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. 20 the ones that occur in animals in which DA deficiency The term "halo' as used herein means halogens and is brought about to mimic the Parkinsonian syndrome. includes fluorine, chlorine, bromine and iodine, unless An important model was developed by U. Ungerstedt, stated otherwise. . Acta. Physiol. Scand., Suppl. 367, 69-93 (1971) who, by The term "cyclo(lower)alkyl' as used herein means means of unilateral injections of 6-hydroxydopamine saturated cyclic hydrocarbon radicals containing from 25 (6-OHDA) into the DA pathway, could produce selec three to six carbon atoms and includes cyclopropyl, tive lesions of the ascending DA pathways on one side cyclobutyl, cyclopentyl and cyclohexyl. of the brain. Ungerstedt (1971) demonstrated in three The term "cyclo(lower)alkyl substituted with a lower lesioned rats that DA receptor agonists induced rota alkyl' as used herein means saturated cyclic hydrocar tional behavior towards the innervated side. The re bon radicals containing from three to six carbon atoms, 30 sponse is due to the development of receptor supersensi as defined above, which is substituted with a lower tivity in the denervated striatum resulting in a higher alkyl group and includes 1-methylcyclopropyl, 2-ethyl degree of DA receptor activity on the denervated- as cyclobutyl, 4-propylcyclohexyl and the like. compared to the innervated-side after treatment with The term "lower alkanol' as used herein means both DA receptor agonists. Due to this imbalance between straight and branched chain alkanols containing from 35 the two sides, a rotational behavior is elicited, the direc one to four carbon atoms and includes methanol, etha tion being always towards the less activated side. It is of nol, isopropanol, butanol and the like. t interest that in the discovery of the DA receptor stimu The term "organic proton acceptor' as used herein lating properties of bromocriptine, the 6-OHDA rota means the organic bases, or amines for instance, trieth tional model was utilized H. Corrodi et al., J. Pharm. ylamine, pyridine, N-ethyl-morpholine, 1,5-diazabicy Pharmacol., 25, 409–412 (1973)). clo4.3.0non-5-ene and the like. In the test for rotational behavior in rats following The term "inorganic proton acceptor' as used herein the unilateral 6-OHDA-induced destruction of one n1 means the inorganic bases, preferably the alkali metal grostriatal pathway, the method described by C. J. hydroxides, carbonates and bicarbonates, for example, Pycock and C. D. Marsden, Europ. J. Pharmacol., 47. sodium hydroxide, potassium hydroxide, sodium car 45 167 (1978) was followed. The rats (230–250 g) were bonate, sodium bicarbonate, potassium carbonate and anesthetized with sodium pentobarbital (40 mg/kg i.p.) the like. and intracerebral injections were made using a Stoelting The term "proton acceptor' as used herein means a stereotaxic instrument, (C. H. Stoelting Co., Chicago, proton acceptor selected from an organic proton accep Ill., U.S.A.). Unilateral injections of 6-OHDA hydro tor and inorganic proton acceptor, as defined herein. 50 bromide (8 g/3 ul delivered at a rate of 1 ul per min) The compounds of formula I are capable of forming were made into the ascending median forebrain bundle acid addition salts with therapeutically acceptable (MFB) in the lateral hypothalamus according to the acids. The acid addition salts are: prepared by reacting coordinates of the De Groot brain atlas, J. De Groot, the base form of the appropriate compound of formula Verhandel, Koninkl. Ned. Akad. Wetenschap. Natuurk. I with one or more equivalents, preferably with an 55 52: 1-40 (1959), (A: +4.6, L: - 1.9, V: -2.7). 6-OHDA excess, of the appropriate acid in an organic solvent, for was made up in ice-cold distilled water containing 0.2 example, diethyl ether or an ethanol-diethyl ether mix mg/ml ascorbic acid. ture. These salts, when administered to a mammal, pos Three weeks after operation, the rats were tested for sess the same pharmacologic activities as the corre rotational behavior in response to apomorphine hydro sponding bases. For many purposes it is preferable to chloride (0.25 mg/kg, s.c.). Rats which consistently administer the salts rather than the base compounds. showed more than 5 turns/min after apomorphine were Examples of suitable acids to form these salts include: selected and the compound of formula I was then ad the common mineral acids, e.g., hydrohalic, sulfuric or ministered. The rat was immediately placed in the ro phosphoric acids; the organic acids, e.g., formic, acetic, tometer, described by K. Voith and J. R. Cummings, maleic, malic, citric, or tartaric acid; and acids which 65 Can. J. Pharmacol., 54, 551 (1976), and the rotation was are sparingly soluble in body fluids and which impart continuously recorded until drug effect subsided. By slow-release properties to their respective salts, e.g., using this test, the compounds of formula I can be pamoic acid, tannic acid or carboxymethyl cellulose. shown to be effective dopamine receptor agonists. 