PL179341B1 - Diaryl methyl piperazine and diaryl methyl piperidine compounds exhibiting properties equal to those of opioides as well as method obtaining and using them - Google Patents

Abstract

1. Diphenylmethylpiperazine compounds Formula 1 wherein A is a group phenyl having on one atom the ring carbon substituent Y, which represents a carboxamide, sulfonamide group or aminomethyl, Z is a group hyd ^ ri ^^ k ^ s ^ Jlo ^^ the G is nitrogen, R2 is hydrogen, R3 and R5 are R4 is a methyl group, R6 is -CH2-CH = CH2, R7 is a hydrogen atom.

Description

The present invention relates to diphenylmethylpiperazine compounds that are useful as receptor binders, in particular as agonist / antagonist paired conjugates for correcting and / or determining receptor and neurotransmitter function. Compounds of the invention include benzhydryl piperazines useful as compounds which bind to the μ (mu) and / or δ (delta) opioid receptors mediating anesthesia and as compounds useful in combating drug addiction, alcohol dependence, recovery from overdose, mental disorders, urinary incontinence, cough, pulmonary edema, diarrhea, depression, cognitive disorders, respiratory and digestive system disorders.

So far, many endogenous and non-endogenous opioid substances have been identified in opioid biochemistry studies. In these efforts, research to elucidate the mechanism of action of opioid compounds, especially with regard to opiate cell receptors and differentiated tissue receptors, was important.

Opioids are usually classified based on their binding selectivity for the opiate cell receptors and the different tissue receptors to which the drug binds as a ligand. Such receptors include mi (μ), delta (δ), sigma (σ), and kappa (k) receptors.

Known opioid drugs such as morphine and its analogs are selective for the mu opioid receptor. Mi receptors mediate anesthesia, respiratory depression and inhibition of gastrointestinal motility. Kappa receptors mediate anesthesia and sedation. Sigma receptors mediate many biological processes.

The existence of the opioid delta receptor is a relatively recent discovery after which endogenous enkephalin peptides ligands for this delta receptor have been isolated and characterized. Research over the last decade has resulted in a significant understanding of the delta receptor, but so far no clear picture of its function has emerged. Delta receptors mediate analgesia, however, it seems that they do not inhibit the motility of the gastrointestinal tract in the manner characteristic of mu receptors.

Opioids are often characterized as having agonist or antagonist activity. Both agonists and antagonists are substances that recognize and bind to a given receptor, influencing (by initiating or blocking) biochemical / physiological pathways. This process is called transduction. Agonists inhibit or suppress neurotransmitter release in receptor-containing tissues, e.g. by inhibiting the pain response or by influencing other processes related to pain response. Antagonists also bind to receptors but do not inhibit neurotransmitter release. Thus, antagonists bind to receptor sites and block binding to an agonist selective for the same receptor.

With regard to receptor specific ligands, a distinction is made between agonists and antagonists of delta receptors by determining their activity in an attempt to stimulate the vas deferens of mice with electrical current, which is generally considered to be

179 341 suitable diagnostic tissue for the delta receptor. In contrast, mi receptor agonists are characterized by their activity in an electrical stimulation test of a guinea pig ileum.

Few of the substantially pure delta-selective agents are known and, with the exception of the delta opioid antagonists disclosed by Portoghese in U.S. Patent No. 4,816,586, all known delta-selective opioids are peptides. , including endogenous enkephalins and other endorphins as well as exogenous peptide analogs. The previously synthesized exogenous peptide analogs suffer from various disadvantages associated with their peptide structure related to the stability, potential suitable routes for their drug delivery and tissue distribution in vivo.

So far, various physiological effects of known opioid peptide ligands have been studied, including analgesic effects, respiratory depression, effects on the digestive system, mental and emotional functions, cognitive processes, and effects mediating and modulating other physiological processes.

In U.S. Patent No. 4,816,586 P.S. Portoghese revealed various structurally specific compounds with delta opioid receptor antagonists. The disclosed compounds are obtained by coupling the indole, benzofuran, benzopyrazine or quinoline ring system to the carbon of the naltrexone ring. These compounds are described as having a unique opioid receptor antagonist profile, including those highly selective for the delta opioid receptor.

In U.S. Patent No. 4,518,711, J. Hruby et al. Describe cyclic analogs of forced conformation enkephalins. This group of compounds includes both delta agonists and antagonists; the authors report that among these compounds, compounds with agonist activity induce pharmacological and therapeutic effects such as anesthesia. The authors conclude that antagonists from the group of the disclosed compounds may have utility in the treatment of schizophrenia, Alzheimer's disease, and respiratory and cardiovascular disorders.

In addition to the above-mentioned literature references to opioid compounds, the polyarylpiperazines related to the compounds of the present invention are known and are described in the various publications listed below.

S. Goenechea et al. In the work: "Investigation of the Biotransformation of Meclozine in the Human Body" (J.Clin.Chem.Clin.Biochem., 1988, 26, 2, 105-15) described the oral administration of a polyarylpiperazine compound in studies metabolism of meclozine in humans.

Meuldermans W. et al. In the work: "Plasma Levełs, Biotransformation and Excretion of Oxatomide in Rats, Dogs and Man" (Xenobiotica, 1984, 15, 6, 445-62) disclosed studies of metabolism, including plasma levels, biotransformation and excretion of the drug oxatomide.

T. Iwamoto et al. In the work: "Effects of KB-27796, A New Calcium Antagonist, and Otłier Diphenylpiperazines on [ ³ H] nitrendipine Binding" (Jpn.J.Phaimacol., 1988, 48, 2, 241-7) described the effect of structured polyarylpiperazine as a calcium antagonist.

K. Natsuka et al. In the publication: "Synthesis and Structure-Activity Relationships of 1-Substituted 4- (1,2-diphenylethyl) piperazine Derivatives Having Narcoric Agonist and Anthagonist Activity" (J.Med.Chem., 1987, 30, 10, 1779-1787) disclose racemic mixtures and enantiomers of 1-substituted 4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine derivatives.

European Patent Application EP 458,160 describes substituted diphenylmethane derivatives as analgesic and anti-inflammatory agents, including compounds in which the bridged methylene group (connecting two phenyl residues) may have a piperidine or piperazine group as a substituent on the methylene carbon.

South African Patent Application No. 8,604,522 discloses N-substituted arylalkyl- and arylalkylene-substituted aminoheterocycles, including piperidine derivatives, described as useful cardiological, antihistamine, and anti-secretory agents.

In European Patent Application, EP 133,323, diphenylmethylpiperazine compounds useful as non-sedative antihistamines are disclosed.

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There is a continuing need for improved opioid compounds, especially compounds which are devoid of the addictive properties and other undesirable side effects exhibited by conventional opiates such as morphine and peptidine.

The present invention relates to compounds difenylometylopiperazyny of formula 1 wherein Ar is a phenyl group having one carbon atom of the ring Y, which represents a carboxamide, sulfonamide, or aminomethyl, Z is hydroxy, G is nitrogen, R ² is hydrogen, R ³ and R ⁵ is methyl R ⁴ is hydrogen, R ⁶ is -CH 2 -CH = CH 2, R ⁷ is hydrogen.

Preferably Y is a carboxamide, sulfonamide or aminomethyl group.

The invention also relates to diphenylmethylpiperazine compounds of formula I, in which Ar is a phenyl group having a Y substituent on one ring carbon atom, which is a carboxamide group of formula CONR ⁹ R ¹⁰ , located at the para or meta position on the attached phenyl ring, in which R ⁹ is a hydrogen atom or a C 1 -C 6 -alkyl group and R ¹⁰ is a C 1 -C 6 -alkyl, phenyl group, Z is a hydroxyl group, G is a nitrogen atom, R ² is a hydrogen atom, R ³ and R ⁵ are a methyl group, R ⁴ is hydrogen, R ⁶ is -CH-CH = CH 2, R ⁷ is hydrogen.

The invention also relates to compounds selected from the group consisting of:

(±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -4- (methylsulfonyl) benzyl} -phenol;

(±) N- {4 - [(aR *) - α- (2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) benzoyl} glycylglycine;

(±) -4 - {(aR *) - a - [(2R *, 5S *) - 2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide;

cis-4- {α- [4 - ((Z) -2-butenyl) -3,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide;

N, N-diethyl-4- {3-hydroxy-α- [cis-3,4,5-trimethyl-1-piperazinyl] benzyl} benzamide;

N, N-diethyl-4- {3-hydroxy- (aR) -ix [(2S, 5S) -2,4,5-trimethyl-1-piperazinyl] benzyl} benzamide;

N, N-diethyl-4- {3-hydroxy- (aR) -a [(2R, 5R) -2,4,5-trimethyl-1-piperazinyl] benzyl} benzamide;

(±) -3 - {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol;

(±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzamide;

(±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-alhlo-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -Netyl-N- (2- hydroxyethyl) benzamide;

(±) -5 - {(ccR *) ^ c - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -3-bromo-N, N-diethyl -2-thiophenecarboxamide;

(±) -3 - {(R *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] (2-thienyl) methyl} phenol;

(±) -3 - {(aS) -a - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol;

(±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (3-thienyl) methyl} phenol;

(±) -4 - {(aR *) - a [(2S ⁺ , 5R *) - 4- (cyanomethyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethyl- benzamide (±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (3-pyridylmethyl} phenol;

(±) -4 - {(aR *) - a [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzenesulfonamide;

(±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N-methyl-N-propylbenzamide;

(±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -Nethyl-N-methyl-benzamide ;

(±) -3 - {(aR *) - a [(2S *, 5R *) -4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -Nethylbenzamide;

(±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N-cyclopropyl-N-methylbenzamide;

179 341 (±) -3 - {(aR *) - 4- (1-pyrrolidinylcarbonyl) -a - [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -benzyl }phenol; and a pharmaceutically acceptable salt of the compound.

