US3717634A - N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones - Google Patents

N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones Download PDF

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US3717634A
US3717634A US00879604A US87960469A US3717634A US 3717634 A US3717634 A US 3717634A US 00879604 A US00879604 A US 00879604A US 87960469 A US87960469 A US 87960469A US 3717634 A US3717634 A US 3717634A
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formula
heteroarcyclic
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piperazine
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Y Wu
J Rayburn
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Mead Johnson and Co LLC
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Priority to US00879604A priority patent/US3717634A/en
Priority to ZA707826A priority patent/ZA707826B/en
Priority to DK589670AA priority patent/DK141753B/en
Priority to NL7017031A priority patent/NL7017031A/xx
Priority to FR7041860A priority patent/FR2073406B1/fr
Priority to CY886A priority patent/CY886A/en
Priority to GB5590870A priority patent/GB1332194A/en
Priority to DE19702057845 priority patent/DE2057845A1/en
Priority to CH1741770A priority patent/CH552607A/en
Priority to CH341874A priority patent/CH552608A/en
Priority to US312543A priority patent/US3907801A/en
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Priority to HK61/77A priority patent/HK6177A/en
Priority to MY151/77A priority patent/MY7700151A/en
Priority to ES530335A priority patent/ES530335A0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

Definitions

  • n is the integer 4 or 5.
  • the symbol -A which connects the spiroglutarimide and the N-(heteroarcyolic)piperazine represents a divalent alkylene chain of 2 to 6 carbon atoms inclusive. Said alkylene chain can be straightor branched-chain hydrocarbon grouping in which the ring connecting bonds are on different carbon atoms such as hexamethylene (CH2 CH2 CH2CH CHzCHz) 2-methyl-1,2-propylene OH2C and the like.
  • the piperazine substituent represented by the symbol B is selected from the group consisting of imidazoyl and a heteroarcyclic. Said heteroarcyclic is represented by the symbol:
  • W and Y are independently selected from th group consisting of CH and nitrogen.
  • heteroancyclic as used herein, it is meant substituents comprised of nitrogen, carbon, and hydrogen which when taken together form a heteroaromatic system.
  • R and R substituents of the heteroarcyclic referred to above are independently selected from the group consisting of hydrogen, lower alkyl from 1 to 4 carbon atoms inclusive, alkoxy of from 1 to 4 carbon atoms inclusive, hydroxy, amino, alkylthio of 1 to 4 carbon atoms inclusive, halogen, trifiuoromethyl, alkanoamido of from 1 to 6 carbon atoms inclusive, and alkanesulfonamido of 1 to 6 carbon atoms inclusive.
  • lower alkyl as employed herein it is meant straight or branched chain alkyl radicals including methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, Z-methylpropyl, and tert.-butyl.
  • alkyl fragment of the alkylthio substituent refers to straight or branched chain radicals described above.
  • Straight or the branched chain alkanes of 1 to 6 carbon atoms inclusive comprise the alkane radical of alkanoamido and alkanesulfonamido groupings.
  • non-toxic pharmaceutically acceptable acid addition salts refers to a combination of compounds of the present invention with relatively nontoxic inorganic or organic acids.
  • acids which may be used are sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, and related acids.
  • Conversion of the compounds of the present invention to pharmaceutically acceptable acid addition salts is accomplished by admixture of these compounds with substantially one chemical equivalent of any of the various acids hereinbefore defined.
  • the reactions are carried out in an inert solvent.
  • Suitable solvents are ethanol, benzene, ethyl acetate, ether, and halogenated hydrocarbons.
  • Method A is carried out by reacting a spiro-substituted glutaric anhydride of Formula II with the l-(w-aminoalkyl) 4 (heteroarcyclic)piperazines of Formula III to provide products of Formula I.
  • the reaction is carried out at elevated temperatures in a reaction inert organic solvent.
  • inert organic solvent as referred to herein is meant any protic or aprotic solvent or diluent which does not enter into the reaction to any substantial degree.
  • Pyridine is the preferred solvent.
  • Temperatures of about 100 C. to about 200 C. are preferred to facilitate completion of the reaction.
  • the duration of the reaction is critical only to the extent of providing maximum yields and reaction periods of from about 16 hr. to as much as 11 days are preferred. The lengthy reaction periods are necessary in some instances to obtain complete conversion of glutaric acid half-amides of Formula VIII which are initially formed when an anhydride of Formula II is combined with an amine of Formula III.
  • the glutaric acid half-amides of Formula VIII may be also transformed into Formula I products by heating in boiling acetic anhydride which is a well known standard organic procedure for ring closure useful in the formation of cyclic imides.
  • Method B is carried out under reaction conditions amply described in literature wherein teritary amines are formed by alkylation of a secondary amine with an alkyl halide, sulfate, phosphate, tosylate, or mesylate.
  • the Formula IV and Formula V intermediates are preferably reacted in an inert liquid reaction medium at temperatures of from about 60 C. to about 200 C. in the presence of a base suitable for use as an acid binding agent.
  • Sodium carbonate is a particularly preferred acid binding agent but other inorganic and tertiary organic base may be employed including other alkali and alkaline earth metal carbonates, bicarbonates, or hydrides and tertiary amines. Reaction periods ranging from about 2 hrs.
  • a particularly preferred solvent is n-butanol but any inert reaction medium is generally applicable to use in this reaction.
  • the duration of the reaction period depends upon the temperature and reaction solvent selected. By way of illustration, alkylation is facilitated and the reaction period is appreciably shortened if dimethylformamide is employed as the reaction medium compared to a solvent such as benzene.
  • Method C is another method useful for preparation of compounds of Formula I.
  • the spiroglutarirnide metal salt depicted by Formula VI is reacted with substituted piperazines of Formula VII.
  • Standard laboratory procedures are employed in carrying out the reaction such as those described for the alkylation step of the Gabriel synthesis-S. Gabriel, Ber. 20, 2224 (1887).
  • the reactants are combined in an inert reaction medium at temperatures ranging from about 25 C. to 200 C.
  • Preferred solvents for carrying out the reaction are dimethylformamide, acetone, benzene, n-butanol, ethanol and the like.
  • N (heteroarcyclic)piperazines of Formula V have been described by K. L. Howard at al. in J. Org. Chem., 18, 1484 (1953). Their procedures are applicable to the preparation of other N-(heteroarcyclic)piperazine intermediates not specifically disclosed but which are required for the preparation of compounds embraced in the present invention.
  • the l-(w-aminoalkyl)-4-(heteroarcyclic)piperazine of Formula III are obtained according to methods described in U.S. Pat. 3,398,151 by alkylation of N- (heteroarcyclic)piperazines of Formula V with haloalkylnitriles to provide 1 (w cyanoalkyl) 4 (heteroarcyclic)piperazine intermediates which are subsequently reduced to the Formula III substituted piperazines.
  • Reduction of the cyano intermediate may be carried out catalytically, preferably with W-6 Raney Nickel catalyst under high pressure, or alternatively with hydrazine and W-6 Raney Nickel.
  • the intermediate azaspirodecane-and undecanediones of Formula IV having the -A-X- group attached to the nitrogen atom are prepared according to procedures described in U.S. Pat. 3,398,151. Reaction 'of the glutaric anhydrides of Formula II with an alkanolamine of the formula H NAOH are carried out under conditions similar to those described hereinabove for Method A.
  • the resulting intermediate .g'lutarimide has the structure shown for Formula IV wherein X is OH. Esterification of this material is accomplished by conventional techniques well known to the art to provide the intermediate of Formula IV.
  • Conventional techniques which are adequately described in the literature are employed to provide the bromides, iodides, phosphates, sulfates, tosylates, and mesylates corresponding to Formula IV.
  • the piperazine reactant of Formula VII having the X-A- grouping attached to the nitrogen atom is prepared according to standard organic procedures.
  • Formula VIII This intermediate is then esterified according to conventional techniques well known to the art to provide the Formula VH reactants. For instance, thionyl chloride acting upon the compounds of Formula VIII provides the Formula VII intermediate in which X is chlorine. In a similar fashion, bromides, and iodides are prepared. Phosphates, sulfates, tosylates, mesylates corresponding to Formula VII are obtained with conventional laboratory techniques.
  • azaspiroalkanedione of Formula I are prepared in accordance with the unitary process of the present invention by reacting a piperazine of the Formula Y-bi NB Formula IX wherein Y is selected from the group consisting of hydrogen (Formula IXa), H 'NA- (Formula IXb), or XA-- (Formula IXc), and A and X are as hereinbefore defined, with a spirO-glutaric acid anhydride of Formula II.
  • N- (heteroarcyclic)piperazine alkyl derivatives of azaspirodecanediones and azaspiroundecanediones are highly active and specific tranquilizing agents and in addition also exhibit anti-emetic properties.
  • Present compounds are improved tranquilizing agents compared to the azaspirodecanediones and azaspiroundecanediones of United States Pat. 3,398,151, in that tranquilizing activity is more potent and specific.
  • Tranquilizing properties of the compounds of this invention can be demonstrated in rats by a shuttle box technique described by I. R. Albert and L. E. .Allen in the Ph'armacologist 4, '152 (1962). This test is designed to differentiate tranquilizing agents from non-specific central nervous system depressants such as sedatives and hypnotics. Tranquilizing effects are observed when the compounds of the present invention are administered intraperitoneally to the rat in dosages ranging from 1.5 to mg./kg. of body weight.
  • the tranquilizing action of the compounds of the present invention can be demonstrated in Rhesus monkeys by observing general behavioral effects. Intramuscular administration of present compounds to the monkey in dosages ranging from 2 to 16 mg./kg. of body Weight affords tranquilizing effects similar to those produced by chlorpromazine.
  • the compounds of the present invention are relatively non-toxic compounds.
  • the intraperitoneal 50% lethality dose of 8 [4 [4 (2pyrimidinyl)- 1 piperazinyl1butyl] 8 azaspiro[-4.5]decane-7,9-dione hydrochloride is 146 mg./kg. of body weight in the mouse.
  • Systemic administration of the compounds of the present invention to mammals in dosages ranging from about 0.01 to 40 mg./kg. of body weight per day induce effective tranquilizing responses in the mammalian recipient.
  • Oral, parenteral and rectal routes are preferred forms of systemic administration.
  • Forms of parenteral administration include intramuscular, intravenous, and subcutaneous administration.
  • the dosage of the compounds of the present invention will vary with the form and mode of administration and in some instances with the particular compound chosen. Generally, it will be found that when a compound of the present invention is administered orally, a larger quantity of the active agent is required to produce the same effect as a smaller quantity thereof which is given parenterally. It is generally preferred to administer the compounds of this invention at a concentration level that will produce effective tranquilizing effects without causing any harmful or deleterious side effects.