4,469,694 5 6 A recently developed animal model, described by G. few drops of polysorbate 80 (Tween 80; "Tween' is a P. Smith and R. C. Young in "Advances in Neurology', registered trade mark). If the compound was an oil, 0.4 Vol. 5, F. H. McDowell and A. Barbeau, Eds., Raven ml of dimethyl sulfoxide was added. Solutions were Press, New York, pp. 427-432 (1974), shows that rats prepared fresh on the day of the experiment. The 6 exhibit almost complete akinesia in an open field follow OHDA solution was kept in ice throughout the injec ing the bilateral injection of 6-OHDA into the anterolat tion procedure. All doses refer to the base. eral hypothalamus. The troponylpiperazines of formula Using the above described method, apomorphine at a I are able to reverse this 6-OHDA-induced hypokinesia dose of 0.5 mg/kg exhibited a score of 135-41 and and as a result, function as dopamine receptor agonists. bromocriptine at a dose of 10 mg/kg exhibited a score In this test for dopamine receptor agonists, the com 10 of 112-23. Similarly, the following representative pounds of formula I exhibit a pharmacological response compounds of formula I are effective dopamine recep that is quantitatively comparable to that of apomophine toragonists (the amount of the compound and its cumu and bromocriptine. lative ambulation score are indicated in the parenthe Experiments were performed on male Sprague-Daw ses): 2-(4-methyl-1-piperazinyl)-2,4,6-cycloheptatrien ley rats housed in air-conditioned quarters. The room 15 1-one (described in Example 1, at a dose of 50 mg/kg was lighted between 0700 and 1900 hr daily and was exhibited a score of 278-57), 4-(2-oxo-3,5,7-cyclohep maintained at a temperature of 24 C.E.2 C. tatrien-1-yl)-1-piperazine carboxylic acid, ethyl ester The method of Smith and Young, cited above, was (described in Example 1, at a dose of 50 mg/kg exhib followed. Rats (approximately 280 g) were operated on ited a score of 79-31), 2-4-(2-propenyl)-1-piperazinyl under sodium pentobarbital anesthesia. Using a Stoelt 20 2,4,6-cycloheptatrien-1-one (described in Example 4, at ing stereotaxic instrument, the tip of a 26 gauge cannula a dose of 50 mg/kg exhibited a score of 155-43), 2-4- was positioned in the anterolateral hypothalamus (7 mm (2-propynyl)-1-piperazinyl-2,4,6-cycloheptatrien-1-one anterior to the interaural line, 2 mm lateral to the mid (described in Example 4, at a dose of 50 mg/kg exhib line and 8 mm below the dura) according to the De ited a score of 28-6), 2-4-(1-methylethyl)-1- Groot brain atlas, noted above. Via a polyethylene 25 piperazinyl)-2,4,6-cycloheptatrien-1-one (described in tubing (PE 20) the cannula was connected to a 10 ul Example 4, at a dose of 50 mg/kg exhibited a score of syringe which was mounted in a Starrett micrometer 431-113), 2-(4-ethyl-1-piperazinyl)-2,4,6-cyclohepta head drive, C. H., Stoelting Co., Chicago, Ill. U.S.A. trien-1-one (described in Example 4, at a dose of 50 All injections were bilateral. Each injection consisted of mg/kg exhibited a score of 70-15), 2-(4-propyl-1- 4 pil of distilled water containing 6-OHDA (6.5 ug 30 piperazinyl)-2,4,6-cycloheptatrien-1-one (described in base/ul) and ascorbic acid (0.4 ug/ul). Example 4, at a dose of 50 mg/kg exhibited a score of The animals had free access to Purina Laboratory 15934), and N-(2-4-(2-oxo-3,5,7-cycloheptatrien-1- Chow pellets and tap water. However since anterolat yl)-1-piperazinyl)ethyl)acetamide (described in Exam eral hypothalamic 6-OHDA injections produce aphagia ple 7 at a dose of 50 mg/kg exhibited a score of 36-8). and adipsia, intragastric feeding was necessary in order 35 The above described test method for dopamine re to prevent drastic weight less. The rats received a daily ceptor agonists shows that the compounds of formula I gastric intubation of 2 g of the "modified rat tube feed are active as dopamine receptor agonists. The com ing diet” (ICN Pharmaceuticals, Inc., Cleveland, Ohio, pounds, thus, can be used clinically in the treatment of U.S.A.) mixed with approximately 2 ml tap water. hyperprolactinemia, galactorrhoea, amenorrhoea, im Ambulation in the open field was evaluated in an potence, diabetes, Parkinsonism, acromegaly, hyperten apparatus consisting of a wooden box (69 cm x 69 sion and other central nervous system disorders which cm x 42 cm) with an arborite floor. The floor was di respond to dopamine-receptor stimulation. vided into 36 squares (11.5 cm× 11.5 cm). The place The compounds of formula I of this invention are ment of all four limbs in one square was taken as one used alone or in combination with pharmacologically ambulation score. 45 acceptable carriers, the proportion of which is deter In the present experiments all compounds were eval mined by the solubility and chemical nature of the com uated four days after the intracerebral injection of 6 pound, chosen route of administration and standard OHDA. The rat was placed into the center of the open biological practice. For example, they are adminis field and observed for a 2-min period. Only rats with tereed orally in solid form i.e. capsule or tablet. They almost total akinesia were used. Apomorphine, bromo 50 can also be administered orally in the form of suspen criptine or the compounds of formula I were injected sions or solutions or they may be injected parenterally. s.c. to groups of 4-12 rats. Subsequently, the number of For parenteral administration they can be used in the squares were counted which the animal entered during form of a sterile solution containing other solutes, for several 2-min observation periods. Apomorphine was example, enough saline or glucose to make the solution evaluated at 5, 10, 15, 20 and 30 min; bromocriptine at 2, 55 isotonic. 