The invention also relates to compounds selected from the group consisting of:

3 - {(R) - [(2S, 5R) -4-allyl) -2,5-dimethyl-1-piperazinyl] - (2-thienyl) methyl} phenol;

3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethylbenzamide;

3 - {(aR) -a [(2S, 5R) -4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethylbenzamide or a pharmaceutically acceptable salt thereof.

As to enantiomeric forms, the compounds of the invention include the individual enantiomers of the compounds of formula I, present as single forms substantially free of the second enantiomer and in mixtures (mixtures of enantiomeric pairs and / or mixtures of multiple enantiomeric forms).

Compounds of the invention exhibit receptor / receptor binding selectivity. Depending on the structure and stereospecificity of the particular compound, they may be capable of binding to receptors belonging to the delta, mu, kappa, sigma group of receptors, and combinations of these receptors.

Many of the compounds of the invention exhibit delta agonist activity which is associated with anesthesia-mediating. Other compounds of the invention have delta antagonist activity as will be described in more detail hereinafter. Still other compounds of the invention exhibit activity at mu receptors, and in particular, in some cases, mixed activity at mu receptors and delta receptors.

Examples of compounds of the invention are synthesized compounds. To facilitate their identification, each compound is given a sequence number assigned to the given chemical name in the remainder of the description.

1. (±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4- (methylsulfonyl] benzyl] phenol

2. (±) -4 - {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} N, N-dimethylbenzenesulfonamide

3. (±) -4 - {(ctR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} N, N-diethylbenzenesulfonamide

4. N- {4 - [- {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) benzolyl} -glycylglycine

5. (±) - {4 - [- {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide

6. (±) - {4 - [- {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide

7. (±) - {4 - [- {(oR *) - a - [(2S *, 5R *) - 2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide

8. (±) -4 - {(aR *) - a - [(2R *, 5S *) - 2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide

9.cis-4- {a- [4 - ((Z) -2-butenyl) -3,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide

10. (±) -3 - {(aR *) - a - [(2R *, 5S *) - 4-alhlo-2,5-dimethyl-1-piperazinyl] A-bromobenzyl} -phenol

11. (±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-alkyl-2,5-dimethyl-1-piperazinyl] R-bromobenzyl} -phenol

12. N, N-diethyl-4- [3-hydroxy-α- (cis-3,4,5-trimethyl-1-piperazinyl) benzyl] benzamide

13. (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzoic acid

14. N, N-diethyl-4- (3-hydroxy- (aR) -a ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl} benzamide

15. N, N-diethyl-4- {3-hydroxy- (aR) -a [(2R, 5R) -2,4,5-trimethyl-1-piperazinyl] benzyl} benzamide

16. N- (4 - {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl} -3-hydroxybenzyl] benzoyl) -L-phenylalanyl- L · -leucine

17. (±) -3 - {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol

18. (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzonitrile

19. (±) -4 - {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzoic acid

20. (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzamide

21. (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} N-ethyl-N- (2-hydroxyethyl) benzamide

22. (±) -5 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} 3-bromo-N, N-diethyl-2-thiophenecarboxamide

23. (±) -3 - {(R *) - a [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thienyl) methyl} phenol

24. (±) -3 - {(aR *) - a. [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thiazolyl) methyl} phenol

25. (±) -3 - {(R *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piper2ynyl] (4-bromo-2-thienyl) methyl isphenol ( +) - 3 - {(aS) -a [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol

27. (±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} N, N-diethylbenzamide

28. (±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (3-thienyl) methyl} phenol

29. (±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thienyl) methyl} phenol

30. (±) -4 - {(aR *) - a [(2S *, 5R *) - 4- (cyanomethyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N- diethylbenzamide

31. (±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (3-pyridylmethyl} phenol

32. (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (3-hydroxybenzyl} N, N-diethylbenzamide

33. (+) - 3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-pyridylmethyl} phenol

34. (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) N, N-diethylbenzenesulfonamide

35. (±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) N-methyl-N- propylbenzamide

36. (±) -3 - {(R * or S *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thiazolyl) methyl) phenol

37. (±) -3 - {(aR *) - <x - [(2S *, 5R *> 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl-netyl N-methylbenzamide

38. (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl-N, N-dimethylbenzamide

39. (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -Netylbenzamide

40. (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenz} to) -N-cyclopropyl-N- methylbenzamide

41. (±) -3 - {(aR *) - 4- (1-pyrrolidinylcarbonyl) -a - [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -benzyl } phenol

The compounds of general formula I and exemplified exemplified compounds (1-41) have utility as exogenous combination compounds that bind to the receptor, i.e., compounds useful for binding to a receptor such as delta receptor, mu receptor, sigma receptor, kappa receptor or two or more of these receptors. Such a combination compound may be an agonist / antagonist conjugate used in studies of the transaction of neurotransmitter function in appropriate cellular systems or in a variety of tissue systems. In addition to attempts to determine receptors, differential binding, and special applications for monitoring and evaluation purposes at the cellular, tissue and systemic levels, the compounds of the invention exhibit particular biological activity in various ways, rendering them useful as therapeutic agents in a variety of physiological and pathological conditions.

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Compounds of the invention include various types of analgesia-mediating agonists and those useful in the treatment of diarrhea, depression, urinary incontinence, mental illness, cough, pulmonary edema, digestive disorders, spinal injury, and drug addiction.

The compounds of the invention also exhibit antagonist activity which may prove useful when used as agonist conjugates for neurotransmitter determinations and for the treatment of alcoholism and opiate drug overdose; these compounds also include other types of agonists.

In addition, in cases where degeneration or dysfunction of opioid receptors is present or suspected, in disease states where tissue or certain cell loci are involved, isotope-labeled versions of the opioid compounds of the invention find use in diagnosis and imaging, e.g. on positron emission tomography (PET) of the brain.

As mentioned above, opioid receptor sites are loci found on cells to recognize and bind opiates and opioid drugs, which in turn influence (initiate or block) sequences of biochemical / physiological reactions known as transduction.

With regard to the non-peptide opioids included in the invention, the structure, activity, and function of the various compounds falling within the general formula 1 are very divergent, and even slight differences, such as changes in stereochemical structure, may result in a different effect on transduction. Thus, formula 1 includes compounds of the agonist genus and compounds of the antagonist genus. Furthermore, empirical experiments with the compounds of the invention provide strong evidence for the existence of a delta receptor subtype in the brain that is distinct from the mouse vas delta receptor.

As a consequence of the existence of such delta receptor subtypes, other assay methods or techniques for screening, binding to the receptor, e.g., anesthesia screening assays instead of the mouse vas deferens assay, should be used as indicators of agonist or antagonist activity of certain specific compounds of the invention in some cases.

As for mi receptor agonists, their activity is in principle distinguishable and measured in an attempt to electrically stimulate guinea pig ileum.

Particularly preferred compounds from the above list of exemplary 41 compounds are: 1, 4, 8, 9, 12, 14, 15, 17, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 34, 36, 35, 37, 38, 39, 40 and 41 and pharmaceutically acceptable salts thereof.

Specific examples of the compounds broadly described above are the three compounds of the invention having the chemical structures shown in Formulas 2 (compound "A"), 3 (compound "B") and 4 (compound "C"). These compounds A, B and C are highly selective ligands of opioid receptors.

Compound A, 3 - {(R) - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thienyl) methyl} phenol, is a predominantly mi receptor agonist and can find application e.g. for surgical anesthesia.

Compound B, 5 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -3-bromo-N, N- diethyl-2-thiophenylcarboxamide is essentially a delta agonist and can be used in epidural analgesia.

Compound C, 3 - {(aR) -a - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} N, N-diethyl benzamide, is a mixed agonist of mi and delta receptors use in analgesia, in particular for surgical and / or post-operative anesthesia.

The above compounds are preferably prepared in substantially pure enantiomeric form with an enantiomeric purity of at least 90% enantiomeric excess (EE), preferably at least 95% EE, more preferably at least 98% EE and most preferably at least 99% EE. The enantiomeric excess values provide a quantitative measure of the excess of the percentage of the major isomer relative to the percentage of the minor isomer present therein. They can be readily determined by suitable methods known in the art, e.g., chiral high pressure liquid chromatography (HPLC), chiral gas chromatography (GC), nuclear magnetic resonance (NMR) using chiral shift reagents, and similar methods.

179 341

The mixed affinity properties of compound C for mu and delta receptors and other and related compounds within the scope of the invention are a potential significant advantage over various known mu receptor binding compounds currently used as analgesic drugs.

The vast majority of potent painkillers in use today such as morphine fentanyl, meperidine sufentanil, and codeine are compounds that bind to mu receptors. It is well known that these compounds, although highly effective in pain management, have associated side effects that include confusion, decreased mental acuity, muscle stiffness and respiratory depression, and rejection side effects such as nausea, vomiting, shock, seizures and sweating. myself. Such side effects are generally absent or at least less pronounced with agents which bind to anesthesia-mediating delta receptors. Thus, the use of compounds of the invention that bind to mixed mu and delta receptors can reduce or even eliminate the side effects normally associated with the use of compounds that bind to mu receptors.

Compound A prepared as pure enantiomer has a strong mu-receptor analgesic effect comparable to fentanyl, a leading opiate analgesic for surgical anesthesia. Comparative studies in the rats of Compound A and fentanyl, considering the effects on respiration and anesthesia, showed similar activity and duration of action profiles. Additionally, Compound A turned out to be much safer than fentanyl when used at higher (equivalent) doses.