  • the compounds of Formula I may be administered to mammals in the form of free bases or in the form of non-toxic acid addition salts.
  • the compounds are relatively insoluble in water but are soluble in most organic sol vents such as lower alkyl alcohols, esters, acetones, chloroform and the like.
  • the present compounds in the form their acid addition salts are, in general, soluble in water and methanol but relatively insoluble in solvents such as benzene, ether, petroleum ether and the like.
  • the compounds of Formula I may be compounded and formulated into pharmaceutical compositions and unit dosage suitable for systemic administration.
  • Organic or inorganic Examples of representative compounds of the present invention prepared according to Procedure 1 are indicated in Table I.
  • compositions considered within the scope of this invention may take the form of tablets, powder, granules, capsules, suspensions, solutions, suppositories, elixirs, ointments and the like. Unit dosages ranging from about 1 to 500 mg. are employed.
  • Suitable pharmaceutical carriers comprise both solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethylene glycol, water, sesame seed oil, peanut oil, propylene glycol, and the like.
  • the azaspiroalkanedione product is purified as the free base by stripping oi the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof.
  • Suitable acid addition salts of the product are prepared by treating an ethanol solution of the free base with an equi-molar amount of the appropriate acid.
  • Examples 8-28.Additional exemplification of compounds of the present invention is given in Table II along with the mode of preparation according to Method A, Method B, or Method C and the appropriate intermediates. Although only a single method of preparation TABLE II-Contlnued Product Ex. No. 11 A Het. Method Intermediates 21 4 (CHz)4- O-C(CH;); B 8-(4-ehlorobutyl)-8-azaspir0I4.5]decane-7,9-dlone and l-[2-(4-tert.-butylpyrimidinympiperazine.
  • azaspiroalkanedione compounds of the present invention are formulated for parenteral administration according to the following example.
  • a sterile solution suitable for intravenous injection is prepared by dissolving 21.9 g. of 8-[4- [4-(2-pyrimidinyl) 1 piperazinyl]butyl] 8 azaspiro[4.5]decane-7,9-dione hydrochloride in 2 liters of water for injection, USP.
  • the solution is adjusted to pH 4.2 with 0.1 N-sodium hydroxide.
  • the solution is sterilized by passage through a bacteriological filter and ml. glass ampules aseptically filled in order to provide 10 mg. of active ingredient per ampule.
  • n is the integer 4 or 5;
  • A is a divalent straight or branched alkylene chain of 2 to 6 carbon atoms inclusive and connects the nitrogen atoms as shown through at least 2 carbon atoms;
  • R and R are independently selected from the group consisting of hydrogen, lower alkyl from 1 to 4 carbon atoms inclusive, and lower alkoxy of from 1 to 4 carbon atoms inclusive;

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Abstract

THE PRESENT INVENTION CONCERNS THE CLASS OF HETEROCYCLIC CARBON COMPOUNDS COMPRISED OF N-(HETEROARCYCLIC)PIPERAZINYLALKYL DERIVATIVES OF AZASPIROALKANEDIONES WHICH HAVE POTENT AND SPECIFIC TRANQUILIZING ACTION AND ANTIEMETIC PROPERTIES. FURTHER, THIS INVENTION IS CONCERNED WITH THE SYNTHETIC PROCESS FOR THE PREPARATION OF N-(HETEROARCYCLIC)PIPERAZINYLALKYLAZASPIROALKANEDIONES WHICH COMPRISES REACTION OF SPIRO-SUBSTITUTED GLUTARIC ANHYDRIDE OR IMIDE WITH N(HETEROARCYCLIC)PIPERAZINE DERIVATIBES. TYPICAL EMBODIMENTS OF THIS INVENTION ARE 8-(4(4-(2-PYRIMIDINYL)-1-PIPERAZINYL)-BUTYL)-8-AZASPIRO(4.5) DECANE-7,9-DIONE AND 8-(4-(4-(2-PYRIDYL)-1-PIPERAZINYL)) BUTYL)-8-AZASPIRO(4,5) DECANE-7,9-DIONE.

Description

United States Patent C ice 3,717,634 N-(HETEROARCYCLIC)PIPERAZINYLALKYL- AZASPIROALKANEDIONES Yao Hua Wu and James W. Rayburn, Evansville, Ind, assignors to Mead Johnson & Company, Evansville,
Ind. No Drawing. Filed Nov. 24, 1969, Ser. No. 879,604 Int. Cl. C07d /42 US. Cl. 260-4564 N 7 Claims ABSTRACT OF THE DISCLOSURE SUMMARY OF THE INVENTION This invention relates to new compounds characterized by the following general structural formula and the nontoxic pharmaceutically acceptable acid addition salts thereof.
Formula I In the foregoing Formula I, n is the integer 4 or 5. The symbol -A which connects the spiroglutarimide and the N-(heteroarcyolic)piperazine represents a divalent alkylene chain of 2 to 6 carbon atoms inclusive. Said alkylene chain can be straightor branched-chain hydrocarbon grouping in which the ring connecting bonds are on different carbon atoms such as hexamethylene (CH2 CH2 CH2CH CHzCHz) 2-methyl-1,2-propylene OH2C and the like. The piperazine substituent represented by the symbol B is selected from the group consisting of imidazoyl and a heteroarcyclic. Said heteroarcyclic is represented by the symbol:
I WWY Na 3,717,634 Patented Feb. 20,. 1973 wherein W and Y are independently selected from th group consisting of CH and nitrogen. By the term heteroancyclic as used herein, it is meant substituents comprised of nitrogen, carbon, and hydrogen which when taken together form a heteroaromatic system. The R and R substituents of the heteroarcyclic referred to above are independently selected from the group consisting of hydrogen, lower alkyl from 1 to 4 carbon atoms inclusive, alkoxy of from 1 to 4 carbon atoms inclusive, hydroxy, amino, alkylthio of 1 to 4 carbon atoms inclusive, halogen, trifiuoromethyl, alkanoamido of from 1 to 6 carbon atoms inclusive, and alkanesulfonamido of 1 to 6 carbon atoms inclusive. By the term lower alkyl as employed herein it is meant straight or branched chain alkyl radicals including methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, Z-methylpropyl, and tert.-butyl. Similarly, the alkyl fragment of the alkylthio substituent refers to straight or branched chain radicals described above. Straight or the branched chain alkanes of 1 to 6 carbon atoms inclusive comprise the alkane radical of alkanoamido and alkanesulfonamido groupings.
The term non-toxic pharmaceutically acceptable acid addition salts as used herein refers to a combination of compounds of the present invention with relatively nontoxic inorganic or organic acids. Illustrative of the variety of acids which may be used are sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, and related acids.
Conversion of the compounds of the present invention to pharmaceutically acceptable acid addition salts is accomplished by admixture of these compounds with substantially one chemical equivalent of any of the various acids hereinbefore defined. Generally the reactions are carried out in an inert solvent. Suitable solvents, merely by way of example, are ethanol, benzene, ethyl acetate, ether, and halogenated hydrocarbons.
Illustrative of the nomenclature employed herein for the naming of the products of this invention are partial structures corresponding to the substituted glutarimide portions of Formula I are shown below with the positions numbered.
| a 7 a 4 e 8-Azaspiro[4.5]decane-7, 9-dione Formula I, n=4
3-Azaspiro[5.5]undeca.ne-2, 4-dioue Formula 1, n=5
General embodiments of the process for the preparation of compounds of the present invention are schematically illustrated below and labeled Method A, Method B and Method C. The use of a particular method to produce compounds embraced by this invention is dietated to a large extent by conditions which will be apparent to those skilled in the art. In practice, the selection of the method used for the preparation of any one compound of the present invention is principally determined by the commercial availability of the necessary intermediates and/or by the case which available compounds can be converted to desired intermediates.
METHOD A O (W HzN-A-N NB Formula I Formula II Formula III METHOD B (4112) N-A-X HN NB FormulaI Formula IV Formula V METHOD C i H2) N-M X-A-N NB FormulaI Formula VI Formula VII In the foregoing reaction schemes, the symbols n, -A, and B have the same meanings as previously defined relative to Formula I. The symbol X refers to the acid residue of a reactive ester grouping such as a chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate. M comprises an alkali metal salt of the substituted glutarimide and is preferably sodium or potassium.
Method A is carried out by reacting a spiro-substituted glutaric anhydride of Formula II with the l-(w-aminoalkyl) 4 (heteroarcyclic)piperazines of Formula III to provide products of Formula I. Preferably, the reaction is carried out at elevated temperatures in a reaction inert organic solvent. By the term inert organic solvent, as referred to herein is meant any protic or aprotic solvent or diluent which does not enter into the reaction to any substantial degree. Pyridine is the preferred solvent. Temperatures of about 100 C. to about 200 C. are preferred to facilitate completion of the reaction. The duration of the reaction is critical only to the extent of providing maximum yields and reaction periods of from about 16 hr. to as much as 11 days are preferred. The lengthy reaction periods are necessary in some instances to obtain complete conversion of glutaric acid half-amides of Formula VIII which are initially formed when an anhydride of Formula II is combined with an amine of Formula III.
i rins NHAN NB o-orr Formula VIII The glutaric acid half-amides of Formula VIII may be also transformed into Formula I products by heating in boiling acetic anhydride which is a well known standard organic procedure for ring closure useful in the formation of cyclic imides.
Method B is carried out under reaction conditions amply described in literature wherein teritary amines are formed by alkylation of a secondary amine with an alkyl halide, sulfate, phosphate, tosylate, or mesylate. The Formula IV and Formula V intermediates are preferably reacted in an inert liquid reaction medium at temperatures of from about 60 C. to about 200 C. in the presence of a base suitable for use as an acid binding agent. Sodium carbonate is a particularly preferred acid binding agent but other inorganic and tertiary organic base may be employed including other alkali and alkaline earth metal carbonates, bicarbonates, or hydrides and tertiary amines. Reaction periods ranging from about 2 hrs. to approximately 4 days are preferred in order to obtain satisfactory yields of the present compounds. A particularly preferred solvent is n-butanol but any inert reaction medium is generally applicable to use in this reaction. To a large extent, the duration of the reaction period depends upon the temperature and reaction solvent selected. By way of illustration, alkylation is facilitated and the reaction period is appreciably shortened if dimethylformamide is employed as the reaction medium compared to a solvent such as benzene.
Method C is another method useful for preparation of compounds of Formula I. In this method, the spiroglutarirnide metal salt depicted by Formula VI is reacted with substituted piperazines of Formula VII. Standard laboratory procedures are employed in carrying out the reaction such as those described for the alkylation step of the Gabriel synthesis-S. Gabriel, Ber. 20, 2224 (1887). For example, the reactants are combined in an inert reaction medium at temperatures ranging from about 25 C. to 200 C. Preferred solvents for carrying out the reaction are dimethylformamide, acetone, benzene, n-butanol, ethanol and the like.
