phases were dried (Na2S04), and concentrated jn vacuo to give a white solid (2.50 g). The solid was dissolved in acetonitrile (25 mi), and a solution of di-p-toluoyl-L-tartaric acid (2.56 g, 6.32 mmol) in - acetonitrile (5 mi) was added. The solution was concentrated Ln vacuo to give a solid residue, which was treated with acetonitrile (20 mi) and heated. During heating, crystallisation was observed, and the mixture was allowed to stand overnight. The product was collected to give the (S)- title compound as its di-p-toluoy]-L-tartrate (4.08 g), 1400-1450C (dec.).
Elemental analysis for C24H33N302C20H1805'0.25 H20 Caidd: C, 67.2; H, 6.6; N, 5.3 Found: G, 67.1; H, 6.6; N, 5.3 The di-p-toluoyi-L-tartrate of the (R)-title compound was dissolved in chloroform (50 ml), and the solution was washed with N aqueous sodium hydroxide (60 m]). The aqueous phase was extracted with chloroform (50 mi), and the combined chloroform phases were dried (Na2S04), and concentrated in vacuo to give 24 _ 7.40C (c, 0.65 in CHC13). The the (R)-title compound as the free base, [all) free base was dissolved in ethyl acetate (90 m]) and the solution was acidified with AHP-9500-F ethereal hydrogen chloride (5 mi). The mixture was concentrated in vacuo, and the residue was triturated with hot acetonitrile (100 mi), to give the (R)-title compound as the dihydrochloride (1.79 g, 76% overall) m.p. 2000-2150C (dec.), [a] 24 + 420C (c, 1.1 in Me01-1-H20, 1:7). D Elemental analysis for C24H33N302.2 HCl Calc'd: C, 61.5; H, 7.5; N, 9.0 Found: C, 61.8; H, 7.5; N, 9.0 The di-p-toluoyl-L-tartrate of the (S)-title compound was treated in the same way as the di-p-toluoy]-L-tartrate of the (R)-title compound, to give the (S)-titie compound as the free base, [a] 24 + 80C (c, 0.55 in CHC13). The free D base was converted to its dihydrochloride with the same procedure used above to give the (S)-title compound as the dihydrochloride (2.03 g, 86% overall), m.p. 2000- 24 21WC (dec.), [a]D 440C (c, 1.1 in MeOH-H20, 1:7).
Elemental analysis for C24H33N302.2 HCl CaVd: C, 61.5; H, 7.5; N, 9.0 Found: C, 61.3; H, 7.3; N, 8.9 The compounds of this invention have been demonstrated to possess 5HT1A receptor binding properties which characterize them as useful anxiolytic and/or antidepressant agents. Where the compounds of this invention also display D2 receptor site binding properties, they also have an anti- psychotic element which is of use in treatment of anxiety, depression, senile dementia (SDAT), Huntington's chorea, stroke and sexual disturbances.
Those compounds in which R5 is alkyl of 4 to 8 carbon atoms or optionally substituted phenyl or benzyl, selectively bind to receptors of the 5-HT1A type to a much greater extent than they bind to other receptors such as al and D2 receptors.
The pharmacological profile of the compounds of this invention resembles that of buspirone obtained by measuring the compound's ability to displace 131-118OH DPAT (dipropylaminotetralin) from the 5-HT1 A serotonin receptor by the AHP-9500-F procedure of Hall Cl a[., J. Neurochem. 44: 1685-1696, 1985. The compounds of this invention, like buspirone, exhibited potent affinity for this serotonin receptor subtype. The anxiolytic activity of buspirone is currently believed to be due, at least in part, to this receptor (Vander Maclen glal., Eur. J. Pharmacol. 1986, 129 (1- 2)123-130.