Compound B is an agonist at the delta opioid receptor. Agents of this type induce analgesia at the level of the spinal cord. Core analgesics such as lidocaine and morphine pose the risk of side effects due to leakage from the core chamber onto the periphery. In contrast, compound B had no apparent side effects when peripherally administered to rats and mice. The absence of such side effects makes Compound B and related derivatives of the present invention more useful in spinal anesthesia.

Compound C as outlined above is an enantiomerically pure analgesic which is agonist at both mu and delta opioid receptors. In rodent experiments, compound C showed an analgesic potency comparable to morphine, the analgesic mi type, but induced much less pronounced muscle stiffness and respiratory depression. In addition, rodent studies have shown that compound C is devoid of the pro-convulsive activity that may be associated with structurally related pure delta agonists.

Compounds 1 to 41 above exemplified by the compounds of the invention include compounds exhibiting significant potency in the receptor binding assay (rat brain), compounds active predominantly at one or the other of the delta receptor subtypes, and compounds with affinity for mu and delta receptors.

The receptor binding and anesthesia tests show that the compounds of the invention mediate anesthesia differently, depending on a wide variety of stimuli and physiological disturbances. This in turn is evidence of the high degree of complexity of the neural conduction functions dependent on stimulus responses associated with various opioid receptors, including mu, delta and delta receptor subtypes.

As can be seen from the foregoing description, the compounds of the invention have broad utility in the treatment of a wide variety of physiological conditions and disorders. The compounds according to the invention therefore find use in the preparation of medicaments intended for the treatment or prophylaxis of such physiological conditions and disorders. In addition to the therapeutic uses mentioned, other uses of the compounds of the invention include the treatment of bronchial disorders such as asthma, emphysema and apnea.

Endogenous opioids such as enkephalins and endorphins and their neurological systems have been identified in connection with various disorders of the central nervous system, such as compulsive behavior, depression, psychosis, and the like. Agonists and antagonists containing the compounds of the invention are useful in controlling such conditions.

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Various types of agonists and antagonists of the compounds of the invention may also find application in the treatment of drug (opioid / narcotic) addiction and therefore may replace methadone or other conventional agents used in drug addiction treatment programs as conventional drugs used in drug addiction treatment have side effects. and other unfavorable features that constitute contraindications or limit their use.

With regard to the treatment of drug addiction with effective compounds falling within the broad scope of the invention, it should be noted that methadone is an opioid that binds to the mu-receptor with morphine-like activity, which means that methadone itself poses a risk of addiction. This drug is used in the "maintenance therapy" of opioid addicts in such a way that they keep functioning to meet their drug needs in a more safe, non-criminal way. In this aspect, the compounds of the invention may find use in replacing or supplementing current drug addiction treatment of naltrexone, methadone, clonidine and similar drugs.

Certain compounds within the scope of the invention are applicable to local anesthesia such as spinal anesthesia and some may be useful in suppressing appetite and similar applications.

The compounds of the invention include a wide variety of compounds that are agonists of the delta opioid subgroup in the water mouse semen assay as well as compounds that are antagonists of the delta subtype. Compounds of the invention also include compounds that are agonists or antagonists at the delta receptors in the brain which, based on empirical studies, appear to be a different subtype of delta receptors from the delta receptors in the vas deferens of mice. A significant amount of the compounds of the present invention having the general formula I exhibit either agonist or antagonist activity at both of these receptor subtypes. Many of these compounds exhibit high activity at the mu opioid receptor, either by binding only to the mu receptors or by exhibiting mixed binding activity to both mu and delta receptors. Still other compounds of the invention show significant affinity for sigma receptors.

In in vitro assays for agonist / antagonist activity, such as receptor binding affinity assays and assays for the inhibition of electrically stimulated muscle contractions, the compounds of the invention exhibit potency ranging from nanomolar to micromolar concentrations, depending on the particular compound to be assayed.

Particularly preferred diphenylmethylpiperazines according to the invention are the compounds A-C described above and the compounds H-K of the formulas 5, 6, 7 and 8, respectively.

Compound H (Formula 5) exhibits delta receptor agonist activity, indicating that this compound should participate in analgesia with the same efficacy as delta-opioid peptide compounds.

Compounds I and K (formulas 6 and 8), in addition to acting on delta opioid receptors, possess marked mu opioid (morphine binding) agonist activity. These compounds, in addition to their multi-receptor profile, are potent analgesics and may exhibit morphine-like activity in reduced respiratory depression.

Compound J (Formula 7) has potent delta agonist activity.

The compounds of the invention exhibit therapeutic effects, including but not limited to analgesic activity, and are useful in the treatment of animals, especially mammals, including humans, in conditions where pain analgesia is required.

A method of obtaining an analgesic response in an animal in need of such treatment is to administer a compound of Formula 1 to the animal at an analgesic dose.

Moreover, various compounds according to the invention having appropriate therapeutic utility can be successfully used in the treatment of conditions such as drug and alcohol addiction / overdose, mental, emotional and cognitive disorders, cough, pulmonary edema and digestive system disorders. Accordingly, the use of the compounds according to the invention allows the treatment of animals in and in need of the conditions mentioned above; this method is to administer

To an animal, an effective amount of a compound of the invention exhibiting a therapeutic effect in the disease state in question.

Both humans and other animals (e.g. birds, dogs, cats, cattle, horses) are treated with the compounds of the invention, but preferably the treatment is for mammals and most preferably humans.

Depending on the particular condition to be treated, the animals are administered compounds of formula I in an appropriate, therapeutically effective and safe dose, which can be readily determined by known methods not requiring excessive experimental testing.

In general, for therapeutic benefit, including treatment of the conditions described above, the compounds of formula 1 are administered in doses ranging from 1 µg to 100 mg / kg body weight of the recipient / day, preferably in the range of 10 µg. to 50 mg / kg body weight / day and most preferably in the range from 10 µg to 50 mg / kg body weight / day. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage form, containing, for example, from 10 µg to 1000 mg, preferably from 50 µg to 500 mg and most preferably from 50 µg to 250 mg of active ingredient in a given unit form. Alternatively, if the condition of the recipient requires it, these doses can be administered in the form of continuous infusions.

The mode of administration and dosage forms will, of course, affect the therapeutic amounts of the compounds required and effective in a given therapeutic application.

For example, for the same active ingredient, orally administered doses are usually at least 2 to 10 times the parenteral doses. When administered orally to induce pain analgesia, the dose levels for the mu receptor binding compounds of the invention range from 5 to 200 mg / 70 kg body weight / day. The dose rates of intrathecal drugs are generally about 10% of the parenteral dose level level. In tablet dosage forms, a typical dosage amount of an anesthetic inducing active agent is in the range of 10 to 100 mg / tablet.

The compounds of formula I are administered as such and in the form of pharmaceutically acceptable salts thereof.

Examples of pharmaceutically acceptable salts of compounds of formula I include those derived from suitable bases such as alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium), ammonium and NX4 ⁺ salts where X is C1- C4-alkyl. Pharmaceutically acceptable salts of the amino group include those with: organic carboxylic acids such as acetic, lactic, tartaric, malic, lactobionic, and succinic acids; with organic sulfonic acids such as methanesulfonic, ethanesulfonic, isothionic, benzenesulfonic and p-toulenesulfonic acids, and with inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acid. Pharmaceutically acceptable salts of compounds having a hydroxyl group consist of the anion of the compound in combination with a suitable cation such as Na ⁺ , NH / or ΝΧ / (where X is for example a C1-C4 alkyl group).

For therapeutic purposes, the salts of the compounds of Formula 1 will be pharmaceutically acceptable, that is, they will be those derived from a pharmaceutically acceptable acid or base. However, non-pharmaceutically acceptable acid or base salts may also find use, e.g., in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention.

Pharmaceutical compositions containing one or more compounds according to the invention as an active ingredient are also used in veterinary and human medicine, and also compounds according to the invention, such as compounds of formula 1 as described above, are used in the manufacture of medicaments for the treatment or prevention of a medical condition. and the disorders described above.

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In such pharmaceutical and medicinal compositions, the active ingredient is preferably used together with one or more pharmaceutically acceptable carriers, and optionally with other therapeutic ingredients. These carriers must be pharmaceutically acceptable in the sense that they must not be incompatible with the other ingredients and not be harmful to the recipient. The active ingredient is incorporated in the amount necessary to produce the desired pharmacological effect as described above and in the amount required to achieve the desired daily dose.

The dosage forms include those adapted for parenteral and non-parenteral use; specific routes of administration include: oral, rectal, topical, intranasal, ocular, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intraarticular, intraarterial, subarachnoid, bronchial, lymphatic, and vaginal. Dosage forms adapted for parenteral administration are preferred.

When the active ingredient is used in formulations containing a liquid solution, these forms are preferably used parenterally. When the active ingredient is used in forms containing liquid suspensions or in powder form, in biocompatible carriers, these forms are preferably used orally, rectally or intrabronchially.

Oral administration is a convenient route of administration when the active ingredient is used directly in powder form. Alternatively, it can be administered intra-bronchially by nebulizing the powder in a carrier gas with which it forms a gaseous dispersion that the patient inhales with a stream supplied from a suitable nebulizer.

For some applications, it may be advantageous to administer the active ingredient in a "targeted" form, obtained by encapsulating the ingredient in liposomes or other environment which provides an encapsulated environment for it, or by binding the active ingredient e.g. a biological molecule such as a protein, lipoprotein, glycoprotein, or polysaccharide.