With respect to the reactants for Methods A, B and C, many of them, including 3,S-tetramethyleneglutaric anhydride, (Formula II, 11:4) are known compounds which are readily available from commercial sources. Others, which are not commercially available, can be prepared in accordance with standard synthetic procedures which are known to those skilled in the art.
Preparation of N (heteroarcyclic)piperazines of Formula V have been described by K. L. Howard at al. in J. Org. Chem., 18, 1484 (1953). Their procedures are applicable to the preparation of other N-(heteroarcyclic)piperazine intermediates not specifically disclosed but which are required for the preparation of compounds embraced in the present invention.
The l-(w-aminoalkyl)-4-(heteroarcyclic)piperazine of Formula III are obtained according to methods described in U.S. Pat. 3,398,151 by alkylation of N- (heteroarcyclic)piperazines of Formula V with haloalkylnitriles to provide 1 (w cyanoalkyl) 4 (heteroarcyclic)piperazine intermediates which are subsequently reduced to the Formula III substituted piperazines. Reduction of the cyano intermediate may be carried out catalytically, preferably with W-6 Raney Nickel catalyst under high pressure, or alternatively with hydrazine and W-6 Raney Nickel.
The intermediate azaspirodecane-and undecanediones of Formula IV having the -A-X- group attached to the nitrogen atom are prepared according to procedures described in U.S. Pat. 3,398,151. Reaction 'of the glutaric anhydrides of Formula II with an alkanolamine of the formula H NAOH are carried out under conditions similar to those described hereinabove for Method A. The resulting intermediate .g'lutarimide has the structure shown for Formula IV wherein X is OH. Esterification of this material is accomplished by conventional techniques well known to the art to provide the intermediate of Formula IV. Preferably, thionyl chloride is reacted with the alcohol precursor of Formula 1V (X=OH) to provide the intermediate wherein X is chlorine. Conventional techniques which are adequately described in the literature are employed to provide the bromides, iodides, phosphates, sulfates, tosylates, and mesylates corresponding to Formula IV.
The piperazine reactant of Formula VII having the X-A- grouping attached to the nitrogen atom is prepared according to standard organic procedures. By way of example, reaction of the piperazines of Formula V with alkanol halides of the Formula HOA-X proides intermediate of Formula VIII.
Formula VIII This intermediate is then esterified according to conventional techniques well known to the art to provide the Formula VH reactants. For instance, thionyl chloride acting upon the compounds of Formula VIII provides the Formula VII intermediate in which X is chlorine. In a similar fashion, bromides, and iodides are prepared. Phosphates, sulfates, tosylates, mesylates corresponding to Formula VII are obtained with conventional laboratory techniques.
General embodiments of the process of the present invention for the preparation of compounds of Formula I as hereinabove described are considered to be a unitary process. Thus, the azaspiroalkanedione of Formula I are prepared in accordance with the unitary process of the present invention by reacting a piperazine of the Formula Y-bi NB Formula IX wherein Y is selected from the group consisting of hydrogen (Formula IXa), H 'NA- (Formula IXb), or XA-- (Formula IXc), and A and X are as hereinbefore defined, with a spirO-glutaric acid anhydride of Formula II.
( fl) n X Formula II wherein n is as hereinbefore defined, when Y is the group H N-A-; or a N-substituted spiro-glutaric acid imide of Formula IV.
( C Hz) 21 X N-A-X Formula IV wherein A and n are as hereinbefore defined and X is a reactive ester group, when Y is hydrogen; or a spiroglutarimide of Formula VI.
Formula VI tion. In the instant case, it has been discovered that N- (heteroarcyclic)piperazine alkyl derivatives of azaspirodecanediones and azaspiroundecanediones are highly active and specific tranquilizing agents and in addition also exhibit anti-emetic properties. Present compounds are improved tranquilizing agents compared to the azaspirodecanediones and azaspiroundecanediones of United States Pat. 3,398,151, in that tranquilizing activity is more potent and specific.
With respect to side effects such as sedative and alphaadrenergic blockade which are exhibited by a number of prominent tranquilizing agents the present compounds are unique in that such adverse reaction is substantially diminished or practically non-existent. By way of illustration, 8- [4- [4-(2-pyrimidinyl)-1-piperazinyl]butyl]- 8 azaspiro[4.5]decane-7,9 dione hydrochloride has only about the alpha-adrenergic blocking activity of the well known tranquilizer, chloropromazine.
Tranquilizing properties of the compounds of this invention can be demonstrated in rats by a shuttle box technique described by I. R. Albert and L. E. .Allen in the Ph'armacologist 4, '152 (1962). This test is designed to differentiate tranquilizing agents from non-specific central nervous system depressants such as sedatives and hypnotics. Tranquilizing effects are observed when the compounds of the present invention are administered intraperitoneally to the rat in dosages ranging from 1.5 to mg./kg. of body weight.
The tranquilizing action of the compounds of the present invention can be demonstrated in Rhesus monkeys by observing general behavioral effects. Intramuscular administration of present compounds to the monkey in dosages ranging from 2 to 16 mg./kg. of body Weight affords tranquilizing effects similar to those produced by chlorpromazine.
The compounds of the present invention are relatively non-toxic compounds. For example, the intraperitoneal 50% lethality dose of 8 [4 [4 (2pyrimidinyl)- 1 piperazinyl1butyl] 8 azaspiro[-4.5]decane-7,9-dione hydrochloride is 146 mg./kg. of body weight in the mouse.
Systemic administration of the compounds of the present invention to mammals in dosages ranging from about 0.01 to 40 mg./kg. of body weight per day induce effective tranquilizing responses in the mammalian recipient. Oral, parenteral and rectal routes are preferred forms of systemic administration. Forms of parenteral administration include intramuscular, intravenous, and subcutaneous administration. Those skilled in the art will recognize that the dosage of the compounds of the present invention will vary with the form and mode of administration and in some instances with the particular compound chosen. Generally, it will be found that when a compound of the present invention is administered orally, a larger quantity of the active agent is required to produce the same effect as a smaller quantity thereof which is given parenterally. It is generally preferred to administer the compounds of this invention at a concentration level that will produce effective tranquilizing effects without causing any harmful or deleterious side effects.
For pharmaceutical purposes, the compounds of Formula I may be administered to mammals in the form of free bases or in the form of non-toxic acid addition salts. In the free base form, the compounds are relatively insoluble in water but are soluble in most organic sol vents such as lower alkyl alcohols, esters, acetones, chloroform and the like. The present compounds in the form their acid addition salts are, in general, soluble in water and methanol but relatively insoluble in solvents such as benzene, ether, petroleum ether and the like. In either the free base or the acid addition salt form, the compounds of Formula I may be compounded and formulated into pharmaceutical compositions and unit dosage suitable for systemic administration. Organic or inorganic Examples of representative compounds of the present invention prepared according to Procedure 1 are indicated in Table I.
TABLE I.-8-[4 (N-HETEROARCYCLIC)-l-PIPERAZINYLALKYIJ-B-AZASPIRO[4.51DECANE-73-DIONE PRODUCTS Product Base Hydrochloride Analyses Ex. B.P., 0. Percent No. Method 11 Hot. (mm. g) yield M.P., O. Crystn.solvent Formula C H N Cl 1 A 2 208 -2U9 5 Eula-I101 CzoHggN4Og-HC1 61.11 7.25 14.26 8.81
2 A 4 Same as above (a 76 172173.5 Z-butanone C H Mm-HCI 63.01 7.89 13.55 8.29
N 3 2 2302 90 200207 Absolute ethanol CnHzrNsOa-HCI 58.00 7.23 17.75 0.03
4 B 3 Same as above 214-215 Absolute ethanol-amen. CzoHzpNgOrHCl 59.06 7.30 17.24 l- 5 A i do 61 201.5-20215 Absolute ethanol ommlmol-nci 60.29 7.41 16.60 8.48 s A 5 do 23 39 52 188.5190.5 Methanolethyl acetate" caramel-H01 60.44 7.93 10.01
7 B 3 23 59 mas-234.5 Ethanol oflnammnm 00.12 7.73 13.01 7.98
CHzO
used herein it is meant forms of administration such as METHOD B oral, parenteral and rectal. Pharmaceutical compositions considered within the scope of this invention may take the form of tablets, powder, granules, capsules, suspensions, solutions, suppositories, elixirs, ointments and the like. Unit dosages ranging from about 1 to 500 mg. are employed. Suitable pharmaceutical carriers comprise both solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethylene glycol, water, sesame seed oil, peanut oil, propylene glycol, and the like.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are illustrative of the process and products of the present invention and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit and scope thereof.
METHOD A Procedure l.-Condensation with Substituted Glutaric Anhydride.A mixture of 0.1 mole of the substituted glutaric anhydride (Formula II), 0.1 mole of l-(w-aminoalkyl) 4 (heterocycle)piperazine (Formula 111), and 300 ml. of pyridine is refluxed until imide formation is complete. The degree of reaction is readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibits typical infrared imide bands at 1700 and 1710 cm? whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, .1760, and 3300 cm.-
The azaspiroalkanedione product is purified as the free base by stripping oi the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof.
Suitable acid addition salts of the product are prepared by treating an ethanol solution of the free base with an equi-molar amount of the appropriate acid.
Procedure 2.-Alkylation of N(heteroarcyclic)piperazines.-A mixture of 4.9 g. (0.02 mole) of 8-[3- chloro- 1-propyl)-8-azaspiro [4.5] decane-7,9di0ne, 3 .3 g. (0.02 mole) prepared in the manner of US. Pat. 3,398,- 151, N-(2-pyrimidyl)piperazine, and 2.2 g. (0.02 mole) of sodium carbonate in 75 ml. of n-butanol is refluxed for three days and filtered. The filtrate is concentrated in vacuo and the residue taken up in ml. of benzene. Addition of 4.0 ml. of 5.0 N ethanolic hydrogen chlo ride to the benzene solution of the free base provides the product 8-[3-[4-(2-pyrimidinyl)-l-piperazinyllpropyl]-8-azaspiro[4.5]decane7,9-dione as a hydrochloride salt which is collected and crystallized from absolute ethanol-ether, yield 3.4 g., M.P. 214-215 C. (corn).
Examples of representative products of this invention and physical properties thereof prepared according to Method B are listed in Table 1.