3, 4, 5, 6 and 7hr; and the compounds of formula I at 15, The tablet compositions contain the active ingredient 30, 45, 60, 90 and 120 min after injection. Each animal in admixture with non-toxic pharmaceutical excipients was used only once. The results are expressed as cumu known to be suitable in the manufacture of tablets. Suit lative number of ambulation scores which are the sums able pharmaceutical excipients are, for example, starch, of the scores obtained during the 2-min observation milk sugar, certain types of clay and so forth. The tab periods. lets can be uncoated or they can be coated by known The following substances were used; apomorphine techniques so as to delay disintegration and absorption hydrochloride (Macfarlan Smith Ltd., Edinburgh, in the gastrointestinal tract and thereby provide a sus Scotland), bromocriptine (CB-154) (Sandoz Pharma tained action over a longer period. ceuticals, East Hanover, N.J., U.S.A.) and 6-OHDA 65 The aqueous suspensions of the compounds of the hydrobromide (Aldrich Chemical Co., Inc., Milwau formula I contain the active ingredient in admixture kee, Wis., U.S.A.). The compounds were dissolved in with one or more non-toxic pharmaceutical excipients distilled water or suspended in distilled water with a known to be suitable in the manufacture of aqueous 4,469,694 7 8 suspensions. Suitable excipients are, for example, meth formula I, or its therapeutically acceptable salt, is ad ylcellulose, sodium alginate, gum acacia, lecithin and so ministered as described previously. forth. The aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or PROCESS more flavoring agents and one or more sweetening Reaction scheme I illustrates a method for preparing agents. a number of the compounds of formula I. Non-aqueous suspensions can be formulated by sus pending the active ingredient in a vegetable oil, for REACTION SCHEME 1 example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, for example liquid paraffin, and the O O suspension may contain a thickening agent, for example 2 beeswax, hard paraffin or cetyl alcohol. These composi tions can also contain a sweetening agent, flavoring agent and antioxidant. The dosage of the compounds of formula I as dopa 15 mine receptor agonists will vary with the form of ad ministration and the particular compound chosen. Fur (II) (III) thermore, it will vary with the particular host as well as the age, weight and condition of the host under treat O ment as well as with the nature and extent of the symp a toms. Generally, treatment is initiated with small dos Ri / & ages substantially less than the optimum dose of the N N-R compound. Thereafter, the dosage is increased by small increments until the optimum effect under circum R2 stances is reached. In general, the compounds of this 25 invention are most desirably administered at a concen (I) tration level that will generally afford effective results without causing any harmful or deleterious side effects. The 2-alkoxy-tropones of formula II suitable as start For example, the effective dopamine receptor stimulat ing materials are described in a number of reports; for ing amount of the compounds for i.p. administration 30 example, see the review on tropone derivatives, their usually ranges from about 0.1 mg to about 250 mg per preparation and their interconversions by F. Pietra, kilogram body weight per day in single or divided doses Chem. Rev., 73, 293 (1973). Thus, the 2-alkoxy-tro although as aforementioned variations will occur. How pones are either known or they can be prepared by ever a dosage level that is in the range of from about 1.0 conventional means. to about 100 mg per kilogram body weight per day in 35 single or divided doses is employed most desirably for Also, the piperazine and piperazine derivatives of i.p. administration in order to achieve effective results. formula III are known, commercially available or can For oral administration, effective amounts can range be prepared by conventional means. For example, one from about 1.0 to about 250 mg per kilogram body useful method of preparing a compound of formula III weight per day in single or divided doses preferably wherein R is other than hydrogen, the appropriate about 5.0 to 100 mg per kilogram body weight per day. nitrogen of the piperazine of formula III wherein R2 is The compound of formula I, or a therapeutically as defined herein and R3 is hydrogen is first protected acceptable salt thereof, also can be used to produce with an amino protecting group, for instance, benzyl, beneficial effects in the treatment of Parkinsonism, formyl, tert-butoxycarbonyi and the like. The desired hyperprolactinemia and related disorders when com 45 R group is then introduced onto the other nitrogen of bined with a therapeutically effective amount of an this protected piperazine; various methods of introduc agent commonly used in the treatment of Parkinsonism, ing the R3 group are described hereinafter. Subsequent hyperprolactinemia and related disorders. Such agents removal of the protecting group, for example, hydroge include, for example, apomorphine and its derivatives, nation in the case of benzyl, gives the corresponding piribedil and its derivatives, dopaminergic ergot deriva 50 piperazine derivative of formula III wherein R3 is other tives, especially bromocriptine and lergotrile, 2-amino than hydrogen. 6,7-dihydroxy-(1,2,3,4)-tetrahydronaphthalene With reference to reaction scheme 1, the 2-alkoxy (ADTN), levodihydroxyphenylalanine (levodopa), tropone of formula II in which R represents a substitu combination of levodopa with carbidopa, L-prolyl-L- ent at positions 3, 4, 5, 6 or 7 of the 2,4,6-cycloheptatri leucylglycinamide (MIF) and its derivatives, especially 55 en-1-one ring and is selected from hydrogen, halo, L-propyl-N-methyl-D-leucylgylcinamide (pareptide), lower alkyl, lower alkoxy, trifluoromethyl or 1-oxoG biperiden, cycrimine hydrochloride, procyclidine, tri lower)alkylamino and R is lower alkyl, preferably hexyphenidyl hydrochloride, benztropine mesylate, methyl or ethyl, is condensed with the piperazine deriv chlorphenoxamine hydrochloride, diphenhydramine ative of formula III in which R2 is hydrogen or lower hydrochloride, orphenadrine hydrochloride, ethopro alkyl having one to three carbon atoms; and R is hy pazine hydrochloride and the enzymes, monoamine drogen, phenyl, lower alkyl, lower alkenyl, lower alky oxidase B and catechol-O-methyl transferase. A combi nyl, cyclo(lower)alkyl, lower alkoxycarbonyl, -oxoG nation of the foregoing agents can be substituted for a lower)alkyl, cyclo(lower)alkyl substituted with a lower single agent. Suitable methods of administration, com alkyl; lower alkenyl substituted with phenyl; phenyl positions and dosages of the agents are well known in 65 mono-, di- or trisubstituted with lower alkyl, halo, the art; for instance, "Physican Desk Reference', 32 lower alkoxy, hydroxy or trifluoromethyl: 2-(4,5-dihy ed., Medical Economics Co., Oradell, N.J., U.S.A., dro-2-oxazolyl)benzoyl, 2,3-dihydro-8-oxo-cyclohep 1978. When used in combination, the compound of tablfuran-2-ylmethyl, 1-oxo-2,4,6-cycloheptatrien-2-yi, 4,469,694 9 10 2-(acetylamino)ethyl, 2,3-diacetyloxypropyl, 2-(1,3- hours to three days, and the compound of formula I is dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, or 5-methyl isolated. 