Usage forms containing the compounds of the invention as active agent are conveniently prepared in unit dosage form by methods known in the pharmaceutical technology. In general, these methods include the step of bringing into association the active compound with the carrier which constitutes one or more excipients. In general, these forms are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired dosage form.

Pharmaceutical forms of the compounds of the invention adapted for oral administration are presented in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient in the form of a powder or granules; suspensions in an aqueous or non-aqueous medium, such as a syrup, elixir, emulsion or decoction, can also be prepared.

Tablets are made by compression or molding, optionally with the addition of one or more auxiliary agents. Compressed tablets are prepared by compression in a suitable machine, the active ingredient being administered in a pourable form such as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or antistatic agent. Molded tablets containing the mixture of the powdered active ingredient with a suitable carrier are prepared by molding in a suitable machine.

A syrup is made by adding the active compound to a concentrated aqueous sugar solution, e.g. sucrose, to which solution is further added additional ingredients such as flavorings, suitable preservatives, sugar retarders, and agents that promote the solubility of other ingredients such as alcohols. polyhydroxy, e.g. glycerol or sorbitol.

Forms for parenteral administration conveniently are sterile, aqueous preparations of the active ingredient. They are preferably isotonic with the blood of the recipient (e.g., saline solutions). These forms may include suspensions

And thickeners, and liposomes or other microparticle systems designed to deliver the compound to blood components or one or more organs. These forms are presented in unit dose form or in multiple dose form.

Nasal sprays contain purified aqueous solutions of the active ingredient with preservatives and isotonic agents. These forms are adjusted to a pH value and isotonic in accordance with the nasal mucosa.

Forms for rectal administration are prepared as suppositories with a suitable carrier such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

Ophthalmic forms are prepared similarly to nasal sprays, except that the pH and isotonic values are adjusted so as not to irritate the eye.

Topical forms are prepared by dissolving or suspending the active ingredient in one or more media, such as mineral oil, kerosene, polyhydric alcohols, or other bases applied to topical pharmaceutical forms.

The transdermal forms are prepared by incorporating the active agent into a thixotropic or jelly-like carrier, such as a cellulose carrier, e.g.

In addition to the adjuvants mentioned, the formulations may also contain one or more additional excipients selected from diluents, buffers, fragrances, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.

A compound of formula I as defined above, wherein G is nitrogen, or pharmaceutically acceptable salts, is prepared by a process consisting of the following steps:

(A) alkylating the piperazine of Formula 10 with an alkylating agent of formula 9 wherein Ar, R ² R ^7, Y and Z have the meanings given in the definition of formula 1, and also, if appropriate, Z can be protected by a suitable protective group, like a tert-butyldimethylsilyl group and X ¹ is a suitable cleavable group such as chloride, bromide, toluenesulfonate ([CH ₃ (C ₆ H4) SO3-], methylsulfonate (CH ₃ SO ₃ -) or other known group of this type, or (B) transformation of a compound of formula 11, wherein the importance of a substituent Y defined in the formula 1 is restricted to reactive halogen (eg. bromine or iodine) and Ar, R ² -R ^6, Z have the meanings given in the definition of formula 1, and furthermore where indicated, Z may be protected with a suitable protecting group such as a tert-butyldimethylsilyl group for a compound of formula 1 where G is nitrogen, R ⁷ is hydrogen and Y may be all groups given in the definition of formula 1 according to transformation by a substitution reaction for metals from the preparation ia metalloaryl intermediates, which allows the introduction of new Y substituents in place of the previous Y substituent (reactive halogen or hydrogen).

A compound of formula 1 where G is nitrogen can be prepared by reacting an alkylating agent of formula 9 with a piperazine of formula 10 in a solvent such as toluene or acetonitrile. The R ⁶ group on the piperazine in a compound of Formula 10 may initially be hydrogen, and upon reaction to give a compound of Formula 1 where G is nitrogen and R ⁶ is hydrogen, the compound of Formula 1 may be alkylated with a suitable R ⁶ -X alkylating agent. where R ⁶ is the group -CH 2 -CH = CH 2. These alkylating agents are commercially available or can be prepared by methods described in the literature. As an alternative to alkylation with an R ⁶ -X ² alkylating agent, reductive amination can be used by treating a compound of Formula 1 where G is nitrogen and R ⁶ is hydrogen with a suitable commercially available aldehyde in the presence of a reducing agent such as cyanoborohydride in solvents such as alcohols or ethers, introducing the desired group R ⁶ .

A compound of Formula I where G is nitrogen can also be prepared from a compound of Formula 11 by treating it with a cyanating agent such as cuprous cyanide in a suitable solvent such as dimethylformamide or N-methylpyrrolidone.

The corresponding compound of Formula I, wherein Y is nitrile, is obtained. This compound can then be hydrolyzed in an alkaline medium or in an aqueous inorganic acid solution to a compound of formula I, where Y is a carboxylic acid residue. This carboxylic acid can then be converted to a compound of formula 1 where Y is a carboxamide (CONR ⁹ R ¹⁰ or CONR AB) as defined in formula 1 by various methods known in the art such as acid chloride formation, (e.g. with thionyl chloride) or by formation of mixed anhydride (e.g., by treatment with isobutyl chloroformate) or by formation of an activated ester by reaction with conventional peptide coupling reagents (e.g., dicyclohexylcarbodiimide or benzotriazol-1-yloxy-tris hexafluorophosphate (dimethylamino) can convert any of these activated phosphonium intermediates; into the desired carboxamide by reaction with an appropriate amine (NHR ⁹ R ¹⁰ or NHR ⁹ ANR ⁹ H) in a suitable solvent such as dichloromethane or dimethylformamide Similarly, reacting these activated intermediates with a peptide gives compounds of formula 1 where Y is the peptide carboxamide conjugate .

Alternatively, a compound of formula 1 where Y is a carboxylic (or sulfinic) acid group can be prepared directly from a compound of formula 11 by a low temperature (e.g. -60 ° C to -78 ° C) exchange of a reactive halogen to metal by a reaction of with an organometallic reagent such as n-butyl lithium or an activated form of a metal such as lithium or magnesium.

The organometallic intermediate produced from a compound of formula 11 can be treated with the appropriate carbamoyl chloride (C1CONR ⁹ R ¹⁰ ) to produce a compound of formula 1 where Y is CONR ⁹ R ¹⁰ . A compound of formula 11 can also be treated with a transition metal catalyst such as tetrakis (triphenylphosphine) palladium in the presence of an excess of amine and carbon monoxide in a solvent such as tetrahydrofuran or acetonitrile to provide a compound of formula 1 where Y is CONR ^ ¹ .

Optionally, the organometallic compounds prepared above can be treated with commercial alkylating agents such as iodomethane or dimethylpharmamide to provide a compound of Formula I where Y is alkyl or acyl, respectively. A compound of formula 1 where Y is a carboxylic acid residue can optionally be converted to a compound of formula 1 where Y is an alkoxyaminocarbonyl residue using a known Curtius rearrangement reaction, e.g. by producing an acyl azide by adding sodium azide to the acid chloride or other active form of the carboxylic acid as noted above, and heating the resulting acyl azide to the appropriate alcohol.

A compound of formula I can be obtained as a pure single enantiomer by classical resolution with an enantiomerically pure acid such as mandelic acid or by preparation of easily separable diasteromers by treatment with an enantiomerically pure derivatizing agent or by chiral chromatography or by enzymatic separation of a compound of formula I or a corresponding derivative thereof or by preparing a compound of formula I from enantiomerically pure precursors which can themselves be obtained in the form of pure enantiomers in a similar manner.

Compounds of formula 9 are prepared from the corresponding alcohols of formula 12 where the Z substituent is protected with an appropriate protecting group by methods such as halogenation with thionyl chloride or the reagent: triphenylphosphine / carbon tetrabromide, or by reaction with methanesulfonyl chloride or with toluenesulfonyl chloride in a solvent such as dichloromethane.

The piperazines of formula 10 are commercially available or can be obtained by methods published in the literature or by modification of these methods when R ⁶ is changed by appropriate alkylation with R ⁶ -X ^r .

Compounds of formula 11 are prepared by alkylating a piperazine of formula 10 with an alkylating agent of formula 13 in a manner similar to the above-described alkylation of piperazine. Alkylating agents of formula 13 are obtained from alcohols of formula 14 by methods similar to those described above for compounds of formula 9.

Alcohols of formulas 12 or 14 can be prepared by a low temperature (-60 ° C to -78 ° C) addition reaction of a substituted metalloaryl compound prepared from

Compounds of Formula 15 wherein X ² is a reactive halogen (e.g. iodine or bromine) by the methods described above to the Z-protected benzaldehydes of Formula 16 including compounds where R ⁷ is hydrogen to give compounds of Formula 14.

Compounds of formulas 12 or 14 can also be prepared by a similar addition reaction of a Z-protected metallophenyl compound derived from compounds of formula 18 including compounds wherein R ⁷ is hydrogen (in this case the compounds of formula 14 are obtained) to arylaldehydes of formula 17.

Compounds of formulas 15 to 17 and their correspondingly protected derivatives are either commercially available or can be prepared by literature methods.

The compound of formula I is converted in a pharmaceutically acceptable manner in the usual manner, e.g. by treatment with an appropriate acid. A salt of a compound of formula I can be converted to the parent compound, for example, by a hydrolysis reaction.

From the foregoing description and the general principles of synthesis, it can be seen that various synthetic routes can be used to prepare the diphenylmethylpiperazine compounds of the invention, which will be readily apparent to those skilled in the art.

Illustrative synthetic methods for the preparation of the compounds of the invention are given below by way of example only. It is understood that these compounds can be made by a variety of other synthetic routes and methods.