METHOD C Procedure 3.Alkylation of Azaspiroalkaneimides.-- A solution of 0.1 mole of 3,3-tetramethyleneglutarimide in methanol ml.) is treated with 0.1 mole of sodium methoxide. The solvent is removed in vacuo to provide a residue consisting of the sodium salt of 3,3-tetramethyleneglutarimide which without further purification is combined with 0.1 mole of 1-(2-chlorobutyl)-4-(pyrimidiny1) piperazine in 150 ml. of n-butanol. The mixture is refluxed for a period of time of sufiicient duration to provide approximately 0.1 mole of precipitated sodium chloride as a by-product. Isolation of the product by standard laboratory procedures provide 8-[3-[4-(2-pyrimidinyl) -lpiperazinyl1propyl1-8 azaspiro[4.5]decane 7,9-dione which is also a product of Procedure 2.
Examples 8-28.Additional exemplification of compounds of the present invention is given in Table II along with the mode of preparation according to Method A, Method B, or Method C and the appropriate intermediates. Although only a single method of preparation TABLE II-Contlnued Product Ex. No. 11 A Het. Method Intermediates 21 4 (CHz)4- O-C(CH;); B 8-(4-ehlorobutyl)-8-azaspir0I4.5]decane-7,9-dlone and l-[2-(4-tert.-butylpyrimidinympiperazine.
22 4 -(CH1)4- B 8-(4-chlorobutyl)-8-azaspiro[4.5]decane-7,Q-dione and 1-[2-(6-trlfluoromethylpyridinympiperazine.
23....- 4 -(CH=); N A 3,3-tetramethyleneglutar1e anhydrlde and 1-(4-aminobutyD-4-[2-(1,3,5-
N triazinyl)]piperazine.
24"-.. 4 (CH NO; C 3, B-t-etramethyleneglutarimlde and 1-(2-chloroethyl)4-[2-(4-nltm4, 3, 5-
N mazinympiperazine.
25.-- 4 (CHz)4- N A 3, 3-tetramethyleneglutarlc anhydride and 1-(4-aminobutyD-4-[2-(3-propionylamidopyridinyb]piperazine.
NH 0 01H;
26..." 4 (CH:) NHSOICH; A 3, 3-tetramethyleneglutarlc anhydride and 1-(4-amlnobutyl) -4-[4-(2, 6
dimethanesulfonamidopyrimidinyl)1p1perazine. N.-
NHSOaCHa 27-.." 4 (OH )4 N A 3, a-tetramethyleneglutarlc anhydride and 1-(4-amlnobutyl)-4-[2-(4-hydroxy- H pyrimldinyl) piperazine.
28..-" -(CHa)4- A 3, s-pentamethyleneglutaric anhydride and 1-(4-aminobutyD-4-(2-pyridinybpiperazine.
8 [4-[4-(4,6dimethyl-2-py1imidinyl)-l-piperazinyllbntyll-ileazaspiro[4.5]decane-7,Q-dione hydrochloride. M.P. 216.5217.5 0. (corn), crystallized from absolute ethanol-anhydrous ether. Analysis-Salad. for CzaHauClNaOz! C, 61.38; H, 8.06; N, 15.56. Found: C, 61.26; H, 8.10; N, 15.53.
Procedure 4.1-(3cyanopropyl)-4-(2 pyrimidinyl)- piperazine.-A mixture of l-(2-pyrimidinyl)pipera2ine (6.0 g., 0.04 mole), 4.6 g., (0.044 mole) of 3-chloropropionitrile and sodium carbonate (4.24 g., 0.04 mole) in m1. of n-butanol is gently refluxed for 16 hours. The reaction mixture is concentrated in vacuo and the residual oil dissolved in about 100 ml. of cyclohexane.
On standing a white crystalline material separates which is crystallized from cyclohexane to provide 6.5 g. (yield of the cyano intermediate, M.P. 56.658 C. Representative examples of cyano intermediates useful in Procedure 5 along with information relative to the preparation thereof according to Procedure 4 are listed in Table III.
TABLE III.-1-(w-C YANOALKYL) 1(HETE ROABC YCLIC) PIPE RAZINES Analysis Intermediate B.P., 0.
number Hats 11 Yield (mm. Hg) M.P., 03" Formula C H N 1 1 32 u uN4 same as abm 3 92 %?85} 1 47-49 0.3mm.
3 1 8O 1 98400 CmHnNs 59. 12 6. 62 34. 77
4 Same as above 3 7O 1 56-58 CnHuH; 2.04 7.31 30.08 5- do 4 80 1 77-78 C15H19N5 63.49 7. 62 28. 41
6 NH, 3 87 5 191-192 CflHflN? 37.84
TABLE IIICntlnued Analysis Intermediate B.P., 0. number Het 11 Yield (mm. Hg) M.P., 0. Formula C H N 7 CHBO a 46{ ounflmo, 56.90 1.01 23.41
CHgO
3 uooj 109-110 CiaHmNu 59.94 7.66 32.48
1 Crystalline solvent is cyclohexane.
2 Crystalline solvent is methanol.
! Crystalline solent is ethyl acetate-Skellysolve F. 4 Crude.
Procedure 5.1-(4-aminobutyl) 4 (2 pyrimidinyl) piperazine.(A) A solution of 11.5 g. (0.05 mole) of 1-(3-cyanopropyl)-4-(2-pyrimidinyl)piperazine in 150 ml. of absolute ethanol is saturated with ammonia. W-6 Raney nickel catalyst is added and the mixture hydrogenated under 1200 psi. When the hydrogenation is completed the mixture is filtered and the residual oil distilled under reduced pressure to provide 8.2 g. (70%) of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine.
Reduction of cyano intermediates of Procedure 4 in the manner described for Procedure 5 or alternatively by reduction with hydrazine and Raney nickel provide the amino intermediates of Formula III. The following procedure is illustrative of hydrazine and Raney nickel reductions.
(B) Hydrazine hydrate 85% (640 ml.) is added drop- Wise to 4-[4-(2-pyrimidinyl) l piperazinylJbutyronitrile (189.8 g., 0.82 mole), Raney nickel (190 g.Wet with water, activated by washing with 2-propanol) and 2-propanol (1.4 liter) in 2 hours at reflux. The reaction is stirred for 5 minutes, filtered, concentrated in vacuo and the residual material distilled to yield 168.2 g. (87%) of 1-(4-aminobutyl)-4-(Z-pyrimidinyl)piperazine, B.P. 143- 6" C. at 0.1 mm. (11 15582).
Procedure 6.Solution for parenteral injection-The azaspiroalkanedione compounds of the present invention are formulated for parenteral administration according to the following example. A sterile solution suitable for intravenous injection is prepared by dissolving 21.9 g. of 8-[4- [4-(2-pyrimidinyl) 1 piperazinyl]butyl] 8 azaspiro[4.5]decane-7,9-dione hydrochloride in 2 liters of water for injection, USP. The solution is adjusted to pH 4.2 with 0.1 N-sodium hydroxide. After adjusting the pH, the solution is sterilized by passage through a bacteriological filter and ml. glass ampules aseptically filled in order to provide 10 mg. of active ingredient per ampule.
Procedure 7.Tablets.The azaspiroalkanedione compounds of the present invention are compounded into tablets in accord with the following example.
Material: Amount, grams 8-[4-[4-(2 pyrimidinyl) 1 piperazinyHbutyl] -8-azaspiro [4.5 decane-7,9-dione hydrochloride 54.8 Magnesium stearate 1.3 Corn starch 12.4 Corn starch pregelatinized 1.3 Lactose 180.2
a compound having the formula n is the integer 4 or 5;
A is a divalent straight or branched alkylene chain of 2 to 6 carbon atoms inclusive and connects the nitrogen atoms as shown through at least 2 carbon atoms;
B is
wherein one of W and Y is CH and the other is nitrogen,
R and R are independently selected from the group consisting of hydrogen, lower alkyl from 1 to 4 carbon atoms inclusive, and lower alkoxy of from 1 to 4 carbon atoms inclusive;
References Cited UNITED STATES PATENTS 8/1968 Yao Hua Wu 260-268 PH OTHER REFERENCES Howard et al., J. Org. Chem. 18, 1484 (1953).
ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R.
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BE759371D BE759371A (en) 1969-11-24 HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION
US00879604A US3717634A (en) 1969-11-24 1969-11-24 N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones
ZA707826A ZA707826B (en) 1969-11-24 1970-11-19 Heterocyclic azaspirodecanediones and process for the preparation thereof
NL7017031A NL7017031A (en) 1969-11-24 1970-11-20
FR7041860A FR2073406B1 (en) 1969-11-24 1970-11-20
DK589670AA DK141753B (en) 1969-11-24 1970-11-20 Analogous process for the preparation of azaspirodecan and undecanedione derivatives or acid addition salts thereof.
CH341874A CH552608A (en) 1969-11-24 1970-11-24 PROCESS FOR THE PRODUCTION OF AZASPIROALCANDIONE DERIVATIVES.
GB5590870A GB1332194A (en) 1969-11-24 1970-11-24 Heterocyclic azaspiroalkanediones
CY886A CY886A (en) 1969-11-24 1970-11-24 Heterocyclic azaspiroalkanediones
DE19702057845 DE2057845A1 (en) 1969-11-24 1970-11-24 Heterocyclic azaspirodecanediones and process for their preparation
CH1741770A CH552607A (en) 1969-11-24 1970-11-24 PROCESS FOR THE PRODUCTION OF AZASPIROALCANDIONE DERIVATIVES.
US312543A US3907801A (en) 1969-11-24 1972-12-06 N-{8 (4-pyridyl-piperazino)-alkyl{9 -azaspiroalkanediones
KE2691A KE2691A (en) 1969-11-24 1977-01-14 Heterocyclic azaspiroalkanediones
HK61/77A HK6177A (en) 1969-11-24 1977-01-27 Heterocyclic azaspiroalkanediones
MY151/77A MY7700151A (en) 1969-11-24 1977-12-30 Heterocyclic azaspiroalkane diones
ES530335A ES530335A0 (en) 1969-11-24 1984-03-07 PROCEDURE TO OBTAIN 8-4-4- (2-PIRIMIDINYL) -1-PIPERAZINYL-BUTYL-8-AZASPIRO 4,5-DECANE-7,9-DIONA.

