United States Patent (19) 11 Patent Number: 4,469,694 Bagli et al. 45) Date of Patent: Sep. 4, 1984 54) 2-(1-PPERAZINYL)-2,4,6-CYCLOHEPTATRI Toda, et al., "Chemical Abstracts', vol. 76, 1972, col. EN-1-ONE DERVATIVES 72185f. 75 Inventors: Jehan F. Bagli, Kirkland; Tibor Veracini, et al., "J. Chem. Soc. Commun.", 1977, pp. Bögri, Montreal; Katherine Voith, 623-624. Dorval, all of Canada Abadir, et al., "J. Chem. Soc.'', 1952, pp. 2350-2353. Nozoe, et al., "Chemical Abstracts', vol. 70, 1969, col. 73) Assignee: Ayerst, McKenna & Harrison Inc., 87244Z. Montreal, Canada Primary Examiner-Donald G. Daus 21 Appl. No.: 124,164 Assistant Examiner-James H. Turnipseed 22 Filed: Feb. 25, 1980 Attorney, Agent, or Firm-Arthur E. Wilfond 51 Int. C. ................... A61K 31/495; C07D 241/04 57 ABSTRACT 52 U.S. Cl. .................................... 424/250; 544/358; 2-(1-Piperazinyl)-2,4,6-cycloheptatrien-1-one deriva 544/368; 544/369,544/370, 544/373; 544/376; tives, therapeutically acceptable acid addition salts 544/392; 544/399 thereof, processes for their preparation, methods of 58 Field of Search ................ 424/250; 544/368-369, using the derivatives and pharmaceutical compositions 544/370, 376, 373,389, 392,358; 542/429 of the derivatives are disclosed. The derivatives exhibit dopamine-receptor stimulating activity in a mammal 56) References Cited and are useful for treating hyperprolactinemia, galac PUBLICATIONS torrhea, amenorrhea, impotence, Parkinsonism, diabe Sianesi, et al., "J. Med. Chem.'', vol. 10, 1967, pp. tes, acromegaly, hypertension and other central ner 1144-148. vous system disorders. Biggi, et al., “J. Amer. Chern. Soc.'', vol. 94, 1972, pp. 4700-4707, vol. 95, 1973, pp. 7101-7107. 35 Claims, No Drawings 4,469,694 1. 2 dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- 2-(1-PPERAZINYL)-2,4,6-CYCLOHEPTATRIEN ylmethyl; or a therapeutically acceptable acid addition 1-ONE OERVATIVES salt thereof. - - A preferred group of compounds of this invention is BACKGROUND OF THE INVENTION 5 represented by formula I in which R1 is hydrogen; R2 is This invention relates to novel 2-(1-piperazinyl)- hydrogen or lower alkyl having one to three carbon 2,4,6-cycloheptatrien-1-one derivatives, to therapeuti atoms; and R3 is hydrogen, phenyl, lower alkyl, lower cally acceptable acid addition salts thereof, to a process alkenyl, lower alkynyl, cyclo(lower)alkyl, lower alk for their preparation, to methods of using the deriva oxycarbonyl, 1-oxo(lower)alkyl, cyclo(lower)alkyl sub tives and to pharmaceutical compositions of the deriva 10 stituted with a lower alkyl; lower alkenyl substituted tives. These derivatives exhibit dopamine-receptor with phenyl; phenyl mono-, di- or trisubstituted with stimulating activity in a mammal. Thus, they can be lower alkyl, halo, lower alkoxy, hydroxy or trifluoro useful for treating hyperprolactinemia, galactorrhea, methyl;: 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy amenorrhea, impotence, Parkinsonism, diabetes, acro dro-8-oxo-cycloheptablfuran-2-ylmethyl, 1-oxo-2,4,6- megaly, hypertension and other central nervous system 15 cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- disorders which respond to dopamine-receptor stimula diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-iosin tion. dol-2-yl)ethyl, or 5-methyl-2,4-imidazolidinedione-5- The following references were obtained from a litera ylmethyl; or a therapeutically acceptable acid addition ture search for 2-substituted tropones: E. Sianezi et al., salt thereof. J.Med. Chem, 10, 1144 (1967); G. Biggiet al., J. Amer. 20 A more preferred group of compounds of this inven Chem. Soc., 94, 4700 (1972); T. Toda et al., Chem. tion is represented by formula I in which R1 is hydro Abstr., 76, 72185f (1972) for Bull. Chem. Soc. Jap., 45, gen; R2 is hydrogen or methyl; and R3 is hydrogen, 226 (1972); G. Biggi et al., J. Amer. Chem. Soc., 95, phenyl, lower alkyl, lower alkenyl, lower alkynyl, cy 7101 (1973); C. A. Veracini et al., J. Chem. Soc. Com clo(lower)alkyl, lower alkoxycarbonyl, 1-oxo(lower)al mun., 623 (1974); B.J. Abadir et al., J. Chem. Soc., 2350 25 kyl, cyclo(lower)alkyl substituted with a lower alkyl; (1952) and T. Nozoe et al., Chem. Abstr., 70, 87244z phenyl monosubstituted with lower alkyl, halo or triflu (1969) for Bull. Chem. Soc. Jap., 41,2978 (1968). These oromethyl: 2-(4,5-dihydro-2-oxazolyl)benzoyl, 1-oxo references disclose compounds which like the com 2,4,6-cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- pounds of this invention are 2,4,6-cycloheptatrien-1-one diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoin derivatives. Of these 2,4,6-cycloheptatrien-1-one deriv 30 dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- atives, the 2-piperidinyl-2,4,6-cycloheptatrien-1-one ylmethyl; or a therapeutically acceptable acid addition described by G. Biggi et al., J. Amer. Chem. Soc., 