When the synthetic procedures used to prepare the compounds of the invention as reaction products yield racemic mixtures, such racemic mixtures can be separated by any suitable known methods, e.g. conventional way.

Scheme 1 shows an exemplary synthesis of (±) -4 - {(aR *) - a [(2S *, 5R *) -4allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N , N-diethylbenzamide, hereinafter referred to as compound L and its separation into individual enantiomers as described in more detail in Example VI. This synthesis scheme and separation methodology may be used to synthesize and resolve other compounds of the invention, or alternatively, those skilled in the art may use other synthetic and / or separation methodologies.

Regarding Scheme 1, the starting benzhydryl alcohol can be prepared from 3- (t-butyldimethylsilyloxy) bromobenzene by the reaction shown in Scheme 2. The intermediate can also be obtained via the corresponding benzophenone which in turn is prepared by addition of an organometallic compound to 4-bromobenzonitrile according to Scheme 3.

Alternatively, similar intermediates can be obtained by Friedel-Crafts reaction, by acylating bromobenzene with the appropriate Lewis acid catalyst and using the appropriate acid-stable protecting group R for phenol, as shown in Scheme 4. (The Friedel-Crafts reaction can also produce ortho -substituted isomeric benzhydryl alcohol).

Other alternative routes to prepare intermediates are the condensation of an appropriately substituted piperazine with a carbonyl compound. Condensation with benzaldehyde should yield an ammonium salt that binds the aryl lithium to form benzhydrylpiperazine compounds, where X is CONEt2 and Y is CH2CH = CH2 or X is Br and Y is CJ ^ CE ^ CFk as mixtures with their diastereomers or protected precursors of these compounds (Scheme 5) .

Likewise, reductive amination of the corresponding benzophenone with the appropriate piperazine can lead to the desired compound directly (Scheme 6).

Compound L can also be synthesized by alternative synthetic routes illustrated in schemes 7 and 8.

The N-allyl-trans-2,5-dimethylpiperazine reagent used in synthesis scheme 8 is conveniently prepared as shown in scheme 9.

The chiral synthesis method used to prepare the benzhydryl piperazines is shown in Scheme 10. When enantiomerically pure N-allyl-trans-2,5-dimethylpiperazine is treated with racemic benzhydryl chloride, a mixture of two enantiomerically pure diastereoisomers is formed which can be separated by conventional methods such as chromatography. or fractionated crystallization.

This N-allyl-trans-2,5-dimethylpiperazine can, for example, be obtained as a pure enantiomer by the method illustrated in scheme 11.

Compound L is also synthesized by synthesis via nitrile. As the nitrating agent, cuprous cyanide is used. This synthesis is illustrated in Scheme 12 where the BOP reagent is a compound of formula 19.

Alternative methods for preparing L from the appropriate halo compound are given in Scheme 13.

The methods described above are illustrated in the examples of synthetic techniques that have been successfully used to prepare compounds such as compound L as well as other diphenylmethylpiperazines according to the invention by suitable or analogous reagents. Of the synthetic methods for the preparation of compound L outlined above, the nitrile route is preferable for practical reasons as it is somewhat more convenient than the other methods described.

Selected compounds of the invention identified below by the numbers of examples in which their synthesis is described were determined in in vitro pharmacological tests for activity at opioid receptors. Various receptor systems were used including brain tissue (delta IC50 receptor and Mi receptor IC50), mouse vas deferens (ED50) and guinea pig ileum (ED50). The test procedures are given below.

In vitro tests: The vas deferens were dissected from mice and suspended between platinum electrodes with a tension of 0.5 g, in chambers-baths containing modified Krebs buffer with the following composition (in millimoles): NaCl, 118; KC1 4.75; CaCh 2.6; KH2PO4 1.2; NaHCO ₃ 24.5; glucose 11. This buffer was saturated with a gas composed of 95% oxygen and 5% carbon dioxide and kept at 37 ° C. The tissues were stimulated with an electric current of over the maximum voltage, series of pulses at a frequency of 10 Hz for 400 milliseconds, with the time between pulses being 10 seconds and the duration of the pulses - 0.5 milliseconds.

The entire ileum (approximately 3 cm long) was dissected from a guinea pig and suspended under an Ig tension in a bath such as in the mouse vas experiments. The modified Krebs buffer also contained MgSO4 (1.20 mM). The steering wheel was stimulated by pulses of electric current with a square wave with a frequency of 0.1 Hz. Pulse time was 0.5 milliseconds at over the maximum voltage. The percent inhibition of electrically induced muscle contractions was determined for the individual compounds and the different cumulative concentrations. ED50 values were extrapolated from curves showing the concentration of test compound versus response (J.A.H. Lord, A.A. Waterfield, J. Hughes, H.W. Kosterlitz: Nature 267, 495, 1977). Receptor Binding Inhibition Assay: After the brain membranes of Sprague-Dawley rats were dissected, binding assays were performed at 24 ° C for 60 minutes as described by Chang et al. (J. Biol. Chem. 254, 2610, 1979) and Mol. Pharmacol. 16, 91, 1979) using the filtration method known as "GF / C filier".

Binding assays with the delta receptor were carried out against the highly selective mi receptor agonist, [N-MePhe ³ , D-Pro ⁴ ] morficeptin to attenuate the mu receptor cross-reactivity using ¹²⁵ J labeled [D-Ala ² , D-Leu ⁵ ] -enkephalin at a concentration of 0.24 nM.

The mu receptor binding ^{assays were performed using 125} J labeled [D-Ala ² , NMePhe ⁴ , Met (O) ^W5 ] -enkephalin at a concentration of 0.1 nM. Non-specific bindings were determined against the ΙμΜ of the corresponding unlabeled ligand.

The potency of the test compounds in inhibiting the binding of ^{125 I-} labeled enkephalin analogues was expressed as the concentration reducing the binding of these labeled compounds by 50% (IC50). The test results are given in the table.

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Representative examples of in vitro activity of compounds of the invention at opioid receptors ^a

Example Delta receptor; IC50 (nM) Mouse ED _{J0 vas deferens} (nM) IC ₅₀ receptor (nM) Guinea pig's vertebrate ED ₅₀ (nM) VI 1-8 (7) 0.20 (8) 15 (6) 143 (12) νιπ 16 40 (8) 1.1 4.0 (12) IX 1.5 > 10000 (4) 600 3600 (4) X 1.2 2.0 (4) 150 > 10000 (4) XI 2.8 (pA ₂ = 7.0) ^b 2400 > 10000 (4) XIII 0.7 4400 (4) 120 2700 (4) XVI 0.4 2-0 (4) 70 300 (4) XVII 4.0 > 10000 (4) > 10,000 3700 (4) XIX 11 37 (4) 0.8 8.0 (4) XXI 1.3 42 (4) 40 5600 (4) Xxv 6.5 0 30 (12) twenty 86 (4) XXX 27 20 (8) 0.3 2.1 (8) XXXVI 1.6 8.6 (8) 3.0 10 (8)

^{and the} reported values are the average of the number (n) of experiments, or if the number (n) is not given in brackets then they represent one determination.

^b potency as antagonist (pA ₂ value) as determined by the method of Schild (Arunlakshana O., Schild HO; Brit. J. Pharmacol, 1959, 14, 48-58): data for blockade of the inhibitory effect [D-Ala ² , D- Leu ⁵ ) -enkephalin in an electrically stimulated contraction of the muscles of the vas deferens in mice.

Preferred compounds of the invention (made by one of the convenient synthetic routes, e.g. by nitrile formation) are compounds selected from the group numbered 1, 4, 8, 9, 12, 14, 15, 17, 20, 21, 22, 23 , 26, 27, 28, 29, 30, 31, 32, 34, 36, 35, 37, 38, 39, 40 and 41, and pharmaceutically acceptable salts. The compounds of the invention find use in the treatment of conditions and disorders such as physiological pain, diarrhea, urinary incontinence, mental disorders, conditions of overdose and drug and alcohol addiction, pulmonary edema, cough, depression, asthma, emphysema and apnea, cognitive disorders and system disorders. digestive. For example, the compounds of the invention are administered in a pharmaceutically safe and effective dose and in a suitable dosage form to an animal, including a human, to inhibit pain in that individual.

A very preferred compound of the invention is compound C, i.e., 3 - {(aR) α - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N -diethylbenzamide.

The compounds of the invention highly selectively bind to opioid receptors, showing utility as receptor binding agents, i.e., as agonist / antagonist paired conjugates, for the verification and determination of receptor and neurotransmitter function.

Highly preferred compound of the invention, 3 - {(aR) -a - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzamide is a mixed agonist of opioid receptors mu and delta, showing significant advantages over various known compounds having affinity for the mu receptor and currently used as analgesics.

The essential features and advantages of the invention are more fully apparent from the following non-limiting examples.

Some general principles and methods common to many chemical synthesis examples are given below:

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Melting points were determined with a Thomas-Hoover apparatus and are not corrected. Except for some chemical reagents where the manufacturer's name is indicated, all other reagents were supplied by Aldrich Chemical Company, Milwaukee, Wisconsin. Commercial solvents were used without further purification, except for tetrahydrofuran which was distilled from potassium. Nuclear magnetic resonance (NMR) analyzes were performed on Perkin-Elmer R-24 and Varian XL-200 or XL-300 instruments. HPLC analyzes were carried out in a "Waters" liquid chromatography system equipped with a "700 Satellite WISP 600E System Controller" control system and a "991 Photodiode Array" photodiode detector with a 4.6 x 250 mm "Cyclobond" column (supplied by Advenced Separations Technologies, Whippany, NJ), at a flow rate of 1 ml / min. Optical rotations were determined on a Perkin-Elmer 241 polarimeter. Mass spectral determinations were performed by Oneida Research Services, Whitesboro, New York. Crystallographic determinations by X-ray spectroscopy were performed at the Molecular Structure Corporation, College Station, Texas. Thin layer chromatography analyzes were performed on Analtech glass plates precoated with GF silica gel (250 µ). Preparative thin layer chromatography was performed on Analtech Uniplates coated with GF silica gel (1000 µ and 2000 µ). Elemental analyzes were performed at Atlantic Microlab, Norcross, Georgia.