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Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907801A (en) * 1969-11-24 1975-09-23 Mead Johnson & Co N-{8 (4-pyridyl-piperazino)-alkyl{9 -azaspiroalkanediones
US4123538A (en) * 1977-08-30 1978-10-31 Mcneil Laboratories, Incorporated (2-Amino-2-oxoethoxy)acetic acid compounds, compositions and methods
DE2920739A1 (en) * 1978-05-22 1979-12-06 Bristol Myers Co USE OF 8-ANGLE CLAMP ON 4-CORNER CLAMP ON 4- (2-PYRIMIDINYL) -1PIPERAZINYL ANGLE CLAMP ON -BUTYL ANGLE CLAMP ON -8-AZASPIRO ANGLE CLAMP ON 4.5 ANGLE CLAMP ON DECAN-7,9-DION
US4305944A (en) * 1980-09-08 1981-12-15 Mead Johnson & Company N-[(4-[3-cyano substituted pyridyl]piperazino)alkyl]-azaspirodecanediones
US4320131A (en) * 1981-03-16 1982-03-16 Mead Johnson & Company N-[(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)alkylene]azaspiroalkanediones and N-[(4-hydroxy-4-phenylpiperidin-1-yl)alkylene]azaspiroalkanediones
FR2492383A1 (en) * 1980-10-16 1982-04-23 Bristol Myers Co SPIRO-QUATERNARY AMMONIUM HALIDES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN PROCESS FOR PRODUCING N- (2-PYRIMIDINYL) PIPERAZINYL-ALKYLAZOSPIRO-ALKANEDIONES
DE3149011A1 (en) * 1980-12-11 1982-07-15 Bristol-Myers Co., 10022 New York, N.Y. METHOD FOR PRODUCING BUSPIRON
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
FR2518993A1 (en) * 1981-12-28 1983-07-01 Bristol Myers Co 2- (4 - ((4,4-DIALKYL-2,6-PIPERIDINEDION-1-YL)) - 1-PIPERAZINYL) PYRIMIDINES, THEIR PREPARATION AND THEIR PHARMACOLOGICAL APPLICATION
FR2521561A1 (en) * 1981-12-23 1983-08-19 Bristol Myers Co DERIVATIVES OF BENZISOTHIAZOLE AND BENZISOXALE PIPERAZINE
US4409223A (en) * 1982-08-06 1983-10-11 Riblet Leslie A Anxiolytic method
US4417049A (en) * 1980-10-16 1983-11-22 Mead Johnson & Company Spiro-quaternary ammonium halides and N-(2-pyrimidinyl)piperazinylalkylazaspiroalkanedione process
WO1984000752A1 (en) * 1982-08-11 1984-03-01 Eastman Kodak Co Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines and methods for their preparation and use
US4438119A (en) 1982-12-23 1984-03-20 Mead Johnson & Company Method for alleviation of extrapyramidal motor disorders
US4452799A (en) * 1981-12-23 1984-06-05 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
US4456756A (en) * 1981-08-03 1984-06-26 Mead Johnson & Company Spirothiazolidinyl piperazine derivatives
FR2540499A1 (en) * 1983-02-07 1984-08-10 Bristol Myers Co ANTIPSYCHOTIC 5-FLUORO-PYRIMIDINE-2-YL PIPERAZINE DERIVATIVE
US4507303A (en) * 1981-12-22 1985-03-26 Sumitomo Chemical Company, Limited Succinimide derivatives, compositions and method of use
US4515947A (en) * 1982-08-11 1985-05-07 Eastman Kodak Company Cyanoalkylpiperazines and methods for their preparation and use
FR2555585A1 (en) * 1983-09-12 1985-05-31 Bristol Myers Co DERIVATIVES OF 1-HETEROARYL-4 ((2,5-PYRROLIDINEDION-1-YL) ALKYL) PIPERAZINE, PROCESS FOR PREPARING THEM AND THEIR PHARMACOLOGICAL APPLICATION
US4562255A (en) * 1984-03-30 1985-12-31 American Home Products Corporation Substituted bi-alicyclic imides
FR2567886A1 (en) * 1984-07-23 1986-01-24 Bristol Myers Co 1- (2-PYRIMIDINYL) -PIPERAZINYL DERIVATIVES OF 1-PYRROLIDINE-2-ONES AND THEIR PSYCHOGERIATRIC APPLICATION
US4581357A (en) * 1983-02-07 1986-04-08 Mead Johnson & Company Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound
US4598078A (en) * 1982-10-21 1986-07-01 Sumitomo Chemical Company, Limited N-(substituted piperazinyl) alkylbicyclic succinimide derivatives
US4612312A (en) * 1984-07-30 1986-09-16 Merrell Dow Pharmaceuticals Inc. Glutarimide antianxiety and antihypertensive agents
US4620002A (en) * 1982-08-11 1986-10-28 Eastman Kodak Company 2-pyrimidyl alkanesulfonates
US4619930A (en) * 1985-01-16 1986-10-28 Bristol-Myers Company Antipsychotic cyclic imide derivatives of 2-(4-butylpiperazin-1-yl)pyridines, compositions and use
US4634703A (en) * 1985-10-25 1987-01-06 Bristol-Myers Company Method for alleviation of panic disorders
US4640921A (en) * 1986-02-04 1987-02-03 Bristol-Myers Treatment of sexual dysfunction with buspirone
DE3622842A1 (en) * 1985-07-08 1987-03-05 Bristol Myers Co DIAZINYLPIPERIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS
FR2587342A1 (en) * 1985-06-22 1987-03-20 Sandoz Sa NOVEL THIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US4668687A (en) * 1984-07-23 1987-05-26 Bristol-Myers Company Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones
US4677104A (en) * 1985-05-06 1987-06-30 Bristol-Myers Company Antipsychotic fused-ring pyridinylpiperazine derivatives
US4687772A (en) * 1986-10-07 1987-08-18 Bristol-Myers Company Method for improvement of short term memory
US4745117A (en) * 1985-03-27 1988-05-17 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and compositions for use as antipsychotic agents
US4777173A (en) * 1987-03-25 1988-10-11 Bristol-Myers Company Method for treatment of alcohol abuse
EP0304941A1 (en) * 1987-08-28 1989-03-01 Bristol-Myers Squibb Company Pharmaceutically useful polymorphic modification of buspirone
US4810789A (en) * 1987-08-28 1989-03-07 Bristol-Myers Company Process for buspirone hydrochloride polymorphic crystalline form conversion
US4812567A (en) * 1985-10-16 1989-03-14 American Home Products Corporation Polycyclic spiroimides with psychotropic activity
US4812461A (en) * 1986-09-26 1989-03-14 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and their use in the treatment psychosis
EP0313535A1 (en) * 1987-10-22 1989-04-26 Bristol-Myers Squibb Company Oral formulation of buspirone and salts thereof
US4826843A (en) * 1985-07-08 1989-05-02 Bristol-Myers Cerebral function enhancing diazinylpiperidine derivatives
EP0238905A3 (en) * 1986-03-05 1989-08-09 Merrell Dow Pharmaceuticals Inc. 4-(2-pyrimidinyl)-1-piperazinyl heterocyclic carbonyl derivatives
US4859671A (en) * 1988-07-08 1989-08-22 American Home Products Corporation 2-substituted 1,2-benzisothiazol-3(2H)-one 1,1-dioxide useful as an anxiolytic agent
US4880930A (en) * 1987-11-30 1989-11-14 New James S Psychotropic acyclic amide derivatives
EP0236931A3 (en) * 1986-03-05 1990-01-17 Merrell Dow Pharmaceuticals Inc. Aromatic omega-alkylimino-tetrahydro-6h-1,3-thiazin-6-one derivatives
WO1990002552A1 (en) * 1988-09-16 1990-03-22 Pfizer Inc. Antipsychotic 4-[4-(3-benzisothiazolyl)-1-piperazinyl]butyl bridged bicyclic imides
EP0314363A3 (en) * 1987-10-26 1990-07-11 Pfizer Inc. Anti-anxiety agents
US5001130A (en) * 1988-02-18 1991-03-19 Bristol-Myers Company Psychotropic heterobicycloalkylpiperazine derivatives
EP0395192A3 (en) * 1989-04-28 1991-05-02 Alkaloida Vegyeszeti Gyar Process for the preparation of 8-(4-(4-pyrimidin-2-yl-piperazinyl)-butyl)-8-aza-spiro(4.5)decane-7,9-dione (buspiron)
US5098904A (en) * 1990-06-27 1992-03-24 Bristol-Myers Squibb Company Cerebral function enhancing pyrimidinyl derivatives
EP0447345A3 (en) * 1990-02-13 1992-04-15 Espanola Prod Quimicos New azaspyro (4.5) decane-7,9-dione derivatives
US5116970A (en) * 1988-02-18 1992-05-26 New James S Psychotropic heterobicycloalkylpiperazine derivatives: 2. fused pyridazinones
US5137894A (en) * 1991-12-05 1992-08-11 New James S 4-(4-Piperidinyl-thieno[3,2-c]pyridine derivatives of n-alkylglutarimides
US5153206A (en) * 1988-12-02 1992-10-06 Pfizer Inc. Arylpiperidine derivatives
US5187277A (en) * 1990-10-29 1993-02-16 Komissarov Igor V DL-3-[4-[4-(2-pyridyl)-1-piperazinyl]-butyl]-1,8,8-trimethyl-3-azabicyclo[(3]octane-2,4-dione having psychotropic and antiemetic effect
US5242911A (en) * 1988-06-17 1993-09-07 Pfizer Inc. Bridged bicyclic imides as anxiolytics and antidepressants
US5338738A (en) * 1993-04-19 1994-08-16 Bristol-Myers Squibb Company Cerebral function enhancers: acyclic amide derivatives of pyrimidinylpiperidines
US5391570A (en) * 1993-10-14 1995-02-21 Bristol-Myers Squibb Aminomethyl-benzodioxane and benzopyran serotonergic agents
US5407938A (en) * 1990-04-10 1995-04-18 Israel Institute For Biological Research Certain 1-methyl-piperidine-4-spiro-4'-(1'-3'-oxazolines) and corresponding -(1',3' thiazolines)
EP0655449A1 (en) * 1993-11-10 1995-05-31 Jin Ro Limited A process for preparing N-( 2-pyrimidyl) piperazinyl butyl imides
US5431922A (en) * 1991-03-05 1995-07-11 Bristol-Myers Squibb Company Method for administration of buspirone
EP0680961A1 (en) * 1994-05-05 1995-11-08 Bristol-Myers Squibb Company Improved, large-scale process for azapirone synthesis
US5468749A (en) * 1988-08-30 1995-11-21 Gawin; Frank H. Method for treatment of substance addiction
US5484788A (en) * 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
WO1996006846A1 (en) * 1994-09-01 1996-03-07 Universidad Complutense De Madrid New arylpiperazine derivatives
ES2082727A1 (en) * 1994-09-01 1996-03-16 Univ Madrid Complutense New arylpiperazine derivatives
US5521313A (en) * 1994-05-05 1996-05-28 Bristol-Myers Squibb Company Process for preparing certain azapirones