2,4-imidazolidinedione-5-ylmethyl to obtain the corre The latter conditions are also useful for the condensa sponding compound of formula I in which R, R2, R3 tion of the compound of formula I in which R1 and R2 and R are as defined herein. The condensation is are as defined herein and R3 is hydrogen with epichlo readily effected by heating a solution of the compound rohydrin to give the corresponding intermediate having of formula II with one to five, preferably 1.3 to 2.0, the 2,3-dihydroxypropyl group at position 4 of the molar equivalents of the piperazine of formula III in an piperzino ring. Acetylation of this intermediate, in the inert organic solvent, for example, a lower alkanol, same manner as described hereinafter, gives the corre benzene, chloroform, acetonitrile, toluene and the like, 10 sponding compound of formula I in which R1 and R2 preferably methanol or ethanol, at 50 to 100 C. for 10 are as defined herein and R3 is 2,3-diacetyloxypropyl. to 60 hours and isolating the corresponding compound Acylation of the compound of formula I in which R1 of formula I. and R2 are as defined herein and R3 is hydrogen, prefer - By using the above condensation conditions, conden ably with about an equivalent of a lower alkanoyl bro sation of the compound of formula II in which R1 is 15 mide or chloride, or an excess of a lower alkanoic anhy hydrogen with about one-half molar equivalent of the dride, in the presence of an organic proton acceptor, compound of formula III in which R2 is as defined preferably benzene or dichloromethane, at 0 to 20 C. herein and R is hydrogen gives the corresponding for one to ten hours, gives the corresponding compound compound of formula I in which R1 is hydrogen, R2 is of formula I in which R1 and R2 are as defined herein as defined herein and R3 is 1-oxo-2,4,6-cycloheptatrien 20 and R3 is 1-oxo(lower)alkyl. When this acylation in 2-yl. volves acetylation, a preferred method of acetylation is The above described condensation of the compounds the reaction of the compound of formula I in which R3 of formula II and formula III is especially useful for is hydrogen with about 5 to 20 molar equivalents of preparing the compounds of formula I in which R1 is acetic anhydride at 10 to 30° C. for about 10 to 60 hydrogen, R2 is as defined herein and R3 is hydrogen, 25 minutes to obtain the corresponding compound of for phenyl, lower alkyl, lower alkoxycarbonyl, 1-oxo-2,4,6- mula I in which R1 and R2 are as defined herein and R3 cycloheptatrien-2-yl or phenyl mono-, di- or trisubstitu is acetyl. ted with lower alkyl, halo or trifluoromethyl. In another series of reactions, the compound of for The above described compounds of formula I in mula I in which R1 and R2 are as defined herein and R3 which R1 and R2 are as defined herein and R3 is hydro -30 is hydrogen is condensed with 1-chloro-2-propanone to gen are especially useful for conversion to other com obtain the corresponding intermediate having a 2-oxo pounds of formula I. In one such conversion, the latter propyl group at position 4 of the piperazine ring. Reac compound of formula I in which R3 is hydrogen is tion of this intermediate with about one molar equiva condensed in the presence of a proton acceptor with a lent of potassium cyanide and about two molar equiva halide of formula X-R3 wherein X is bromo, chloro or 35 lents of ammonium carbonate in a solution of aqueous iodo and R is lower alkyl, lower alkenyl, lower alky methanol at about 50 to 70° C. for about 10 to 30 hours nyl, cyclo(lower)alkyl, lower alkoxycarbonyl, 1-oxo(- gives the corresponding compound-of formula I in lower)alkyl, cyclo(lower)alkyl substituted with a lower which R1 and R2 are as defined herein and R3 is 5-meth alkyl; lower alkenyl substituted with phenyl; 2,3-dihy yl-2,4-imidazolidinedione-5-yl-methyl. dro-8-oxo-cycloheptablfuran-2-ylmethyl, 2,3- In another transformation, the compound of formula diacetyloxypropyl, or 2-(1,3-dihydro-1,3-dioxo-2H I in which R1 and R2 are as defined herein and R3 is isoindol-2-yl)ethyl to obtain the corresponding com 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl is re pound of formula I in which R and R2 are as defined acted with about one molar equivalent of hydrazine herein and R3 is as defined immediately above and 2 hydrate in ethanol or methanol at about 20 to 30' C. for (4,5-dihydro-2-oxazolyl)benzoyl. About one to ten, 45 preferably 1.0 to 1.5 molar equivalents of the proton about 10 to 40 hours to obtain the corresponding inter acceptor and about one to five, preferably 1.0 to 1.5, mediate having an 2-aminoethyl group. Acetylation of molar equivalents of the halide of formula X-R3 are this intermediate with acetic anhydride, in the same used. In this condensation, it should be noted that the manner as described above, affords the corresponding condensation of the compound of formula I in which 50 compound of formula I in which R1 and R2 are as de R is hydrogen with 2-(bromoethyl)-1,3-dihydro-2H fined herein and R3 is 2-(acetylamino)ethyl. isoindol-1,3-dione gives a separable mixture of the com The following