94, salt thereof. m 4700 (1972), cited above, can be considered the most A most preferred group of compounds of this inven closely related to the compounds of this invention. tion is represented by formula I in which R and R2 are However, the latter 2-piperidinyl derivative is treated 35 hydrogen; and R3 is hydrogen, lower alkyl, lower alke as a chemical curiosity without any indicated useful nyl or lower alkoxycarbonyl; or a therapeutically ac pharmacological activity. Furthermore, the compounds ceptable acid addition salt thereof. of this invention differ from the compounds of Biggi et A pharmaceutical composition is provided by admix al by having a 1-piperazinyl group at position 2 of the ing the compound of formula I, or a therapeutically 2,4,6-cycloheptatrien-1-one ring. acceptable acid addition salt thereof, with a pharmaceu SUMMARY OF THE INVENTON tically acceptable carrier. The compounds of this invention are represented by The compounds of this invention are used to stimu formula I late dopamine receptors in a mammal in need thereof by 45 administering to the mammal an effective dopamine receptor stimulating amount of a compound of formula O () I or a therapeutically acceptable acid addition salt 1. thereof. R M V N N-R3 DETAILED DESCRIPTION OF THE 50 INVENTION R2 The term “lower alkyl' as used herein means straight chain alkyl radicals containing from one to six carbon in which R represents a substituent at positions 3, 4, 5, atoms and branched chain alkyl radicals containing 6 or 7 of the 2,4,6-cycloheptatrien-1-one ring, and is 55 three or four carbon atoms and includes methyl, ethyl, selected from hydrogen, halo, lower alkyl, lower alk propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, oxy, trifluoromethyl, or 1-oxo(lower)alkylamino; R2 is hexyl and the like, unless stated otherwise. 1 hydrogen or lower alkyl having one to three carbon Methylethyl and 2-methylpropyl also are known as atoms; and R3 is hydrogen, phenyl, lower alkyl, lower isopropyl and sec-butyl. alkenyl, lower alkynyl, cyclo(lower)alkyl, lower alk The term “lower alkoxy” as used herein means oxycarbonyl, 1-oxoClower)alkyl, cyclo(lower)alkyl sub straight chain alkoxy radicals containing from one to six stituted with a lower alkyl; lower alkenyl substituted carbon atoms and branched chain alkoxy radicals con with phenyl; phenyl mono-, di- or trisubstituted with taining three or four carbon atoms and includes me lower alkyl, halo, lower alkoxy, hydroxy or trifluoro thoxy, ethoxy, 1-methylethoxy, butoxy, hexoxy and the methyl; 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy 65 like. dro-8-oxo-cycloheptablfuran-2-ylmethyl, 1-oxo-2,4,6- The term “1-oxo(lower)alkyl” or “lower alkanoyl” as cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- used herein means straight chain 1-oxoalkyl radicals diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoin containing from two to six carbon atoms and branched 4,469,694 3 4. chain 1-oxoalkyl radicals containing four to six carbon The addition salts thus obtained are the functional atoms and includes acetyl, 1-oxopropyl, 2-methyl-1- equivalent of the parent base compound in respect to oxopropyl, 1-oxohexyl and the like. their therapeutic use. Hence, these addition salts are The term "1-oxo(lower)alkoxy” as used herein means included within the scope of this invention and are straight chain 1-oxoalkoxy radicals containing from two limited only by the requirement that the acids employed to six carbon atoms and branched chain 1-oxoalkoxy in forming the salts be therapeutically acceptable. radicals containing four to six carbon atoms and in The discovery in the mid-1960's of two major dopa cludes acetyloxy, 1-oxopropoxy, 1-oxobutoxy, 2,2- mine (DA) systems indicated that this neurotransmitter dimethyl-1-oxopropoxy, 1-oxohexoxy and the like. exerted control over a number of physiological func The term “lower alkynyl' as used herein means O tions. Against this background an interest arose to de straight chain alkynyl radicals containing from two to velop DA receptor agonists to study the function of the six carbon atoms and a branched chain alkynyl radical dopaminergic systems and to evaluate these agonists as containing four carbon atoms and includes ethynyl, possible therapeutic agents in the Parkinson's disease 2-propynyl, 1-methyl-2-propynyl, 3-hexynyl and the and certain neuroendocrine disorders, for example, like. 15 hyperprolactinemia, galactorrhea, amenorrhea, impo The term "lower alkenyl' as used herein means tence, hypertension and other central nervous system straight chain alkenyl radicals containing from two to disorders. six carbon atoms and branched chain alkenyl radicals The DA receptor agonists exert a variety of pharma containing three or four carbon atoms and includes cological effects, some of the most characteristic being ethenyl, 2-methyl-2-propenyl, 4-hexenyl and the like.