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 FR7041860A priority patent/FR2073406B1/fr
Priority to DK589670AA priority patent/DK141753B/en
Priority to NL7017031A priority patent/NL7017031A/xx
Priority to DE19702057845 priority patent/DE2057845A1/en
Priority to CH341874A priority patent/CH552608A/en
Priority to GB5590870A priority patent/GB1332194A/en
Priority to CY886A priority patent/CY886A/en
Priority to CH1741770A priority patent/CH552607A/en
Priority to US312543A priority patent/US3907801A/en
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Priority to KE2691A priority patent/KE2691A/en
Priority to HK61/77A priority patent/HK6177A/en
Priority to MY151/77A priority patent/MY7700151A/en
Priority to ES84530335A priority patent/ES8505251A3/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;

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
DK589670AA DK141753B (en) 1969-11-24 1970-11-20 Analogous process for the preparation of azaspirodecan and undecanedione derivatives or acid addition salts thereof.
NL7017031A NL7017031A (en) 1969-11-24 1970-11-20
FR7041860A FR2073406B1 (en) 1969-11-24 1970-11-20
CH1741770A CH552607A (en) 1969-11-24 1970-11-24 PROCESS FOR THE PRODUCTION OF AZASPIROALCANDIONE DERIVATIVES.
CH341874A CH552608A (en) 1969-11-24 1970-11-24 PROCESS FOR THE PRODUCTION OF AZASPIROALCANDIONE DERIVATIVES.
DE19702057845 DE2057845A1 (en) 1969-11-24 1970-11-24 Heterocyclic azaspirodecanediones and process for their preparation
GB5590870A GB1332194A (en) 1969-11-24 1970-11-24 Heterocyclic azaspiroalkanediones
CY886A CY886A (en) 1969-11-24 1970-11-24 Heterocyclic azaspiroalkanediones
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
ES84530335A ES8505251A3 (en) 1969-11-24 1984-03-07 N-(heteroaryl) piperazvinylalkyl derivs

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HK6177A (en) 1977-02-04
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FR2073406A1 (en) 1971-10-01
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NL7017031A (en) 1971-05-26
US3907801A (en) 1975-09-23
ES8505251A3 (en) 1985-05-16
BE759371A (en) 1971-05-24
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CH552607A (en) 1974-08-15
DE2057845A1 (en) 1971-06-09
KE2691A (en) 1977-03-04
CH552608A (en) 1974-08-15
MY7700151A (en) 1977-12-31
DK141753B (en) 1980-06-09
FR2073406B1 (en) 1974-10-11
CY886A (en) 1977-03-18

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