examples illustrate further this inven pound of formula I in which R1 and R2 are defined tion. ... ' ', herein and R3 is 2-(4,5-dihydro-2-oxazolyl)benzoyl or EXAMPLE 1 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl. For 55 this condensation, suitable proton acceptors can be 2-[4-(3-Trifluoromethylphenyl)-1-piperazinyl)-2,4,6- selected from organic and inorganic proton acceptors, cycloheptatrien-1-one (I: R and R2=H and for example triethylamine, pyridine, N-ethylmorpho R3=3-trifluoromethylphenyl) line, sodium bicarbonate, sodium or potassium carbon A mixture of 1-(3-trifluoromethylphenyl)-piperazine ate, sodium or potassium lower alkoxide and the like. (2.3 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (2.0 Sodium or potassium carbonate is the preferred proton g) in methanol (50 ml) was refluxed for 24hr and evapo acceptor. Usually the condensation is conducted in an rated. The residue was chromatographed on silica gel inert organic solvent, for example, benzene, toluene, (100 g) using ethyl acetate. The eluates were evaporated dichloromethane, chloroform, lower alkanol, acetoni and crystallized from ethyl acetate-benzene to give the trile, dimethylformide, acetone and the like. Acetoni 65 title compound (4.08 g): mp 112-114 C.; ir (CHCl3) trile and/or methanol is the preferred solvent for the 1570 cm-l; uv max (MeOH)350 (e=10575) and 256 mm condensation. To achieve the condensation, the reac (e=31730); nmr (CDCl3)6 3.5 (m, 8H) and 7.0 (m, 9H); tion mixture is maintained at 20' to 85 C. for three and Anal. Calcd for C18H17F3N2O: C, 64.66% H, 4,469,694 11 12 5.12% N, 8.38% and Found: C, 64.84% H, 5.17% N, Br, R2 = H and R3 = Me): mp 196'-197 C. (crystallized 8.54%. from diethyl ether-methanol); ir(mull) 2600, 1570, 1155 In the same manner, but replacing 1-(3-trifluorome and 1030 cm; uv max(MeOH)352 (e=9225) and 270 thylphenyl)-piperazine with an equivalent amount of nm (e=13800); nmr(DMSO-d6)62.35 (s, 3H), 2.85 (s, 1-methylpiperazine, 1-(2-methylphenyl)piperazine, 1 5 3H), 3.35 (m, 8H), 7.00 (m, 3H) and 8.15 (m, 1H); and (4-chlorophenyl)-3-methylpiperazine, 1-piperazine car Anal. Calcd for C12H15BrN2O.CH3SO3H: C, 41.16% boxylic acid ethyl ester, 1-(1,1-dimethylethyl)pipera H, 5.05% N, 7.39% and Found: C, 41.32% H, 5.01% N, zine, 2 methylpiperazine or 1-phenylpiperazine and 7.35%; and 5-acetylamino-2-(4-methyl-1-piperazinyl)- when desired, preparing the acid addition salt of the 2,4,6-cycloheptatrien-1-one (I: R1 =5-acetylamino, compound of formula I by using the appropriate acid; 10 R2=H and R3 = Me): mp 122-123° C. (crystallized the following compounds of formula I were obtained from methanol); ir(CHCl3) 3420, 3280, 1680 and 1540 respectively: 2-(4-methylpiperazinyl)-2,4,6-cyclohepta cm-l; uv max(MeOH) 252 nm (e= i5230); trien-1-one(Z)-2-butenedioate (I: R and R2=H and nmr(CDCl3)82.15 (s, 3H), 2.30 (s, 3H), 2.55 (t, 4H), 3.30 R=Me): mp 118-120' C. (crystallized from acetone (t, 4H), 7.10 (m, 4-H) and 8.0 (s, 1H); and Anal. Calcd for diethyl ether); ir(CHCl3). 2400, 1705, 1620, 1350 and 5 1570 cm l; uv max(MeOH)343 (e=9440) and 250 mm C14H19N3O2: C, 64.34% H, 7.33% N, 16.08% and (e=14975); and nmr(CDCl3)62.9 (s, 3H), 3.5 (m, 8H), Found: C, 63.87% H, 7.28% N, 15.96%. 6.27 (s, 2H), 7.0 (m, 5H) and 14.5 (broad, 2H); 2-[4-(2- EXAMPLE 2 methylphenyl)-1-piperazinyl-2,4,6-cycloheptatrien 2,2'-(1,4-Piperazindiyl)-bis-2,4,6-cycloheptatrien-1-one 1-one (I: R and R2=H and R3=2-methylphenyl):mp 20 (I: R1 and R2 = H and 115-116 C. (crystallized from diethyl ether-hexane); R= 1-oxo-2,4,6-cycloheptatrien-2-yl) ir(CHCl3) 1565 cm-l; uv max(MeOH)353 (e=10000) and 253 nm (e=20095); nmr(CDCl3)62.33 (s, 3H), 3.05 To a solution of piperazine (7.74 g) in methanol (10 (m, 4H), 3.45 (m, 4H) and 6.9 (m, 9H); and Anal. Calcd ml) at 70 C., a solution of 2-methoxy-2,4,6-cyclohepta for C18H2ON2O: C, 77.20% H, 7.14% N, 10.0% and 25 trien-1-one (8.16 g) in methanol (50 ml) was added drop Found: C, 76.97% H, 7.21% N, 9.86%; 2-[4-(4-chloro by drop. The reaction mixture was heated at 95 C. for phenyl)-2-methyl-1-piperazinyl-2,4,6-cycloheptatrien 5 hr, cooled and evaporated. The residue was dissolved 1-one (I: R = H, R2=2-Me and R3=4-chlorophenyl): in chloroform and water. The organic extract was sepa mp 120-121 C. (crystallized from diethyl ether-hex rated, dried and evaporated. The residue was chromato ane); ir(CHCl3) 1565 cm l; uv max(MeOH)) 352 30 graphed on silica gel (250 g) using chloroform then 5% (e=7250) and 259 nm(e=22285); nmr(CDCl3) 61.13 (d, methanol in chloroform, increasing gradually the con 3H), 3.5 (m, 7H) and 6.9 (m, 9H); and Anal. Calcd for centration of methanol up to 20%. The product was C18H19ClN2: C, 68.60% H, 6.08% N, 8.89% and recrystallized from methanol to yield 2.9 g of the title Found: C, 68.61% H, 6.15% N, 8.86%;4-(2-oxo-3,5,7- compound:mp 184-186 C.; ircCHCl3) 1565 cm-l: uv cycloheptatrien-1-yl)-1-piperazine carboxylic acid ethyl 35 max(MeOH)355 (e= 19075), 256 (e=29080) and 223 mm ester (I: R and R2=H and R3-seethoxycarbonyl): mp (e=22460); nmr(CDCl3) 63.55 (m, 8H) and 7.0 (m, 95-98 C. (crystallized from diethyl ether); ircCHCl3) 10H); and Anal. Calcd for C18H8N2O2: C, 73.45% H, 1690 and 1570 cm-l; uv max(MeOH) 350 (e=9629), 6.16% N, 9.52% and Found: C, 73.76% H, 6.17% N, 254 (e=13089) and 225 nm (e=12171); nimrC Cl3) 81.3 9.45%. (t, 3H), 3.35 (m, 4H), 3.67 (m, 4H), 4.2 (q, 2H) and 6.9 (m, 5H); and Anal. Calcd for C14H18N2O3: C, 64.1% H, EXAMPLE 3 6.92% N, 10.68% and Found: C, 64.19% H, 7.03% N, 2-(1-Piperazinyl)-2,4,6-cycloheptatrien-1-one (I: R, R2 10.53%; B2-4-(1,1-dimethylethyl)-1-piperazinyl)-2,4,6- cycloheptatrien-1-one(Z)-2-butenedioate (I: R1 and and R3 = H) R2=H and R3 = 1,1-dimethylethyl): mp 160-162 C. 45 A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (crystallized from diethyl