Example I. (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol

A solution of 3-bromophenol (500 g, 2.89 mol), tert-butylchlorodimethylsilane (436 g, 2.89 mol) and imidazole (500 g, 7.22 mol) in 500 ml of dimethylformamide was stirred overnight at room temperature. The reaction solution was poured into 3000 ml of water and extracted with two 2000 ml portions of diethyl ether. The combined ether extracts were dried over sodium sulfate and the solvent was removed to give 846 g of 3- (bromophenoxy) -tert-butyl dimethylsilane as a light yellow liquid. NMR (300 MHz, CDCl ₃ ):? 0.2 (s, 6H); 1.0 (s, 9H); 6.75 (m, 1H); 7.0 (br s, 1H); 7.1 (m, 2H).

The crude dilyl ether (146 g, 0.51 mol) was dissolved in dry tetrahydrofuran under a nitrogen blanket and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (318 mL, 0.51 mol) was added dropwise at such a rate that the temperature was kept below -70 ° C. After the addition was complete, the reaction mixture was stirred for 30 minutes and transferred the cold solution to another vessel containing a cold solution (-78 ° C) of 4-bromobenzaldehyde (94.3 g, 0.51 mol) in 1000 ml of dry tetrahydrofuran under nitrogen blanket. The transfer rate was controlled so as to keep the reaction temperature below -70 ° C. The reaction mixture was stirred for a further 45 minutes at -78 ° C and then quenched with 100 ml of saturated aqueous ammonium chloride solution. After warming to room temperature, the mixture was diluted with 2000 ml of water and then washed with 500 ml of saturated sodium chloride solution. The ether solution was dried over sodium sulfate and the solvent was removed to give 197.2 g of crude α- (4-bromophenyl) -3- (tert-butyldimethylsilyloxy) benzyl alcohol as a yellow oil. NMR (200 MHz, CDCl 3): 0.2 (s, 6H); 0.9 (s, 6H); 5.7 (s. 1H); Yellow 75 (dd, J = 2 Hz, J ₂ = 8 Hz, 1H); 6.8 (br s, 1H); 6.9 (d, J = 8 Hz, 1H); 7.15 (t, J = 8 Hz, 1H); 7.25 and 7.45 (AB q, J - 8 Hz, EH).

The crude benzyhydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under reduced pressure. The crude product was redissolved in 500 ml of toluene and the solvent was removed again under reduced pressure to get rid of excess thionyl chloride, yielding crude α- (4-bromophenyl) -3- (tert-butyldimethylsilyloxy) benzyl chloride as a dark oil. NMR (200 MHz, CDCl ₃ ): δ 0.2 (s, 6H); 1.0 (s, 9H); 6.0 (s. 1H); 6.78 (dd, J = 1 Hz, J ₂ = 8 Hz, 1H); 6.9 (m, 2H); 7.2 (t, J = 8 Hz, 2H); 7.27 and 7.47 (AB q, J = 8 Hz, 4H).

The crude benzyhydryl chloride (about 135 mmoles) was combined with 46.3 g (405 mmoles) of trans-2,5-dimethylpiperazine (purified by recrystallization from toluene to m.p. 115-119 ° C) and 30 ml of toluene and refluxed for overnight heating. under nitrogen cover at night. Toluene was removed under reduced pressure and the residue was redissolved

179 341 in 2000 ml diethyl ether and washed with 500 ml 1.0 M sodium hydroxide and 1000 ml water. The ethereal solution was dried over sodium sulfate and the solvent was removed to yield a dark oil. The product was purified by silica gel chromatography with 10% ethanol in dichloromethane, yielding 41.0 g (62%) of (±) -trans-1- (4-bromo-α- (3- (tert-butyldimethylsilyloxy) phenyl) benzyl) -2 , 5-dimethylpiperazine as a 1: 1 mixture of diastereoisomers. NMR (300 MHz, CDCl 3): δ 0.15 (s, 6H); 0.9 (m, 12H); 1.2 (d, J = 6Hz, 3H); 1.4-1.6 (m, 2H); 2.2-3. 0 (m, 5H); 5.2 and 5.3 (s, 1H); 6.6-7.5 (m, 8H).

The purified benzhydryl piperazine (41.0 g, 83.7 mmol) was dissolved in 500 ml of dry tetrahydrofuran with 7.3 ml (84 mmol) of allyl bromide and 22 g (200 mmol) of sodium carbonate and refluxed overnight under a nitrogen blanket. The cooled reaction solution was filtered and the solvent removed to yield 44.1 g of crude (±) -trans-1-allyl-4- (4-bromo-a (3- (tert-butyldimethylsilyloxy) phenyl) benzyl) -2,5-dimethylpiperazine in the form of brown oil. NMR (200 MHz, CDCl ₃ ): δ 0.15 (s, 6H); 0.95 (m, 12H); 1.15 (2 overlapping d, J = 6Hz, 3H); 1.8 (m, 1H); 2.1 (m, 1H); 2.35-2.65 (m, 3H); 2.7-2.9 (m, 2H); 3.35 (dd, fi = Hz, J ₂ = 12 Hz, 1H); 5.0 = 5.2 (m, 3H); 5.85 (m, 1H); 6.6-7.5 (m, 8H).

The crude brown oil product (44.1 g, 83.3 mmol) was dissolved in 200 ml of acetonotrile with 20 g (about 130 mmol) of tetraethylammonium fluoride hydrant and stirred for 1 hour at room temperature. After evaporation of the solvent, the residue was redissolved in dichloromethane and washed with water (pH = 8) to remove most of the ammonium salts. The dichloromethane solution was dried over sodium sulfate and the solvent was removed to give 40 g of a residue. The product was purified by silica gel chromatography (Waters Prep 500) with 0.5-1% ethanol in dichloromethane containing 0.1% triethylamine. Both diastereoisomers of the product were separated by chromatography and were initially obtained as oils. Dichloromethane solutions of the distereoisomers were shaken with water (pH = 8) and the products precipitated as white crystalline solids. The less mobile isomer (Rf = 0.45 on silica gel) with a mixture of dichloromethane: ethanol: ammonium hydroxide / 95: 5: l) gave 7.3 g (21%) (±) -3 - ((aR *) - a- ((2S *, 5R *) -4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol, mp 162-167 ° C. NMR (200 MHz, DMSCO-d ₆ ): δ 0.94 (d, J = 6 Hz, 3H); 1.06 (d, J = 6 Hz, 3H); 1.82 (dd, J = 7.5 Hz, J ₂ = 11.6 Hz, 1H); 2.07 (dd, fi = 7 Hz, J ₂ = 11 Hz, 1H); 2.5-2.6 (m, 3H); 2.71 (dd, J = 3 Hz, J ₂ = 11 Hz, 1H); 2.84 (dd, fi = 7 Hz, J ₂ = 14 Hz, 1H); 3.16 (dd, fi = 6 Hz, J ₂ = 14 Hz, 1H); 4.92 (s. 1H); 5.09 (dd, J = 2 Hz, J ₂ = 10 Hz, 1H); 5.17 (dd, fi = 2 Hz, J ₂ = 17 Hz, 1H); 5.78 (m, 1H); 6.64 (s. 1H); 6.66 (t, J = 7.5 Hz, 2H); 7.13 (t, J = 7.5 Hz, 1H); 7.32 and 7.49 (AB q, J = 8.5 Hz, 4H). A portion was converted to the hydrochloride salt with excess ethanolic hydrogen chloride and the product was precipitated from ethanol with diethyl ether to give a white hygroscopic solid. Calculated for C ₂₂ H ₂₇ BrN ₂ O 2 HCl 0.33 H ₂ O: C, 53.46; H, 6.05; N, 5.67; total halogen, calculated as Cl, 21.43. Found C, 53.65; H, 6.39; N, 5.53; total halogen, calculated as Cl, 20.98. Assignment of the related stereochemistry made on the basis of the X-ray determination of the crystallographic structure.

The above compound could also be obtained by fractional crystallization of an isomer mixture which was partially enriched with the desired isomer by chromatography on a short silica gel column with a 1: 1 mixture of dichloromethane: ethyl acetate. Thus, a mixture of (115 g) (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-alkyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (70%) and (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol ( 30%) was heated to 70 ° C in 2150 ml of acetonitrile and 370 ml of tetrahydrofuran and then filtered hot. The filtrate was cooled to 42 ° C and seeded with (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4- crystals bromobenyl) phenol. The solution was cooled to 34 ° C and filtered to give 18.8 g of (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-allyl-2,5-dimethylpiperazinyl) -4- bromobenzyl) phenol with isomeric purity 95%. The additional harvest yielded 22.2 g of substances of similar purity. A total of 40.0 g was recrystallized in the same manner, yielding 32.7 g of (±) -3 - ((aR *) - a - ((S *, 5R *) - 4-allyl-2,5-dimethyl-1). -piperazinyl) -4-bromobenzyl) phenol with an isomeric purity greater than 98%.