The D2 dopamine receptor binding study was in accordance with a modification of the procedure of Field Clal., Brain Res., 136, pp. 578584 (1977) and Yamamura gll., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978), wherein homogenized limbic brain tissue is incubated with 3H spiroperiodol and various concentrations of test compounds, filtered and washed and shaken with Hydrofluoro scintillation cocktail (National Diagnostics) and counted in a Packard 460CD scintillation counter. The test results of these studies are as follows:
Affinity for 5HT1A Receptor % Inhibition 91 at 0.1 gM 100 at 0.1 gM 86 at 1 gM 98 at 1 gM 98 at 1 liM Affinity for D2 Receptor % Inhibition CompQund of Example 1 Example 2 Example 3 Example 4 Example 5 89 at 1 gM 99 at 1 piM 58 at 1 gM Example 12
1C5o 11.8 nM 98 at 1 gM 86 at 0.1 gM Example 13
1C50 25.0 nM 86 at 1 gM 69 at 0.1 gM 1C50 1740 nM 32 at 1 pM 8 at 0.1 gM Example 14
IC.5C) 11.4 nM Affinity for SHT1 A 38 at 10 gM Affinity for D2 AHP-9500-F CompQund of Receptor % Inhibition, Receptor So Inhibition at 1 gM 90 at 0.1 gM Example 15 98 at 0.1 gM Example 16 56 at 0.1 gM Example 18 85 at 0.1 gM Example 19 67 at 0.1 gM Example 20 100 at 0.1 gM Example 22 ICSO 287.0 nM 72 at 1 gM 18 at 0.1 gM Example 23 1C50 270.0 nM 78 at 1 gM 27 at 0.1 pM 1-5 Example 24 1C5C) 20.0 nM 97 at 1 gM 73 at 0.1 piM Example 26 1C50 118.0 nM 96 at 1 gM 48 at 0.1 gM The very weak D2 receptor binding exhibited by the compounds of Examples 13 and 14 illustrate the selective 5HT1A receptor binding properties of those compounds mentioned, supra, where R5 is alkyl of 4 to 8 carbon atoms or an optionally substituted phenyl or benzyl moiety.
Hence, the compounds of this invention are anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety and in those instances where meaningful D2 binding occurs as antipsychotic agents for treatment of psychoses such as paranoia and schizophrenia, as well as the related secondary AHP-9500-F 1.0 is conditions of sexual dysfunction, senile dementia (SDAT) and the like. As such, the compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, filters, glidants, compression aids, binders or tabl et-dis integrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain suitable pharmaceutical additivzs suGh as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellents.
AHP-9500-F Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active, it can be administered orally either in liquid or solid composition form.
Preferably, the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; theunit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include 1,5 the specific psychosis of state of anxiety and the size, age and response of the patient.
AHP-9500-FI

Claims (1)

  1. A compound of the formula:
    R 1 R 4 R 5 6 R 2 -C-X--- C (CH 2 ----N N-R 13 R in which R 1 is alkyl of 1 to 6 carbon atoms; (I) R 2 and R 3 are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms or taken together with the carbon atom to which they are attached, R 2 and R 3 complete a 5-norbornen-2-yl moiety; is -CO 2-7 - 0C0-, -OCO 2-p- N(R 7)CO -NHNHCO-, -ON(R 7)CO-, -CON(R 7 N(R 7)CO 2 7 -OCON(R 7)- or -N(R 7)CON(R 8)-; wherein R 7 and R 8 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, nitro or perhalomethyl; 7 9 R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; AHP-9500-Fl R 5 is hydrogen, alkyl of 1 to 8 carbon atoms, hydroxyalkyl of 1. to 3 carbon atoms, phenyl, benzyl, substituted phenyl or substituted benzyl in which the substituents are hydroxy, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro. cyano, carbalkoxy of 2 to 7 carbon atoms, carboxAmido. amino alkylamino of 1 to 6 carbon atoms or dialkylamino of 2 to 1.2 carbon atoms; R 6 is phenyl, benzyl, 2-, 3-, or 4pyridinyl, 2-pyrimidinyl or 2pyrazinyl; any of which may be substituted by one or more hydroxy, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluormethyl, nitro, cyano, carbalkoxy of 2 to 7 carbon atoms, carboxamido, amino, alkylamino of 1 to 6 carbon atoms or dialkylamino of 2 to 12 carbon atoms; and n is one of the integers 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof, with the proviso that when X is -CON(R 7) and R 7 is alkyl, R 6 is other than 2-pyrimidinyl.
    MP-9500Fl A compound as claimed in claim 1. in which R 2 and R 3 are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 6 carbon atoms or taken together with the carbon atom to which they are attached, R 2 and R 3 complete a 5-norbornen-2-yl moiety; R 5 is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, phenyl, benzyl, p-hydroxyphenyl, p-methoxyphenyl, o- methoxyphenyl, p-chlorophenyl or p-fluorophenyl; and R 6 is phenyl, 2-alkylphenyl in which the alkyl substituent has 1 to 6 carbon atoms, 2-alkoxyphenyl in which the alkoxy substituent has 1 to 6 carbon atoms, 2-halophenyl, 2-cyanophenyl, 2-nitrophenyl, 2- perhalomethylphenyl, benzyl, 2-, 3- or 4-pyridinyl, 2-pyrimidinyl or 2- pyrazinyl; MP-9500Fl or a pharmaceutically acceptable salt thereof, with the proviso that when X is -CON(R7.)- and R 7 is alkyl, R 6 is other than 2-pyrimidinyl.