ether-methanol); ir(mull) (136 g) and piperazine (136 g) in methanol (250 ml) was 2400, 1700 and 1570 cm-l; uv max(MeOH) 343 refluxed for 4 hr and the reaction vessel was placed in (e=9180) and 250 nm (e= 14380); nmr(CDCl3)81.45 (s, an ice bath. Water (150 ml), then acetic acid was slowly 9H), 3.50 (m, 8H), 6.20 (s, 2H) and 6.90 (m, 5H); and added until the solution was acidic. The mixture was Anal. Calcd for C15H22N2O.C4H4O4: C, 62.97% H, 50 filtered and the filtrate was evaporated and chromato 7.23% N, 7.73% and Found: C, 62.56% H, 7.33% N, graphed on silica gel using chloroform-acetone (1:1) 7.41%; 2-(3-methyl-1-piperazinyl)-2,4,6-cycloheptatri and then with acetic acid-methanol(1:4). The eluates en-1-one (I: Ri and R3 = H and R2=3-Me); and 2-(4- from the latter solvent were evaporated to give an oil of phenyl-lpiperazinyl)-2,4,6-cycloheptatrien-1-one; (I: the acetate salt (153 g) of the title compound. R and R2=H and R3 =Ph): mp. 110-112 C. (crystal 55 Alternatively, the reaction solution was cooled to lized from ethyl acetate-hexane); ir(CHCl3) 1570 cm-l; induce crystallization of the dimer and filtered. The uv max(MeOH)350 (e= 10280), 254 (e=26020) and 230 filtrate was diluted with acetone to 1000 ml and a solu nm (e= 15445); nmr(CDCl3)63.45 (8H) and 7.05 (10H); tion of methane sulfonic acid (106 g) in acetone (250 m) and Anal. Calcd for C17H8N2O: C, 76.66% H, 6.81% was added to the filtrate in an ice bath. The precipitate N, 10.52% and Found: C, 76.54% H, 6.78% N, 10.45%. was collected and washed with acetone and diethyl Similarly, by condensing 1-methylpiperazine with ether to give 146 g of the methane sulfonate salt of the 7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one or 5 title compound: mp 174-176 C.; iromull) 2900, 1563 acetylamino-2-methoxy-2,4,6-cycloheptatrien-1 -one and 1180 cm-l; uv max(MeOH) 343 (e=8910), 252 and when desired, preparing the acid addition salt of the (e=13110) and 223 nm(e= 1 1250); nmr(DMSO-d6) compound of formula I by using the appropriate acid, 65 82.35 (s, 3H), 3.35 (m, 8H), 6.95 (m, 5H) and 8.8 (broad, the following compounds of formula I were obtained, 2H); and Anal. Calcd for CH4N2O.CH3SO3H: C, respectively: 7-bromo-2-(4-methyl-1-piperazinyl)-2,4,6- 50.32% H, 6.33% N, 9.80% and Found: C, 50.06% H, cycloheptatrien-1-one methane sulfonate salt (I: R1 = 7 6.39% N, 9.44%.

4,469,694 15 6 EXAMPLE 6 EXAMPLE 8 5-Methyl-5-4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1- 2-4-(2,3-Diacetyloxypropyl)-1-piperazinyl-2,4,6- piperazinyl)methyl)-2,4-imidazolidinedione (I: R and cycloheptatrien-1-one (I: R1 and R2 = H and R2=H and 5 R=2,3-diacetyloxypropyl) R3=5-methyl-2,4-imidazolidinedione-5-ylmethyl) A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatren A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien 1-one acetate (12.4 g, described in Example 3), epichlo 1-one (12.4 g, described in Example 3), 1-chloro-2- rohydrin (5.55 g), potassium carbonate (11.04 g) and propanone (5.55 g), potassium carbonate (11.04 g) and acetronitrile (120 ml) was refluxed for 48 hr and filtered. acetonitrile (120 ml) was refluxed for 4 hr and filtered. 10 The filtrate was evaporated and the residue (9 g) was Chloroform and water were added to the filtrate. The chromatographed twice on silica gel with methanol organic phase was separated, washed with water, dried ethyl acetate (1:9) to yield 2.92 of a mixture of 2-4-(2,3- and evaporated. The residue was chromatographed on dihydroxypropyl)-1-piperazinyl-2,4,6-cycloheptatrien silica gel using methanol-ethyl acetate and the eluates 1-one and 1,3-bis(4-(2-oxo-3,5,7-cycloheptatrien-1-yl)- were evaporated to give an oil (6.21 g) of 2-4-(2-oxo 15 piperazinyl)-2-propanol. propyl)-1-piperazinyl-2,4,6-cycloheptatrien-1-one: A solution of this mixture (2.8 g) in pyridine (20 ml) ir(CHCl3) 3660,3360, 1720, 1710, 1660 nd 1560 cm-l; and acetic anhydride (20 mi) was stirred at room tem uv max(MeOH)351 (e=9210), 255 (e=13915) and 221 perature for 24 hr and evaporated. The residue was nm(e=11750); nmr(CDCl3) 82.12 (s, 3H), 2.62 (t, 4H), dissolved in ethyl acetate, and the solution was washed 3.21 (s, 2H), 3.35 (s, 4H) and 6.40-7.10 (m, 5H); and with 1N sodium hydroxide, then with water, dried over Anal. Calcd for C14H18N2O2: C, 68.26% H, 7.37% N, magnesium sulfur and evaporated. The residue (1.9 g) 11.37% and Found: C, 67.83% H, 7.59% N, 11.44%. was chromatographed on 100 g silica gel first with ethyl To a solution of the latter compound (7.5 g) in metha acetate to give the title compound (0.66 g): ircCHCl3) nol (10 ml) heated to 55 C. was added a solution of 25 1730, 1612, 1560 and 1250 cm-l; uv max(MeOH) 357 ammonium carbonate (5.78 g) in 15 ml of water, foll (e=4520) and 255 nm(e= 6750); nmr(CDCl3)62.08 (s, lowed by the addition of potassium cyanide (1.98 g) in 6H), 2.55 (d, 2H), 2.65 (m, 4H), 3.25 (m, 4H), 4.09 and 4.5 ml of water. The reaction mixture was maintained at 4.36 (2d, 2H), 5.20 (m, 1H) and 6.68–6.99 (m, 5H); and 55 C. for 16 hr, cooled to room temperature and fil Anal. Calcd for C18H24N2O5: C, 62.05% H, 6.94% N, tered to yield 6.0 g of crude product. Recrystallization 30 8.04% and Found: C, 61.99% H, 7.10% N, 7.70%. The from methanol gave 5.4 g of the title compound: mp above silica gel column was then eluted with acetone. 