US5538985A (en) * 1994-01-27 1996-07-23 Mitsui Toatsu Chemicals, Inc. Pyrrolidinone derivatives
US5602128A (en) * 1994-12-02 1997-02-11 American Home Products Corporation N-heterocycloalkyl carboxamides as serotonergic agents
ES2095811A1 (en) * 1995-07-28 1997-02-16 Univ Madrid Complutense New arylpiperazine derivatives
US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5633009A (en) * 1990-11-28 1997-05-27 Sano Corporation Transdermal administration of azapirones
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity
US5922341A (en) * 1997-10-28 1999-07-13 Vivus, Incorporated Local administration of pharmacologically active agents to treat premature ejaculation
US6008222A (en) * 1996-12-04 1999-12-28 Bristol-Myers Squibb Company Method for oral administration of buspirone and nefazodone
WO2000006163A1 (en) * 1998-07-30 2000-02-10 Bristol-Myers Squibb Company Improved method for treatment of sleep-related respiratory disorders
US6037360A (en) * 1997-10-28 2000-03-14 Vivus, Incorporated Administration of 5-HT3 receptor antagonists to treat premature ejaculation
US6150365A (en) * 1999-08-05 2000-11-21 Bristol-Myers Squibb Company Anxiety method
US6228864B1 (en) 1997-10-28 2001-05-08 Vivus, Inc. Administration of 5-HT receptor agonists and antagonists, to treat premature ejaculation
US6306859B1 (en) 1999-03-02 2001-10-23 American Home Products Corporation N-substituted imide derivatives with serotonergic activity
US6312717B1 (en) 1998-07-07 2001-11-06 Bristol-Myers Squibb Company Method for treatment of anxiety and depression
US6313114B1 (en) 1999-01-07 2001-11-06 American Home Products Corp 3,4-Dihydro-2H-benzo[1,4]oxazinyl-methyl)-[3-(1H-indol-3yl)-alkyl]- amines
US6376494B1 (en) 1998-06-15 2002-04-23 American Home Products Corporation Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US6432956B1 (en) 1990-02-12 2002-08-13 William C. Dement Method for treatment of sleep apneas
US20030069251A1 (en) * 1999-08-05 2003-04-10 Yevich Joseph P. Antianxiety composition
US6566361B2 (en) 1999-06-30 2003-05-20 Laboratories, Upsa Azapirone pain treatment
US20040067962A1 (en) * 2000-11-29 2004-04-08 Schaus John Mehnert 1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl) piperazine and pharmaceutically acceptable salts and solvents thereof
US20040147581A1 (en) * 2002-11-18 2004-07-29 Pharmacia Corporation Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
US6828324B2 (en) 1999-11-12 2004-12-07 Wyeth Branched adamantyl and noradamantyl aryl-and aralkylpiperazines with serotonin 5-HT1A activity
US6831084B1 (en) 1999-11-12 2004-12-14 Wyeth Branched adamantyl and noradamantyl aryl- and aralkylpiperazines with serotonin 5-HT1A activity
US20050107395A1 (en) * 2002-09-05 2005-05-19 Greenblatt Lynne P. Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
US20050137206A1 (en) * 1999-08-05 2005-06-23 Yevich Joseph P. Method for treatment of anxiety and depression
US20050272799A1 (en) * 2000-09-19 2005-12-08 Salvati Mark E Fused Heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
WO2006108591A1 (en) 2005-04-11 2006-10-19 Novartis Ag 1h-quinaz0line-2,4-diones and their use as ampa-receptor ligands
US20090023744A1 (en) * 2007-06-18 2009-01-22 The General Hospital Corporation Combination therapy for depression
US20100184775A1 (en) * 2005-12-16 2010-07-22 Novartis Ag Organic compounds
US20110034475A1 (en) * 2004-06-18 2011-02-10 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
EP2361914A1 (en) 2005-12-16 2011-08-31 Novartis AG [(1h-indol-5-yl)-heteroaryloxy]-(1-aza-bicyclo[3.3.1]nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
WO2012037634A1 (en) 2010-09-24 2012-03-29 Aché Laboratórios Farmacêuticos S.A. Compounds and pharmaceutical compositions for treating disorders associated with the 5-ht1a and 5-ht2a receptors
EP2457911A1 (en) 2004-07-14 2012-05-30 Novartis AG 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-nAChR ligands for the treatment of CNS diseases.
US9012451B2 (en) 2002-09-04 2015-04-21 Novartis Ag Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists
US9186359B2 (en) 2010-10-15 2015-11-17 Contera Pharma Aps Combinations of serotonin receptor agonists for treatment of movement disorders
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4261990A (en) * 1979-03-09 1981-04-14 Ciba-Geigy Corporation N-alkyleneiminoalkyl-dicarboximides as antiallergics and antiasthmatics
US4656173A (en) * 1985-04-24 1987-04-07 Bristol-Myers Company Antipsychotic benzisothiazole S-oxide compound
PL152958B1 (en) * 1987-02-25 1991-02-28 Egyt Gyogyszervegyeszeti Gyar Method for manufacturing piperazine derivatives
US4797488A (en) * 1987-04-03 1989-01-10 American Home Products Corporation Psychotropic polycyclic imides
US4748240A (en) * 1987-04-03 1988-05-31 American Home Products Corporation Psychotropic bicyclic imides
US4732983A (en) * 1987-04-03 1988-03-22 American Home Products Corporation Pyschotropic polycyclic imides
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US4873331A (en) * 1988-12-09 1989-10-10 American Home Products Corporation Noradamantyl-carboxylic acid piperazinoalkyl esters
US4882432A (en) * 1989-01-09 1989-11-21 American Home Products Corporation Polycyclic-carbamic acid piperazinoalkyl esters and amides
GB8909209D0 (en) * 1989-04-22 1989-06-07 Wyeth John & Brother Ltd Piperazine derivatives
US5340812A (en) * 1989-04-22 1994-08-23 John Wyeth & Brother, Limited Piperazine derivatives
US5703088A (en) * 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
FR2654934B1 (en) * 1989-11-29 1994-09-30 Midy Spa USE OF DERIVATIVE [4- (2-PYRIMIDINYL) -1-PIPERAZINYL] BUTYLIC FOR THE PREPARATION OF MEDICINES FOR COMBATING INTESTINAL MOTORITY DISORDERS.
ATE132866T1 (en) * 1990-10-23 1996-01-15 Akzo Nobel Nv 4-(4- OR 6-(TRIFLUORMETHYL-2-PYRIDINYL)>-1- PIPERAZINYL-ALKYL SUBSTITUTED LACTAMES
US5591748A (en) * 1991-06-07 1997-01-07 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US5693645A (en) * 1992-12-23 1997-12-02 Beth Israel Deaconess Medical Center, Inc. Use of spiperone or spiperone derivatives as immunosuppressant agents
EP0690715B1 (en) * 1993-03-26 2003-05-28 Beth Israel Hospital Association Topical and systemic application of buspirone or derivatives thereof for treatment of pathological conditions associated with immune responses
HU217129B (en) * 1993-07-16 1999-11-29 EGIS Gyógyszergyár Rt. Process for the preparation of buspiron as therapeutical active ingredient of high purity
CL2008000467A1 (en) 2007-02-14 2008-08-22 Janssen Pharmaceutica Nv COMPOUNDS DERIVED FROM 2-AMINOPIRIMIDINE, HISTAMINE RECEIVER MODULATORS H4; YOUR PREPARATION PROCEDURE; PHARMACEUTICAL COMPOSITION THAT INCLUDES SUCH COMPOUNDS; AND ITS USE TO TREAT A SELECTED INFLAMMATORY DISORDER OF ALEGIA, ASMA
US20080217501A1 (en) * 2007-02-14 2008-09-11 Chad Jensen Power a-frame
CA2705719C (en) * 2007-09-14 2016-10-11 Janssen Pharmaceutica N.V. Thieno-and furo-pyrimidine modulators of the histamine h4 receptor
CN102118969B (en) 2008-06-12 2017-03-08 詹森药业有限公司 Diaminopyridine, diaminopyrimidine, and diaminopyridazine modulators of histamine H4 receptors

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL143925C (en) * 1965-03-09
US3398151A (en) * 1966-02-01 1968-08-20 Mead Johnson & Co Azaspirodecanediones and azaspiroundecanediones
BE759371A (en) * 1969-11-24 1971-05-24 Bristol Myers Co HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION

Cited By (159)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907801A (en) * 1969-11-24 1975-09-23 Mead Johnson & Co N-{8 (4-pyridyl-piperazino)-alkyl{9 -azaspiroalkanediones
US4123538A (en) * 1977-08-30 1978-10-31 Mcneil Laboratories, Incorporated (2-Amino-2-oxoethoxy)acetic acid compounds, compositions and methods
DE2920739A1 (en) * 1978-05-22 1979-12-06 Bristol Myers Co USE OF 8-ANGLE CLAMP ON 4-CORNER CLAMP ON 4- (2-PYRIMIDINYL) -1PIPERAZINYL ANGLE CLAMP ON -BUTYL ANGLE CLAMP ON -8-AZASPIRO ANGLE CLAMP ON 4.5 ANGLE CLAMP ON DECAN-7,9-DION
US4182763A (en) * 1978-05-22 1980-01-08 Mead Johnson & Company Buspirone anti-anxiety method
DE2920739C2 (en) * 1978-05-22 1991-08-08 Bristol-Myers Squibb Co. (N.D.Ges.D.Staates Delaware), New York, N.Y., Us
US4305944A (en) * 1980-09-08 1981-12-15 Mead Johnson & Company N-[(4-[3-cyano substituted pyridyl]piperazino)alkyl]-azaspirodecanediones
FR2489823A1 (en) * 1980-09-08 1982-03-12 Bristol Myers Co NOVEL N - ((4- (3-PYRIDYL SUBSTITUTED IN POSITION 3) -PIPERAZINO) ALKYL) AZASPIRODECANEDIONES, PROCESS FOR PREPARING THEM AND MEDICAMENT CONTAINING SAME
DE3141256A1 (en) * 1980-10-16 1982-08-19 Bristol-Myers Co., 10022 New York, N.Y. SPIRO-QUATERNAIRE AMMONIUM HALOGENIDES AND N- (2-PYRIMIDINYL) -PIPERAZINYLALKYLAZASPIROALCANDION METHODS
NL8104660A (en) * 1980-10-16 1982-05-17 Bristol Myers Co SPIRO-QUATERARY AMMONIUM HALOGENIDES AND N- (2-PYRIMIDINYL) PIPERAZINYL ALKYLAZAPIROALKANDION PROCESS.