    A compound of Claim 2 in which R 6 is 2, 3 or 4-pyridinyl, 2-pyrimidinyl or 2-pyrazinyl, R 1 R 2 and R 3 are methyl, R 4 and R 5 are hydrogen, X is -CO 2- or NHCO 23 and n is 2.
    A compound of Claim 2 in which R 6 is 2methoxyphenyl, 2-chlorophenyl or 2pyrimidinyl.
    5.
    A compound as claimed in Claim 1 in which R 2 and R 3 are, independently, alkyl of 1 to 6 carbon atoms.
    6. A compound of Claim 1 in which R 2 and R 3 are tetramethylene, pentamethylene or hexamethylene.
    A compound as claimed in any one of Claims 1, 5 or 6 in which R 4 is hydrogen and R 5 is alkyl of 1 to 6 carbon atoms, phenyl or benzyl.
    A compound as claimed in any one of Claims 1, 5, 6 or 7 in which R 6 is 2methoxyphenyl, 2-chlorophenyl or 2-pyrimidinyl.
    AHP-9500-Fl 9.
    10.
    13.
    A compound as claimed in Claim 1 in which R 5 is alkyl of 4 to 8 carbon atoms, phenyl, benzyl, substituted phenyl or benzyl in which the substituents are halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trfluoromethyl, nitro, cyano, carbalkoxy of 2 to 7 carbon atoms, carboxamido, alkylamino of 1 to 6 carbon atoms or dialkylamino of 2 to 12 carbon atoms.
    A compound as claimed in claim 9 in which X 7 7. is N(R)CO or -OCO, where R is hydrogen or alkyl of 1 to 6 carbon atoms, n is 1 and R 2 and R 3 are, independently, alkyl of 1 to 6 carbon atoms.
    The compound of Claim 1 which is N-(1,1-dimethylethyl)-N 1- [4-[4-(2methoxyphenyl)1-piperazinyllbutyllurea, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is N-[4-[4-(2-methoxyphenyl)-1piperazinyllbutyll-2, 2-dimethylpropanamide, or a pharmaceutically acceptable salt thereof.
    The compound of- Claim 1 which is 2,2-dimethylpropanoic acid 2-E4-(2methoxyphenyl) -1-piperazinyllethyl ester, or a pharmaceutically acceptable salt thereof.
    MP-9500-Fl- 1.4.
    16.
    The compound of Claim 1 which is 2,2-dimethylpropanoic acid 3-E4-(2methoxyphenyl) -1-piperazinyllethyl ester, or a pharmaceutically acceptable salt thereof.
    The compound of Claim l which is 2,2-dimethylpropanoic acid 3-E4-(2chlorophenyl) -1-piperazinyllethyl ester, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is 2,2-dimethylpropanoic acid 3-[4-(2pyrimidinyl) -1-piperazinyllethyl ester, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is (R)-N-[1-methyl-2-14-(2-methoxyphenyl)1piperazinyllethyl trimethylacetamide, or a pharmaceutically acceptable salt thereof.
    18. The compound of Claim 1 which is N-2-(4-(2-methoxyphenyl)-1-piperazine)ethy1 2,2-dimethylpropanamide or a pharmaceuticall acceptable salt thereof.
    1.9. The compound of Claim 1 which is N-C1,1-dimethylethyl)-4-(2-methoxyphenyl)-1piperazine acetamide, or a pharmaceutically acceptable salt thereof.
    MP9500-Fl 20. The compound of Claim 1 which is N(1,1d--methyleth.vl)-4-(2pyrimidinyl)-1- piperazinepropanamide, or a pharmaceutically acceptable salt thereof.
    21.
    22.
    The compound of Claim 1 which is 2,2-dimethylpropanoic acid 2-C4-(2pyrimidinyl) -1-piperazinyllethyl ether, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is tertiar-v-butYl 3-[1-C4(2methoxyphenyl) piperazinv'L]12phenyl-propanoate, or a pharmaceutically acceptable salt thereof.
    23. The compound of Claim 1 which is N-tertia-ry-butyl 3-E4-(2-methoxyphenvl) piperazinvll-2phenylpropanamide, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is Ntertiary-butyl 2-[[4(2-methoxyphenyl) piperazinyllmethyll-3- phenylpropanamide, or a pharmaceutically acceptable salt thereof.
    25.