231-232° C.; ir(mull) 3160, 1770, 1710 and 1535 cm-l; The eluates were evaporated to give a residue (1.2 g) uv max(MeOH)353 (e= 9600), 255 (e= 14520) and 218 which was crystallized from diethyl ether-ethyl acetate nm(e=12800); nmr(DMSO-d6) 61.20 (s, 3H), 2.60 (m, to give 0.35 g of 1,3-bis(4-(2-oxo-3,5,7-cycloheptatrien 6H), 3.20 (t, 4H), 6.90 (m, 5H), 7.75 (s, 1H) and 10.40 (s, 35 1-yl)-1-piperazinyl)-2-propanol acetate: mp 104-106 1H); and Anal Calcd for C16H2ON4O3: C, 60.74% H, C.; ir(CHCl3) 1724, 1612 and 1555 cm-l; uv max(- 6.37% N, 17.71% and Found: C, 60.84% H, 6.40% N, MeOH), 358 (e= 19380), 255 (e=291.00) and 220 17.59%. nm(e=23020); nmr(CDCl3)62.06 (s, 3H), 2.55 (d, 4H), 2.65 (t, 8H), 3.33 (t, 8H), 5.20 (m, 1H) and 6.50-7.30 (m, EXAMPLE 7 10H); and Anal. Calcd for C27H34N4O4: C, 67.76% H, N-(2-4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1- 7.16% N, 11.71% and Found: C, 67.45% H, 7.10% N, piperazinyl)ethyl)acetamide (I: R and R2=H and 11.44%. R3=2-(acetylamino)ethyl) We claim: To a solution of 1,3-dihydro-2-4-(2-oxo-3,5,7- 1. A compound of the formula cycloheptatrien-1-yl)ethyl-2H-isoindol-1,3-dione (8.7 45 g, described in Example 4) in ethanol, hydrazine hy O drate (1.305 g) was added and the solution was stirred at Rl 21 ( - room temperature for 24hr. It was then acidified with N N-R 1N hydrochloric acid, left at room temperature for 2 hr 50 and the precipitate was removed by filtration. The fil N /--/ trate was dissolved in water, made alkaline with diluted R2 sodium hydroxide and extracted with chloroform. The chloforom was evaporated and the residue (6 g) was in which R1 represents a substituent at positions 3, 4, 5, chromatographed on 100 g silica gel with acetic acid 55 6 or 7 of the 2,4,6-cycloheptatrien-1-one ring and is ethyl acetate (2:8) to yield 4 g of 2-4-(2-aminoethyl)-1- selected from hydrogen, halo, lower alkyl, lower alk piperazinyl-2,4,6-cycloheptatrien-1-one. A mixture of oxy, trifluoromethyl, or 1-oxo(lower)alkylamino; R2 is this compound (4.0 g) and acetic anhydride (40 ml) was hydrogen or lower alkyl having one to three carbon allowed to react at room temperature for 48 hr. The atoms; and R3 is hydrogen, phenyl, lower alkyl, lower acetic anhydride was evaporated at reduced pressure alkenyl, lower alkynyl, cyclo(lower)alkyl, lower alk and the residue was chromatographed on 200 g silica oxycarbonyl, 1-oxo(lower)alkyl, cyclo(lower)alkyl sub gel with methanol to yield 1.6 g of the title compound: stituted with a lower alkyl: lower alkenyl substituted mp 117-118° C.; ir?CHCl3) 3410, 3330, 1665 and 1560 with phenyl; phenyl mono-, di or trisubstituted with cm-l; uv max(MeOH) 356 (e=9780) and 255 lower alkyl, halo, lower alkoxy, hydroxy or trifluoro nm(e=14600); nmr(CDCl3)62.0 (s, 3H), 2.6 (m, 6H), 65 methyl: 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy 3.35 (m, 6H), 6.0 (broad, 1H) and 6.85 (m, 5H); and dro-8-oxo-cycloheptabl furan-2-ylmethyl, 1-oxo-2,4,6- Anal. Calcd for C15H2N3O2: C, 65.43% H, 7.69% N, cycloheptatrien-2-yl, 2-(acetylamino)ethyl, .3- 15.26% and Found: C, 65.09% H, 7.67% N, 5.11%. diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-ison 4,469,694 17 18 dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- 15. 2-4-(1,1-Dimethylethyl)-1-piperazinyl)-2,4,6- ylmethyl; or a therapeutically acceptable acid solution cycloheptatrien-1-one, a compound of claim 1 wherein salt thereof. R and R2 are hydrogen and R3 is 1,1-dimethylethyl. 2. A compound of claim 1 in which R1 is hydrogen; 16. 7-Bromo-2-(4-methyl-1-piperazinyl)-2,4,6- R2 is hydrogen or lower alkyl having one to three car cycloheptatrien-1-one, a compound of claim 1 wherein bon atoms; and R3 is hydrogen, phenyl, lower alkyl, R1 is 7-bromo, R2 is hydrogen and R3 is methyl. lower alkenyl, lower alkynyl, cyclo(lower)alkyl, alk 17. 5-Acetylamino-2-(4-methyl-1-piperazinyl)-2,4,6- oxycarbonyl, 1-oxo(lower)alkyl, cyclo(lower)alkyl sub cycloheptatrien-1-one, a compound of claim 1 wherein stituted with a lower alkyl; lower alkenyl substituted R is 5-acetylamino, R2 is hydrogen and R3 is methyl. with phenyl; phenyl mono-, di- or trisubstituted with 10 18. 2-[4-(1-Methylethyl)-1-piperazinyl)-2,4,6- lower alkyl, halo, lower alkoxy, hydroxy or trifluoro cycloheptatrien-1-one, a compound of claim 1 wherein methyl; 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy R1 and R2 are hydrogen and R3 is i-methylethyl. dro-8-oxo-cyclohepta furan-2-ylmethyl, 1-oxo-2,4,6- 19.2-(4-Ethyl-1-piperazinyl)-2,4,6-cycloheptatrien cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- 1-one, a compound of claim 1 wherein R and R2 are diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-iosin 15 hydrogen and R3 is ethyl. dol-2-yl)ethyl, or 5-methyl-2,4-imidazolidinedione-5- 20. 2-(4-Propyl-1-piperazinyl)-2,4,6-cycloheptatrien ylmethyl; or a therapeutically acceptable acid addition 1-one, a compound of claim 1 wherein R and R2 are salt thereof. hydrogen and R is propyl. 3. A compound of claim 1 in which R1 is hydrogen; 21. 2-4-(1-Methylpropyl)-1-piperazinyl-2,4,6- R2 is hydrogen or methyl; and R3 is hydrogen, phenyl, 20 cycloheptatrien-1-one, a compound of claim 1 wherein lower alkyl, lower alkenyl, lower alkynyl, cycloClower R1 and R2 are hydrogen and R3 is 1-methylpropyl. )alkyl, lower alkoxycarbonyl, 1-oxo(lower)alkyl, cy 22. 2-(2-Cyclopentyl-1-piperazinyl)-2,4,6-cyclohepta clo(lower)alkyl substituted with a lower alkyl; phenyl trien-1-one, a compound of claim 1 wherein R and R2 monosubstituted with lower alkyl, halo or trifluoro are hydrogen and R3 is cyclopentyl. methyl; 2-(4,5-dihydro-2-oxazolyl)benzoyl, 1-oxo-2,4,6- 25 23. 2-(4-Acetyl-1-piperazinyl)-2,4,6-cycloheptatrien cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- 4-one, a compound of claim 1 wherein R1 and R2 are diacetyloxypropyi, 2-(1,3-dihydro-1,3-dioxo-2H-isoin hydrogen and R3 is acetyl. dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- 24. 5-Methyl-5-4-(2-oxo-3,5,7-cycloheptatrien-1-yl)- ylmethyl; or a therapeutically acceptable acid addition l-piperazinyl)methyl-2,4-imidazolidinedione, a com salt thereof. 30 pound of claim 1 wherein R and R2 are hydrogen and 4. A compound of claim 1 in which R1 and R2 are R3 is 5-methyl-2,4-imidazolinedione-5-ylmethyl. hydrogen; and RIs hydrogen, lower alkyl, lower alke 25. N-2-[4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1- nyl or lower alkoxycarbonyl; or a therapeutically ac piperazinyl)ethyl)acetamide, a compound of claim 1 ceptable acid addition thereof. wherein R1 and R2 are hydrogen and R3 is 2 5. 