FR2492383A1 (en) * 1980-10-16 1982-04-23 Bristol Myers Co SPIRO-QUATERNARY AMMONIUM HALIDES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN PROCESS FOR PRODUCING N- (2-PYRIMIDINYL) PIPERAZINYL-ALKYLAZOSPIRO-ALKANEDIONES
US4351939A (en) * 1980-10-16 1982-09-28 Mead Johnson & Company Spiro-quaternary ammonium halides and N-(2-pyrimidinyl)piperazinylalkylazaspiroalkanedione process
US4417049A (en) * 1980-10-16 1983-11-22 Mead Johnson & Company Spiro-quaternary ammonium halides and N-(2-pyrimidinyl)piperazinylalkylazaspiroalkanedione process
DE3149011A1 (en) * 1980-12-11 1982-07-15 Bristol-Myers Co., 10022 New York, N.Y. METHOD FOR PRODUCING BUSPIRON
AT380686B (en) * 1980-12-11 1986-06-25 Bristol Myers Co METHOD FOR PRODUCING BUSPIRON
US4320131A (en) * 1981-03-16 1982-03-16 Mead Johnson & Company N-[(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)alkylene]azaspiroalkanediones and N-[(4-hydroxy-4-phenylpiperidin-1-yl)alkylene]azaspiroalkanediones
FR2510572A1 (en) * 1981-08-03 1983-02-04 Bristol Myers Co NOVEL THIAZOLIDINEDIONES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATION CONTAINING SAME
US4456756A (en) * 1981-08-03 1984-06-26 Mead Johnson & Company Spirothiazolidinyl piperazine derivatives
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
US4507303A (en) * 1981-12-22 1985-03-26 Sumitomo Chemical Company, Limited Succinimide derivatives, compositions and method of use
US4543355A (en) * 1981-12-22 1985-09-24 Sumitomo Chemical Company, Limited Substituted succinimides, compositions and method of use
FR2521561A1 (en) * 1981-12-23 1983-08-19 Bristol Myers Co DERIVATIVES OF BENZISOTHIAZOLE AND BENZISOXALE PIPERAZINE
US4452799A (en) * 1981-12-23 1984-06-05 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
US4411901A (en) * 1981-12-23 1983-10-25 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
FR2518994A1 (en) * 1981-12-28 1983-07-01 Bristol Myers Co 2- (4- (4,4-DIALKYL-2,6-PIPERIDINEDION-1-YL) BUTYL) -1-PYPERAZINYL) PYRIDINES AND THEIR PHARMACOLOGICAL APPLICATION
US4423049A (en) * 1981-12-28 1983-12-27 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines
DE3248160A1 (en) * 1981-12-28 1983-07-07 Bristol-Myers Co., 10154 New York, N.Y. 2- (4 - ((4,4-DIALKYL-2,6-PIPERIDINDION-1-YL) -BUTYL) -1-PIPERAZINYL) PYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
DE3248138A1 (en) * 1981-12-28 1983-07-07 Bristol-Myers Co., 10154 New York, N.Y. 2- (4- (4,4-DIALKYL-2,6-PIPERIDINDION-1-YL) BUTYL) -1-PIPERAZINYL) PYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
FR2518993A1 (en) * 1981-12-28 1983-07-01 Bristol Myers Co 2- (4 - ((4,4-DIALKYL-2,6-PIPERIDINEDION-1-YL)) - 1-PIPERAZINYL) PYRIMIDINES, THEIR PREPARATION AND THEIR PHARMACOLOGICAL APPLICATION
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
US4409223A (en) * 1982-08-06 1983-10-11 Riblet Leslie A Anxiolytic method
WO1984000752A1 (en) * 1982-08-11 1984-03-01 Eastman Kodak Co Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines and methods for their preparation and use
US4620006A (en) * 1982-08-11 1986-10-28 Eastman Kodak Company Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines
US4515947A (en) * 1982-08-11 1985-05-07 Eastman Kodak Company Cyanoalkylpiperazines and methods for their preparation and use
US4620002A (en) * 1982-08-11 1986-10-28 Eastman Kodak Company 2-pyrimidyl alkanesulfonates
US4598078A (en) * 1982-10-21 1986-07-01 Sumitomo Chemical Company, Limited N-(substituted piperazinyl) alkylbicyclic succinimide derivatives
US4438119A (en) 1982-12-23 1984-03-20 Mead Johnson & Company Method for alleviation of extrapyramidal motor disorders
JPS59148780A (en) * 1983-02-07 1984-08-25 ブリストル―マイヤーズ　スクイブ　カンパニー Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound
US4581357A (en) * 1983-02-07 1986-04-08 Mead Johnson & Company Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound
FR2540499A1 (en) * 1983-02-07 1984-08-10 Bristol Myers Co ANTIPSYCHOTIC 5-FLUORO-PYRIMIDINE-2-YL PIPERAZINE DERIVATIVE
US4524206A (en) * 1983-09-12 1985-06-18 Mead Johnson & Company 1-Heteroaryl-4-(2,5-pyrrolidinedion-1-yl)alkyl)piperazine derivatives
FR2555585A1 (en) * 1983-09-12 1985-05-31 Bristol Myers Co DERIVATIVES OF 1-HETEROARYL-4 ((2,5-PYRROLIDINEDION-1-YL) ALKYL) PIPERAZINE, PROCESS FOR PREPARING THEM AND THEIR PHARMACOLOGICAL APPLICATION
US4562255A (en) * 1984-03-30 1985-12-31 American Home Products Corporation Substituted bi-alicyclic imides
US4668687A (en) * 1984-07-23 1987-05-26 Bristol-Myers Company Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones
FR2567886A1 (en) * 1984-07-23 1986-01-24 Bristol Myers Co 1- (2-PYRIMIDINYL) -PIPERAZINYL DERIVATIVES OF 1-PYRROLIDINE-2-ONES AND THEIR PSYCHOGERIATRIC APPLICATION
US4612312A (en) * 1984-07-30 1986-09-16 Merrell Dow Pharmaceuticals Inc. Glutarimide antianxiety and antihypertensive agents
US4619930A (en) * 1985-01-16 1986-10-28 Bristol-Myers Company Antipsychotic cyclic imide derivatives of 2-(4-butylpiperazin-1-yl)pyridines, compositions and use
US4745117A (en) * 1985-03-27 1988-05-17 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and compositions for use as antipsychotic agents
US4677104A (en) * 1985-05-06 1987-06-30 Bristol-Myers Company Antipsychotic fused-ring pyridinylpiperazine derivatives
FR2587342A1 (en) * 1985-06-22 1987-03-20 Sandoz Sa NOVEL THIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US4892879A (en) * 1985-06-22 1990-01-09 Sandoz Pharm. Corp. 1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and tetrahydro-pyridines useful as anxioltic, psychogeriatric, antisepressant and antischiziphrenic agents
US4737500A (en) * 1985-06-22 1988-04-12 Sandoz Pharm. Corp. 1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and -tetrahydropyridines useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents
DE3622842A1 (en) * 1985-07-08 1987-03-05 Bristol Myers Co DIAZINYLPIPERIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS
US4826843A (en) * 1985-07-08 1989-05-02 Bristol-Myers Cerebral function enhancing diazinylpiperidine derivatives
US4812567A (en) * 1985-10-16 1989-03-14 American Home Products Corporation Polycyclic spiroimides with psychotropic activity
US4634703A (en) * 1985-10-25 1987-01-06 Bristol-Myers Company Method for alleviation of panic disorders
US4640921A (en) * 1986-02-04 1987-02-03 Bristol-Myers Treatment of sexual dysfunction with buspirone
WO1987004621A1 (en) * 1986-02-04 1987-08-13 Ekkehard Othmer Treatment of sexual dysfunction with buspirone
EP0238905A3 (en) * 1986-03-05 1989-08-09 Merrell Dow Pharmaceuticals Inc. 4-(2-pyrimidinyl)-1-piperazinyl heterocyclic carbonyl derivatives
EP0236931A3 (en) * 1986-03-05 1990-01-17 Merrell Dow Pharmaceuticals Inc. Aromatic omega-alkylimino-tetrahydro-6h-1,3-thiazin-6-one derivatives
US4812461A (en) * 1986-09-26 1989-03-14 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and their use in the treatment psychosis
US4687772A (en) * 1986-10-07 1987-08-18 Bristol-Myers Company Method for improvement of short term memory
US4777173A (en) * 1987-03-25 1988-10-11 Bristol-Myers Company Method for treatment of alcohol abuse
EP0304941A1 (en) * 1987-08-28 1989-03-01 Bristol-Myers Squibb Company Pharmaceutically useful polymorphic modification of buspirone
US4810789A (en) * 1987-08-28 1989-03-07 Bristol-Myers Company Process for buspirone hydrochloride polymorphic crystalline form conversion
US5015646A (en) * 1987-08-28 1991-05-14 Bristol-Myers Squibb Co. Pharmaceutically useful polymorphic modification of buspirone
JPH02501744A (en) * 1987-10-22 1990-06-14 ブリストル―マイアーズ・スクウイブ・カンパニー Composition for oral administration of buspirone and its salts
EP0313535A1 (en) * 1987-10-22 1989-04-26 Bristol-Myers Squibb Company Oral formulation of buspirone and salts thereof
JP2674170B2 (en) 1987-10-22 1997-11-12 ブリストル−マイアーズ・スクウイブ・カンパニー Composition for oral administration of buspirone and its salt, and method for producing the same
WO1989003676A1 (en) * 1987-10-22 1989-05-05 Aktiebolaget Astra Oral formulation of buspirone and salts thereof
AU604585B2 (en) * 1987-10-22 1990-12-20 Bristol-Myers Squibb Company Oral formulation of buspirone and salts thereof
EP0314363A3 (en) * 1987-10-26 1990-07-11 Pfizer Inc. Anti-anxiety agents
US4880930A (en) * 1987-11-30 1989-11-14 New James S Psychotropic acyclic amide derivatives
US5001130A (en) * 1988-02-18 1991-03-19 Bristol-Myers Company Psychotropic heterobicycloalkylpiperazine derivatives
US5116970A (en) * 1988-02-18 1992-05-26 New James S Psychotropic heterobicycloalkylpiperazine derivatives: 2. fused pyridazinones
US5242911A (en) * 1988-06-17 1993-09-07 Pfizer Inc. Bridged bicyclic imides as anxiolytics and antidepressants
US4859671A (en) * 1988-07-08 1989-08-22 American Home Products Corporation 2-substituted 1,2-benzisothiazol-3(2H)-one 1,1-dioxide useful as an anxiolytic agent
US5468749A (en) * 1988-08-30 1995-11-21 Gawin; Frank H. Method for treatment of substance addiction
US5077295A (en) * 1988-09-16 1991-12-31 Pfizer Inc. Antipsychoic 4-(4-(3-benzisothiazolyl)-1-piperazinyl)buytl bridged bicycle imides
WO1990002552A1 (en) * 1988-09-16 1990-03-22 Pfizer Inc. Antipsychotic 4-[4-(3-benzisothiazolyl)-1-piperazinyl]butyl bridged bicyclic imides
US5153206A (en) * 1988-12-02 1992-10-06 Pfizer Inc. Arylpiperidine derivatives
EP0395192A3 (en) * 1989-04-28 1991-05-02 Alkaloida Vegyeszeti Gyar Process for the preparation of 8-(4-(4-pyrimidin-2-yl-piperazinyl)-butyl)-8-aza-spiro(4.5)decane-7,9-dione (buspiron)