    The compound of Claim 1 which is N-t2-E4-(2-methoxyphenyl)-1piperazinyl)ethylI -1-meth-vlcyclohexanecarboxamide, or a pharmaceutically acceptable salt thereof.
    4 i AHP-9500-FI The compound of Claim 1. which is 4-(2-methoxyphenyl)-N(1methylcyclohexylli-lpiperazinepropanamide, or a pharmaceutically acceptable salt thereof.
    27.
    28.
    The compound of Claim 1 which is 4-(2-pyrimidinyl)-N-(1-methylcyclohexyl)1 piperazinepropanamide, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1. which is N-[2-[4-(2-methoxyphenyl)-1piperazinyllethyl]-N -(1-methylcyclohexyl)urea, or a pharmaceutically acceptable salt therof.
    The compound of Claim 1. which is N-2-(4-(2-pyrimidinyl)-1.piperazinyl)ethyl-lmethylcyclohexylcarboxamide, or a pharmaceutically acceptable salt thereof.
    30. The compound of Claim 1 which is (R)-N-[2-[4-(2-methoxyphenyl)-1piperazinyll-lmethylethyll-1-methylcyclohexane carboxamide, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is (R)-1.-methyl-N-tl-methyl-2-14-(2-pyrimidinyl)11piperazinyllethyllcyclohexane carboxamide, or a pharmaceutically acceptable salt thereof.
    AHP-9500-Fl 32. The compound of Claim 1 which is N(1,1-dimethylethyl)-3-[4-C2-methoxyphenyl)-1- piperazinyll-propanamide, or a pharmaceutically acceptable salt thereof.
    33.
    The compound of Claim 2. which is 2,2dimethylpropanoic acid 2-(4-(2-methoxyphenyl) piperazinlyl)-1- phenylethyl ester, or a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is 0-(2-C4-(2methoxyphenyl)piperazin-l-yl)ethyl)N-(2-methyl-2propyl)carbamate, or a pharmaceutically acceptable salt thereof.
    35. The compound of Claim 1 which is N-tert-butyl-2-methoxyphenyl-3-(4-C2methoxyphenyl) -piperazin-l-yl)propanamide, or a pharmaceutically acceptable salt thereof.
    36. The compound of Claim 1 which is N-tertbutyl-3[1-[4-(2-methoxy)phenyl1 piperazinyll-2-phenyl-propionhydrazide, or a pharmaceutically acceptable salt thereof.
    37.
    The compound of Claim 1 which is 0-tert-butyl3[1-(4-C2methoxy)phenyl) piperazinyll2-phenyl- propionohydroxamate, or a pharmaceutically acceptable salt thereof.
    7 AHP-9500-Fl 38.
    39.
    The connound of Claim 1 which is R) - -v butvl-3-E4-(2-methoxvlnl,enyll- k -N-tert-r -niperazin-!--vl]-2-phenylpropionamide, ol- a pharmaceutically acceptable salt thereof.
    The compound of Claim 1 which is (S)-N-ter-k--;arv butyl-3-E4-C2-methoxy)phenyllpiperazin-l-yll-2- phenylpropionamide, or a pharmaceutically acceptable salt thereof.
    40. A process for preparing a compound claimed in Claim 1 which comprises:
    (a) reacting an amine of formula R 5 \ 6 R 8 HN CH 1 2) n N-R or an alcohol of formula R 4 R = HO C ( C 11-1 /--\ N-R 6 with an appropriate isocyanate to give a urea or carbamate derivative, or (b) esterifying an alcohol of formula R 4 R 5 HO % C ' CH 2) n IN /--\ N-R 6 \-i to give an ester derivative or AHP-9500-Fl (c) acylating an amine of formula 4 R NH 2- CH 17) n, -R to give a carboxamide derivative or (d) alkylating a compound of formula R R 4 R 5 2_1 \ 11,11 -\ NH R C-CO. NH- 2 13 R or (e) acylating an amine of formula 1 R 2 1 7 R C-NHR 13 R with an acid of formula R 4 R 5 1 2) n-N or with an acylating derivative thereof or esterifying the acid with an alcohol of formula R 1 2 1 R -kwUll 13 R or r AFIP-9500-FI (f) reacting a piperazine isocyanate of formula lr--\ 6 N N-R with an alcohol of formula R 1 2 1 R -G OH 13 R 0- (g) reacting a piperazinylalkylamine of formula R R NHR 7 C with a compound of formula 1 R 2 _1 ' C.O.COHal 13 R (where Hal is halogen) or N1 /--\ 6 N-R (h) alkylati-r.g a piperazine of formula HN /--\ N-R 6 wi4.--h an alkylating agent providing the group 2 1 R 13 R or R R 4 R 5 ".-,11.1 X- 2) n AHP-9500-Fl r (i) reacting a nitrile of formula 1 R- NC (CH 11 ---IN N-R 2 n with a tertiary alcohol of formula R 1 2_1 R L-Uh under acidic conditions or (j) desulphu.rising a sulphur containing compound of formula R 1 S 2_ 1 5 0 -- /--\ 6 R C-INrlk-u. CHR. C N N-R 1 3 R or (k) converting a free base of formula (I) into a pharmaceutically acceptable salt thereof.