2-(4-Methyl-1-piperazinyl)-2,4,6-cycloheptatrien 35 (acetylamino)ethyl. 1-one, a compound of claim 1 wherein R and R2 are 26. 2-4-(2,3-Diacetyloxypropyl)-1-piperazinyl)-2,4,6- hydrogen and R3 is methyl. cycloheptatrien-1-one, a compound of claim 1 wherein 6. 2-4-(2-Methylphenyl)-1-piperazinyl-2,4,6- R1 and R2 are hydrogen and R3 is 2,3-diacetyloxypro cycloheptatrien-1-one, a compound of claim 1 wherein pyl. R1 and R2 are hydrogen and R3 is 2-methylphenyl. 27. 2-(4-Phenyl-1-piperazinyl)-2,4,6-cycloheptatrien 7. 2-4-(4-Chlorophenyl)-2-methyl-1-piperazinyl 1-one, a compound of claim 1 wherein R and R2 are 2,4,6-cycloheptatrien-1-one, a compound of claim 1 hydrogen and R3 is phenyl. wherein R1 is hydrogen, R2 is 2-methy and R3 is 4 28. 2-(4-Cyclopropyl-1-piperazinyl)-2,4,6-cyclohep chlorophenyl. tatrien-1-one, a compound of claim 1 wherein R and 8. 4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine 45 R2 are hydrogen and R3 is cyclopropyl. carboxylic acid ethyl ester, a compound of claim 1 29. 2-4-(2-Methyl-2-propenyl)-1-piperazinyl-2,4,6- wherein R1 and R2 are hydrogen and R3 is ethoxycarbo cycloheptatrien-lone, a compound of claim 1 wherein nyl. R1 and R2 are hydrogen and R3 is 2-methyl-2-propenyl. 9, 2,2'-(1,4-Piperazinidyl)-bis-2,4,6-cycloheptatrien 30, 2-4-(3-Trifluoromethylphenyl)-1-piperazinyl 1-one, a compound of claim 1 wherein R1 and R2 are 50 2,4,6-cycloheptatrien-lone, a compound of claim 1 hydrogen and R3 is 1-oxo-2,4,6-cycloheptatrien-2-yl. wherein R1 and R2 are hydrogen and R3 is 3-tri 10. 2-(1-Piperazinyl)-2,4,6-cycloheptatrien-1-one, a fluoromethylphenyl. compound of claim 1 wherein R1,R2 and R3 are hydro 31. A pharmaceutical composition, for stimulating gen. dopamine receptors in a mammal in need thereof, which 11.2-4-(2-Propenyl)-1-piperazinyl-2,4,6-cyclohepta 55 comprises an effective dopamine receptor stimulating trien-1-one, a compound of claim 1 wherein R1 and R2 amount of a compound of the formula are hydrogen and R is 2-proponyl. 12. 1,3-Dihydro-2-4-(2-oxo-3,5,7-cycloheptatrien-1- O yl)ethyl-2H-isoindol-1,3-dione, a compound of claim 1 M wherein R1 and R2 are hydrogen and R3 is 2-(1,3-dihy Ri M V dro-1,3-dioxo-2H-isoindol-2-yl)ethyl. N N-R3 13. 2-4-2-(4,5-Dihydro-2-oxazolyl)benzoyl)-1- piperazinyl)-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R and R2 are hydrogen and R3 is R2 2-(4,5-dihydro-2-oxazolyl)benzoyl. 65 14. 2-4-(2-Propynyl)-1-piperazinyl)-2,4,6-cyclohep in which R1 represents a substituent at positions 3, 4, 5, tatrien-1-one, a compound of claim 1 wherein R and 6 or 7 of the 2,4,6-cycloheptatrien-1-one ring and is R2 are hydrogen and R3 is 2-propynyl. selected from hydrogen, halo, lower alkyl, lower alk 4,469,694 19 20 oxy, trifluoromethyl, or 1-oxo(lower)alkylamino; R2 is prising an effective dopamine receptor stimulating hydrogen or lower alkyl having one to three carbon amount of a compound of the formula atoms; and R3 is hydrogen, phenyl, lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, lower alk O oxycarbonyl, 1-oxo(lower)-alkyl, cyclo(lower)alkyl W substituted with a lower alkyl; lower alkenyl substituted R y with phenyl; phenyl mono-, di- or trisubstituted with N N-R3 lower alkyl, halo, lower alkoxy, hydroxy or trifluoro methyl; 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy dro-8-oxo-cycloheptablfuran-2-ylmethyl, oxo-2,4,6- 10 R2 cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoin in which R1 represents a substituent at positions 3, 4, 5, dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- 6 or 7 of the 2,4,6-cycloheptatrien-1-one ring and is ylmethyl; or a therapeutically acceptable acid addition selected from hydrogen, halo, lower alkyl, lower alk salt thereof, and a pharmaceutically acceptable carrier 15 oxy, trifluoromethyl, or 1-oxo(lower)alkylamino; R2 is therefor. hydrogen or lower alkyl having one to three carbon 32. A method of stimulating dopamine receptors in a atoms; and R is hydrogen, phenyl, lower alkyl, lower mammal in need thereof, which comprises administer alkenyl, lower alkynyl, cyclo(lower)alkyl, lower alk ing to said mammal an effective dopamine receptor oxycarbonyl, 1-oxo(lower)alkyl, cyclo(lower)alkyl sub stimulating amount of a composition of claim 31. 20 stituted with a lower alkyl; lower alkenyl substituted 33. A method of stimulating dopamine receptors in a with phenyl; phenyl mono-, di- or trisubstituted with mammal in need thereof, which comprises administer ing to said mammal an effective dopamine receptor lower alkyl, halo, lower alkoxy, hydroxy or trifluoro stimulating amount of a composition of claim 31, in methyl; 2-(4,5-dihydro-2-oxazolyl)benzoyl, 2,3-dihy combination with an effective amount of an agent se 25 dro-8-oxo-cycloheptablfuran-2-ylmethyl, 1-oxo-2,4,6- lected from bromocriptine, lergotrile, levodopa, combi cycloheptatrien-2-yl, 2-(acetylamino)ethyl, 2,3- nation of levodopa and carbidopa, L-prolyl-L-leucyl diacetyloxypropyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoin glycinamide and L-prolyl-N-methyl-D-leucylglycina dol-2-yl)ethyl or 5-methyl-2,4-imidazolidinedione-5- mide. ylmethyl; or a therapeutically acceptable acid addition 34. The method of claim 33 wherein the composition 30 salt thereof, and an agent selected from bromocriptine, of claim 31, and said agent are administered sequentially lergotrile, levodopa, combination of levodopa and car or simultaneously. - bidopa, L-prolyl-L-leucylglycinamide and L-prolyl-N- 35. A pharmaceutical composition for stimulating methyl-D-leucylglycinamide. dopamine receptors in a mammal in need thereof com k 35

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