US6432956B1 (en) 1990-02-12 2002-08-13 William C. Dement Method for treatment of sleep apneas
EP0447345A3 (en) * 1990-02-13 1992-04-15 Espanola Prod Quimicos New azaspyro (4.5) decane-7,9-dione derivatives
US5407938A (en) * 1990-04-10 1995-04-18 Israel Institute For Biological Research Certain 1-methyl-piperidine-4-spiro-4'-(1'-3'-oxazolines) and corresponding -(1',3' thiazolines)
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity
US5098904A (en) * 1990-06-27 1992-03-24 Bristol-Myers Squibb Company Cerebral function enhancing pyrimidinyl derivatives
US5187277A (en) * 1990-10-29 1993-02-16 Komissarov Igor V DL-3-[4-[4-(2-pyridyl)-1-piperazinyl]-butyl]-1,8,8-trimethyl-3-azabicyclo[(3]octane-2,4-dione having psychotropic and antiemetic effect
US5837280A (en) * 1990-11-28 1998-11-17 Sano Corporation Transdermal administration of azapirones
US5817331A (en) * 1990-11-28 1998-10-06 Sano Corporation Transdermal administration of azapirones
US5633009A (en) * 1990-11-28 1997-05-27 Sano Corporation Transdermal administration of azapirones
US5431922A (en) * 1991-03-05 1995-07-11 Bristol-Myers Squibb Company Method for administration of buspirone
US5137894A (en) * 1991-12-05 1992-08-11 New James S 4-(4-Piperidinyl-thieno[3,2-c]pyridine derivatives of n-alkylglutarimides
US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5484788A (en) * 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
US5338738A (en) * 1993-04-19 1994-08-16 Bristol-Myers Squibb Company Cerebral function enhancers: acyclic amide derivatives of pyrimidinylpiperidines
US5658941A (en) * 1993-10-14 1997-08-19 Bristol-Myers Squibb Company Aminomethyl-benzodioxane and benzopyran serotonergic agents
US5496847A (en) * 1993-10-14 1996-03-05 Bristol-Myers Squibb Co. Aminomethyl-benzodioxane and benzopyran serotonergic agents
US5391570A (en) * 1993-10-14 1995-02-21 Bristol-Myers Squibb Aminomethyl-benzodioxane and benzopyran serotonergic agents
EP0655449A1 (en) * 1993-11-10 1995-05-31 Jin Ro Limited A process for preparing N-( 2-pyrimidyl) piperazinyl butyl imides
US5538985A (en) * 1994-01-27 1996-07-23 Mitsui Toatsu Chemicals, Inc. Pyrrolidinone derivatives
US5521313A (en) * 1994-05-05 1996-05-28 Bristol-Myers Squibb Company Process for preparing certain azapirones
EP0680961A1 (en) * 1994-05-05 1995-11-08 Bristol-Myers Squibb Company Improved, large-scale process for azapirone synthesis
ES2082727A1 (en) * 1994-09-01 1996-03-16 Univ Madrid Complutense New arylpiperazine derivatives
WO1996006846A1 (en) * 1994-09-01 1996-03-07 Universidad Complutense De Madrid New arylpiperazine derivatives
US5602128A (en) * 1994-12-02 1997-02-11 American Home Products Corporation N-heterocycloalkyl carboxamides as serotonergic agents
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis
ES2095811A1 (en) * 1995-07-28 1997-02-16 Univ Madrid Complutense New arylpiperazine derivatives
US6008222A (en) * 1996-12-04 1999-12-28 Bristol-Myers Squibb Company Method for oral administration of buspirone and nefazodone
US5922341A (en) * 1997-10-28 1999-07-13 Vivus, Incorporated Local administration of pharmacologically active agents to treat premature ejaculation
US6228864B1 (en) 1997-10-28 2001-05-08 Vivus, Inc. Administration of 5-HT receptor agonists and antagonists, to treat premature ejaculation
US6037360A (en) * 1997-10-28 2000-03-14 Vivus, Incorporated Administration of 5-HT3 receptor antagonists to treat premature ejaculation
US6376494B1 (en) 1998-06-15 2002-04-23 American Home Products Corporation Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US7049330B2 (en) 1998-06-15 2006-05-23 Wyeth Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US20030139449A1 (en) * 1998-06-15 2003-07-24 Wyeth Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US6518272B2 (en) 1998-06-15 2003-02-11 Wyeth Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US6312717B1 (en) 1998-07-07 2001-11-06 Bristol-Myers Squibb Company Method for treatment of anxiety and depression
WO2000006163A1 (en) * 1998-07-30 2000-02-10 Bristol-Myers Squibb Company Improved method for treatment of sleep-related respiratory disorders
US6313114B1 (en) 1999-01-07 2001-11-06 American Home Products Corp 3,4-Dihydro-2H-benzo[1,4]oxazinyl-methyl)-[3-(1H-indol-3yl)-alkyl]- amines
US6306859B1 (en) 1999-03-02 2001-10-23 American Home Products Corporation N-substituted imide derivatives with serotonergic activity
US6566361B2 (en) 1999-06-30 2003-05-20 Laboratories, Upsa Azapirone pain treatment
US20050137206A1 (en) * 1999-08-05 2005-06-23 Yevich Joseph P. Method for treatment of anxiety and depression
US20030069251A1 (en) * 1999-08-05 2003-04-10 Yevich Joseph P. Antianxiety composition
US6150365A (en) * 1999-08-05 2000-11-21 Bristol-Myers Squibb Company Anxiety method
US6828324B2 (en) 1999-11-12 2004-12-07 Wyeth Branched adamantyl and noradamantyl aryl-and aralkylpiperazines with serotonin 5-HT1A activity
US6831084B1 (en) 1999-11-12 2004-12-14 Wyeth Branched adamantyl and noradamantyl aryl- and aralkylpiperazines with serotonin 5-HT1A activity
US7517904B2 (en) 2000-09-19 2009-04-14 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20050272799A1 (en) * 2000-09-19 2005-12-08 Salvati Mark E Fused Heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US20040067962A1 (en) * 2000-11-29 2004-04-08 Schaus John Mehnert 1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl) piperazine and pharmaceutically acceptable salts and solvents thereof
US6864262B2 (en) 2000-11-29 2005-03-08 Eli Lilly And Company 1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl) piperazine and pharmaceutically acceptable salts and solvents thereof
US20060223832A1 (en) * 2001-06-20 2006-10-05 Salvati Mark E Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US7470797B2 (en) 2001-06-20 2008-12-30 Bristol-Myers Squibb Company Fused heterocyclic imido and amido compounds
US9012451B2 (en) 2002-09-04 2015-04-21 Novartis Ag Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists
US9849117B2 (en) 2002-09-04 2017-12-26 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists
US9567343B2 (en) 2002-09-04 2017-02-14 Novartis Ag Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists
US7067518B2 (en) 2002-09-05 2006-06-27 Wyeth Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
US20050107395A1 (en) * 2002-09-05 2005-05-19 Greenblatt Lynne P. Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
US20040147581A1 (en) * 2002-11-18 2004-07-29 Pharmacia Corporation Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
US20110034475A1 (en) * 2004-06-18 2011-02-10 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
EP2336129A1 (en) 2004-06-18 2011-06-22 Novartis AG 1-aza-bicyclo[3.3.1]nonanes
US9475811B2 (en) 2004-06-18 2016-10-25 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
EP2457911A1 (en) 2004-07-14 2012-05-30 Novartis AG 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-nAChR ligands for the treatment of CNS diseases.
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
EP2463278A1 (en) 2005-04-11 2012-06-13 Novartis AG 1h-quinaz0line-2,4-diones and their use as ampa-receptor ligands
EP2468732A1 (en) 2005-04-11 2012-06-27 Novartis AG 1H-Quinazoline-2,4-diones
EP2476671A1 (en) 2005-04-11 2012-07-18 Novartis AG 1H-Quinazoline-2,4-diones
WO2006108591A1 (en) 2005-04-11 2006-10-19 Novartis Ag 1h-quinaz0line-2,4-diones and their use as ampa-receptor ligands
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
EP2361914A1 (en) 2005-12-16 2011-08-31 Novartis AG [(1h-indol-5-yl)-heteroaryloxy]-(1-aza-bicyclo[3.3.1]nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
US20100184775A1 (en) * 2005-12-16 2010-07-22 Novartis Ag Organic compounds
US9206181B2 (en) 2005-12-16 2015-12-08 Novartis Ag 1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
EP2354141A1 (en) 2005-12-16 2011-08-10 Novartis AG (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1h-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
US20090023744A1 (en) * 2007-06-18 2009-01-22 The General Hospital Corporation Combination therapy for depression
US8735578B2 (en) 2010-09-24 2014-05-27 Aché Laboratórios Farmacêuticos S.A. Compounds and pharmaceutical compositions for treating disorders associated with the 5-HT1A and 5-HT2A receptors
WO2012037634A1 (en) 2010-09-24 2012-03-29 Aché Laboratórios Farmacêuticos S.A. Compounds and pharmaceutical compositions for treating disorders associated with the 5-ht1a and 5-ht2a receptors
US9186359B2 (en) 2010-10-15 2015-11-17 Contera Pharma Aps Combinations of serotonin receptor agonists for treatment of movement disorders
US10632116B2 (en) 2010-10-15 2020-04-28 Contera Pharma A/S Combinations of serotonin receptor agonists for treatment of movement disorders
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

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CH552607A (en) 1974-08-15
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BE759371A (en) 1971-05-24
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DE2057845A1 (en) 1971-06-09
MY7700151A (en) 1977-12-31
DK141753B (en) 1980-06-09
KE2691A (en) 1977-03-04
HK6177A (en) 1977-02-04
FR2073406A1 (en) 1971-10-01
US3907801A (en) 1975-09-23
GB1332194A (en) 1973-10-03
CH552608A (en) 1974-08-15
ES8505251A3 (en) 1985-05-16
FR2073406B1 (en) 1974-10-11
ES530335A0 (en) 1985-05-16
ZA707826B (en) 1971-07-28

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