    or (1) resolving a racemic compound of formula (I) to give an enantiomer.
    r 41. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore, described with reference to any one of Examples 12 to 14.
    1 4 1 AHP-9500-Fl.
    A process for preparing a compound claimed in Clair 1 substant-ially as hereinbefore described with reference to any one of Examples 1 to 11 or 15 to 27.
    43. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore described with reference to Example 28.
    44. A compound as claimed in Claim 1 wherever prepared by the process claimed in any one of claims 40 to 43.
    45. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 39 or 44 in association with a pharmaceutically acceptable carrier.
    46. A compound as described in any one of claims 1 to 39 or 44 for use as a pharmaceutical.
    Published 1990atThe Patent Office, State House,66 71 I-Ilghliolborn. London WC1R4TP. Further copies maybe obtainedfrom. The Patent Office Sales Branch. St Mary Cray, Orpington. Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray. Kent. Con. 1187
GB9008924A 1989-04-22 1990-04-20 Tertiary alkyl functionalized piperazine derivatives Expired - Fee Related GB2230780B (en)

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GB898909209A GB8909209D0 (en) 1989-04-22 1989-04-22 Piperazine derivatives
US07/428,148 US4988814A (en) 1989-04-22 1989-10-27 Tertiary alkyl functionalized piperazine derivatives

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WO1994015919A1 (en) * 1993-01-06 1994-07-21 John Wyeth & Brother Limited Piperazine derivatives
GB2307858A (en) * 1995-12-09 1997-06-11 American Home Prod Compositions containing piperazine derivatives for the treatment of cancer
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US6696450B2 (en) 2001-04-04 2004-02-24 Wyeth Serotonergic agents with long-acting in vivo effects
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GB2262093A (en) * 1991-12-05 1993-06-09 Wyeth John & Brother Ltd Piperazine derivatives useful for treating anxiety
GB2262093B (en) * 1991-12-05 1995-06-07 Wyeth John & Brother Ltd Piperazine derivatives
WO1994008983A1 (en) * 1992-10-17 1994-04-28 John Wyeth & Brother Limited Amide derivatives
US5637701A (en) * 1992-10-17 1997-06-10 John Wyeth & Brother, Limited Process for preparing optically active amide derivatives
WO1994009780A1 (en) * 1992-11-05 1994-05-11 John Wyeth & Brother Limited Use of piperazine derivatives for the treatment of cognitive disorders
AU682155B2 (en) * 1992-11-05 1997-09-25 John Wyeth & Brother Limited Use of piperazine derivatives for the treatment of cognitive disorders
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US6056942A (en) * 1993-02-26 2000-05-02 John Wyeth & Brother, Ltd. 5-HT1A ligands
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FI93832C (en) 1995-06-12
ATE187718T1 (en) 2000-01-15
JPH0320263A (en) 1991-01-29
GB9008924D0 (en) 1990-06-20
AU619677B2 (en) 1992-01-30
HU221315B1 (en) 2002-09-28
IE64038B1 (en) 1995-06-28
EP0395313A2 (en) 1990-10-31
AU5377890A (en) 1990-10-25
PH26582A (en) 1992-08-19
CA2015033C (en) 2000-06-06
HUT54667A (en) 1991-03-28
DE69033393T2 (en) 2000-05-25
FI901982A0 (en) 1990-04-20
FI93832B (en) 1995-02-28
IL94160A (en) 1994-06-24
GB2230780B (en) 1992-10-21
IL94160A0 (en) 1991-01-31
EP0955296A2 (en) 1999-11-10
JP3054677B2 (en) 2000-06-19
GR3032634T3 (en) 2000-05-31
EP0395313A3 (en) 1991-05-08
PT93824A (en) 1990-11-20
IE901417L (en) 1990-10-22
HU902503D0 (en) 1990-08-28
CA2015033A1 (en) 1990-10-22
DK0395313T3 (en) 2000-06-19
DE69033393D1 (en) 2000-01-20
PT93824B (en) 1996-09-30

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