179 341

Example Π. (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol

The first isomer eluted from the column of Example 1 was obtained as described as 4.84 g (14%) of white crystals, m.p. 184-187 ° C. NMR (200 MHz, DMSOA): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.85 (dd, J = 7.5 Hz, J ₂ = 11 Hz, 1H); 2.1 (dd, J = 7 Hz, J ₂ = 12 Hz, 1H); 2.4-2.65 (m, 3H); 2.7 (dd, J = 4 Hz, J ₂ = 11 Hz, 1H); 2.85 (dd, J = 7 Hz, J ₂ = 14 Hz, 1H); 3.15 (dd, J = 6 Hz, J ₂ = 16 Hz, 1H); 5.1 (d, J = 11Hz, 1H); 5.13 (s. 1H); 5.18 (d, J = 16Hz, 1H); 5.8 (m, 1H); 6.61 (d, J = 8 Hz, 1H); 6.75 (d, J = 8 Hz, 1H); 6.83 (s. 1H); 7.08 (t, J = 8 Hz, 1H); 7.2 and 7.5 (ABq, J = 8Hz, 4H); 9.3 (s, 1H). A portion was converted to salt, the dihydrochloride with excess ethanolic hydrogen chloride, and the product was precipitated from ethanol with diethyl ether to afford a white hygroscopic solid. Calculated for C ₂₂ H _{27 BrN 2} O 2 HCl 0.5 _{H 2} O: C, 53.14; H, 6.08; N 5.63; total halogen, calculated as Cl, 21.39. Found C, 53.23; H, 6.40; N, 5.50; total halogen, calculated as Cl, 21.04.

The above compound could also be obtained by fractional crystallization from a mixture of isomers which was partially enriched with the desired isomer by chromatography on a short silica gel column with a 1: 1 mixture of dichloromethane: ethyl acetate. Thus, a mixture of (614 g) (±) -3 - ((aR *) - a, - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (40%) and (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) 4-bromobenzyl) phenol (60% ) was dissolved in 1350 ml refluxed isopropanol and allowed to cool to 35 ° C. Filtration gave 149.4 g of (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol containing 3% of the second isomer. The additional harvest yielded 40.8 g of similar purity material which was combined for a total of 190.2 g, and after recrystallization from 1200 mL of isopropanol, 119.6 g of white crystals were obtained with an isomeric purity above 99%.

Example ΙΠ. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzonitrile

A solution of (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (example I) (32 , 6 g, 0.0786 mol) and cuprous cyanide (14.1 g, 0.157 mol) in 500 ml of dimethylformamide was refluxed for 3 days under a nitrogen blanket. The reaction mixture was cooled to room temperature and then poured into a mixture of 2000 ml of 30%. sodium cyanide with 1500 ml of diethyl ether. The diethyl ether was washed with 600 ml of water followed by brine. The solvent was removed to give 33.1 g of a brown oil which partially crystallized on standing. The mixture was triturated with diethyl ether and filtered to give 14.6 g (51%) of (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl- 1-piperazinyl) -3-hydroxybenzyl) benzonitrile as a light brown solid. A small amount was recrystallized from ethyl acetate to give a white solid, mp 186-187 ° C. Calculated for C ₂₇ H 36 N 3 O: C, 76.42; H, 7.53; N, 11.62. Found C, 76.31; H, 7.54; N, 11.55. NMR (200 MHz, DMSO-d ₆ ): δ 0.95 (d, J = 6 Hz, 3H); 1.08 (d, J = 6 Hz, 3H); 1.77 (dd, J = 8 Hz, and 11 Hz, 1H); 2.10 (dd, J = 11 Hz and 10.5 Hz, 1H); 2.49-2.90 (m, 5H); 3.18 (dd, J = 5.5 Hz and 14 Hz, 1H); 5.06-5.22 (s, 2d, 3H); 5.7-5.9 (m, 1H); 6.66-6.70 (s, 2d, 3H); 7.15 (t, J = 8 Hz, 1H); 7.6 and 7.8 (ABq, J = 8Hz, 4H); 9.4 (s, 1H).

Example IV. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl} benzamide

Na (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (0.30 g, 0.72 mmol) of Example 1 was treated with tert-butylchlorodimethylsilane to give 0.36 g of a colorless oil which was then treated with n-butyllithium (0.45 mL, 1.6 M in hexane) and carbon dioxide as described in Example 6, Method B, yielding 0.35 g of a colorless vitreous.

Thionyl chloride (78 µΐ, 1.1 mmol) was added to a cold (0 ° C) solution of the above product (0.35 g, 0.70 mmol) in dichloromethane. After 2 hours at 0 ° C, this mixture was added dropwise to cold concentrated ammonium hydroxide (1.5 ml), stirred for 1 hour at room temperature and diluted with water and dichloromethane. The organic layer was washed with water, dried over sodium sulfate and evaporated and the residue was purified by preparative thin layer chromatography (silica gel, dichloromethane:

179 341 ethanol: ammonium hydroxide / 90: 10: 1, yielding 0.21 g (58%) (±) -4 - ((aR *) - a - ((2S *, 5R *) -4-allyl-2 , 5-dimethyl-1-piperazinyl) -3- (tert-butyldimethylsilyloxy) benzyl) benzamide as a yellow oil. NMR (CDCl ₃ ): δ 0.15 (s, 6H); 0.9 (s, 9H); 1.0 (d, 3H); 1.2 (d, 3H); 1.9 (m, 1H); 2.2 (m, 1H); 2.4-2.7 (m, 3H); 2.85 (m, 1H); 2.95 (m, 1H); 3.4 (m, 1H); 5.2 (m, 3H); 5.7-6.1 (m, 2H); 6.0 (br s, 1H); 6.6 (s. 1H); 6.8 (s. 1H); 7.15 (t, 1H); 7.5 (d, 2H); 7.75 (d, 2H).

The above product (0.21 g, 0.43 mmol) was treated with tetraethylammonium fluoride hydrate (0.15 g, about 0.8 mmol) in an acetonitrile solution. The solvent was removed, the residue was extracted between chloroform and pH 8 buffer, and the chloroform layer was dried over sodium sulfate and evaporated. The crude product was converted to the monohydrochloride salt by titration with ethanolic hydrochloric acid then precipitated with diethyl ether to afford 97.4 mg (60%) of a white solid. Calculated for C23H29N3O2 HC10.5 H ₂ O: C, 64.34; H, 7.65; N. 9.38; Cl, 7.91. Found C, 64.44; H, 7.93; N, 9.30; Cl, 7.94, mass spectrum (CI-CH4) m / z 380 (M + 1.100%), 153 (9%), 226 (10%). Part of the crude product was purified by chromatography on silica gel with dichloromethane: ethanol (2-10%) to afford a light yellow foam. NMR (CDCl3): δ 1.0 (d, J - 6 Hz, 3H); 1.1 (d, J = 6Hz, 3H); 3.85 (m, 2H); 3.4 (m, 1H); 5.2 (m, 3H); 5.9 (m, 1H); 6.3 (br s. 2H); 6.6 (m, 3H); 7.1 (t, J - 8Hz, 1H); 7.5 (d, J = 9Hz, 2H); 7.6 (d, J = 9 Hz, 2H).

Example 5 (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoic acid

Solution of (±) -4 - (((xR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzonitrile (example ΙΠ) ( 20.81 g, 0.0575 mol) and pellets of sodium hydroxide (16.1 g, 0.402 mol) in 200 ml of 95% ethanol were refluxed overnight. concentrated hydrochloric acid and the solvent was removed under reduced pressure. The resulting solid was triturated with methylene chloride and filtered to give 42.0 g of (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4) acid. -allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoic acid mixed with sodium chloride as a light brown solid The crude carboxylic acid (1.5 g) was stirred overnight in 40 mL of distilled water. The acid was separated. by filtration and dried in vacuo at 55 ° C. A slurry of the acid (0.47 g) in ethanol was prepared and titrated with 0.2 M ethanolic hydrochloric acid to pH 5.2. The solvent was removed and the resulting solid was reused. not stirred overnight in distilled water. After filtration and drying, 0.27 g of (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3- acid was obtained. hydroxybenzyl) benzoic acid as a brown solid. Calculated for C23H28N2O3 1.5 H2O: C, 67.78: H, 7.67; N, 6.87. Found C, 67.78; H, 7.38; N, 6.90. NMR (200 MHz, D ₂ O / NaOD) δ: 0.83 (<(J = 6 Hz, 3H); 0.98 (d, J = 6 Hz, 3H); 1.9-2.1 (m, 2H ); 2.3-2.8 (br m, 5H); 5.1 (m, 3H); 5.6-5.8 (m, 1H); 6.3 (d J = 7Hz, 1H ); 6.4-6.45 (s, d, 2H); 6.95 (t, J = 8 Hz, 1H); 7.3 and 7.6 (ABq, J = 8 Hz, 4H).

Example VI. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N, N-diethylbenzamide

Method A

Crude (±) -4 - ((ccR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoic acid solution (example V, from 7.1 mmol of Example 1), benzothiiazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (3.1 g, 14 mmol) and diethylamine (3.7 ml, 35 mmol) in 100 ml dimethylformamide was stirred overnight at room. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of 200 ml of 1 M HCl and 200 ml of diethyl ether. The pH of the aqueous layer was adjusted to 8 with 10M sodium hydroxide and then extracted with 350 ml of dichloromethane. The dichloromethane layer was dried over sodium sulfate. The solvent was evaporated to yield 3.59 g of a brown oil. The oil was chromatographed on silica gel with ethyl acetate: hexane to give 1.24 g (40%) (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2, 5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a white solid and 0.78 g as a pink foam. The foam was crystallized from acetonitrile to give 0.55 g (total yield 58%) of the amide as white needles, mp 170-171 ° C. Calculated for C27H27N3O2: C, 74.45; H, 8.56; N, 9.65. Found C, 74.29; H, 8.59; N, 9.70. NMR (200 MHz DMSO-d ₆ ) δ: 0.95 (d, J = 6 Hz, 3H); 1.1 (d, br, tr, 9H); 1.85 (t, J = 11Hz, 1H); 2.05-2.14 (dd, J - 10 Hz and J = 11 Hz);

179 341

2.5-2.9 (br m, 5H); 3.1-3.4 (br m, 5H); 5.0 (s. 1H); 5.1 (2d, 2H); 5.7-5.9 (m, 1H); 6.7 (s. 2d, 3H); 7.15 (dd, J = 8 Hz and J = 8 Hz, 1H); 7.3 and 7.4 (ABq, J = 8Hz, 4H); 9.35 (s, 1H).

Method B (±) -3 - (<xR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (5.3 g , 12.8 mmol, Example 1) was dissolved in 25 ml of dimethylformamide in 2.72 g (18.0 mmol) of tert-butylchlorodimethylsilane and 2.05 g (30 mmol) of imidazole were stirred overnight at room temperature. The reaction solution was poured into 125 ml of water, and extracted with 125 ml of diethyl ether. The ether extract was washed with 75 ml of 0.1 M sodium hydroxide, 75 ml of water and 25 ml of saturated sodium chloride solution. The ether solution was dried over sodium sulfate and the solvent was removed to give 7.4 g of an oil which was purified by chromatography on silica gel with 1-4% ethanol in dichloromethane. The yield of (±) - (2R *, 5S *) - 1-allyl-4- (4-bromo (aS *) - a- (3-tert-butyldimethylsilyloxy) phenyl) benzyl) -2,5-dimethylpiperazine was 6 , 58 g in the form of light yellow oil. NMR (200 MHz, CDCl 3): δ 0.15 (s, 6H); 0.96 (s, 9H); 0.97 (d, J = 6Hz, 3H); 1.15 (d, J = 6Hz, 3H); 1.87 (dd, J = 9.5 Hz, _J2 - 10 Hz, 1H); 2.12 (dd, J = 9.5 Hz, J ₂ = 10.5 Hz, 1H); 2.35-2.65 (m, 3H); 2.75-2.95 (m, 2H); 3.36 (dd, J = 6 Hz, J ₂ = 14 Hz, 1H); 5.12 (s. 1H); 5.15 (m, 2H); 5.85 (m, 1H); 6.59 (s. 1H); 6.75 (d, J = 7.7 Hz, 2H); 7.17 (t, J = 7.7Hz, 1H); 7.31 and 7.39 (ABq, J - 8.8.5 Hz, 4H).

The silyl ether (6.55 g, 12.4 mmol) was dissolved in 60 mL of dry tetrahydrofuran and cooled to -78 ° C under a nitrogen blanket. A solution of 1.35 M n-butyllithium in hexane (9.2 mL, 12.4 mmol) was added dropwise at a rate to keep the temperature below -70 ° C. The orange solution was then stirred for an additional 30 minutes at the low temperature, and then anhydrous carbon dioxide gas was introduced into the reaction solution at a rate that kept the temperature below -60 ° C. Carbon dioxide addition was stopped when the reaction solution turned light yellow. The reaction mixture was allowed to warm to room temperature while stirring, and the solvent was removed in vacuo. The residue was redissolved in 50 ml of toluene and the solvent was removed again in vacuo to remove n-bromobutane. The reaction yielded 6.2 g of lithium salt of (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-l-piperazinyl) -3- ( tert-butyldimethylsilyloxy) benzyl) benzoic acid. Mass spectrum (FAB) m / e: 495 (m + 1.45%), 455 (15%), 369 (15%), 341 (100%), 297 (20%), 277 (50%).

Lithium benzoate salt (6.2 g, 12.6 mmol) was dissolved in 100 ml of dichloromethane and cooled to 0 ° C. A solution of thionyl chloride (1.4 ml, 19 mmol) in 50 ml of dichloromethane was added dropwise. The mixture was stirred for 1.5 hours at 0 ° C and a solution of diethylamine (8.1 ml, 78 mmol) in 80 ml of dichloromethane was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction solution was washed with water and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel with 1-3% ethanol in dichloromethane, yielding 2.15 g (32%) (±) -4 - ((aR *) - a - ((2S *, 5R * ) -4-allyl-2,5-dimethyl-1-piperazinyl) -3- (tert-butyldimethylsilyloxy) benzyl) -N, N-diethylbenzamide as a gummy residue. NMR (300 MHz, CDCl 3): δ 0.15 (s, 6H); 0.95 (s, 9H); 0.97 (d, J = 6Hz, 3H); 1.12 (br m, 3H); 1.18 (d, J = 6Hz, 3H); 1.23 (br m, 3H); 1.87 (dd, J = 9 Hz, J ₂ = 11 Hz, 1H), 2.21 (dd, J = 9 Hz, J ₂ = 11 Hz, 1H); 2.45 (m, 1H); 2.56 (dd, J = 2.5 Hz, J ₂ = 11 Hz, 1H); 2.58 (m, 1H); 2.79 (dd, J = 3 Hz, J ₂ = 11 Hz, 1H); 2.85 (dd, J = 8 Hz, J ₂ = 14 Hz, 1H); 3.25 (br m, 2H); 3.36 (dd, J = 5.5 Hz, J ₂ = 14 Hz, 1H); 3.53 (br m, 2H); 5.1-5.2 (m, 3H); 5.85 (m, 1H); 6.60 (s. 1H); 6.74 (d, J = 8 Hz, 1H); 6.76 (d, J - 8Hz, 1H); 7.17 (t, J = 8 Hz, 1H); 7.28 and 7.46 (ABq, J = 8Hz, 4H).

The above benzamide (2.15 g, 3.91 mmol) was dissolved in 40 ml of acetonitrile with 0.88 g (6 mmol) of tetraethylammonium fluoride hydrate and stirred for 1 hour at room temperature. After evaporation of the solvent, the residue was redissolved in dichloromethane and washed with water (pH = 8), then dried over sodium sulfate and the solvent was removed to give 1.67 g of a gummy residue. The dihydrochloride salt was prepared by treatment with excess ethanolic hydrogen chloride followed by precipitation with diethyl ether, yielding 1.45 g (72%) of (±) -4 - ((aR *) - a - ((2S *, 5R *) - dihydrochloride) 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide in the form of hygrop

179 341 scopic white powder. Calculated for C27H37N3O2 2HCl 0.5 H2O: C, 62.66; H, 7.79; N, 8.12; Cl, 13.70. Found C, 62.47; H, 7.91; N, 8.02; Cl, 13.49). A portion was converted to free amine by adjusting the aqueous solution to pH = 8 and extracting with dichloromethane to give a sample for spectral analysis. NMR (300 MHz, CDCl 3): δ 1.00 (d, J = 6 Hz, 3H); 1.12 (br m, 3H); 1.16 (d, J = 6Hz, 3H); 1.25 (brm, 3H); 1.90 (dd, Jj = 9 Hz, J ₂ = 11 Hz, 1H); 2.14 (dd, J = 9 Hz, J ₂ = 11 Hz, 1H); 2.45-2.7 (m, 3H); 2.8-2.9 (m, 2H); 3.3 (br m, 2H); 3.41 (dd, J = 5 Hz, J ₂ = 14 Hz, 1H); 3.55 (br m, 2H); 5.18 (s. 1H); 5.14-5.23 (m, 2H); 5.88 (m, 1H); 6.586.64 (m, 3H); 7.11 (t, J = 7.8 Hz, 1H); 7.28 and 7.45 (ABq, J = 8Hz, 4H). Mass spectrum (CI-CH4) m / e: 436 (m + 1.48%), 284 (100%), 153 (57%).

Example VH. (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-aUyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) benzoic acid

Solution of the crude lithium salt of 4 - ((aR *) - a - ((2R *, 5S *) - 2,5-dimethyl-1-piperazinyl) -3-tert-butyldimethylsiloxybenzyl) benzoate (11.5 g, from 23 mmol of Example 1 According to the procedure of Example 6, method B) in tetrahydrofuran was treated with 6M aqueous hydrochloric acid at room temperature for 18 hours. After diluting with water, the mixture was extracted with diethyl ether and the aqueous layer was adjusted to pH 8 with aqueous sodium hydroxide and extracted with dichloromethane. The aqueous layer was titrated to pH 6 with concentrated hydrochloric acid and the precipitated solid was filtered, washed with water and dried under reduced pressure (60 ° C) to give 2.65 g (30%) of the acid (±) -4 ((aR *) - a - ((2R *, 5S *) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoic as an off-white powder. NMR (DMSO-d6) δ: 0.9 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.8 (dd, J = 11 Hz, J ₂ = 7 Hz, 1H); 2.1 (dd, J = 11 Hz, J ₂ = 7 Hz, 1H); 2.5 (m, 6H); 2.7 (d, J = 11Hz, 1H); 2.9 (dd, J = 7 Hz, J ₂ = 14 Hz); 3.1 (dd, J = 14 Hz, J ₂ = 5 Hz, 1H); 4.9-5.2 (m, 3H); 5.6-5.8 (m, 1H); 6.5 (dd, J = 8 Hz, J ₂ = 2 Hz, 1H); 6.8 (m, 2H); 7.1 (t, J = 8 Hz, 1H); 7.3 (m, 1H); 7.4 (d, J = 8Hz, 2H); 7.9 (d, J = 8Hz, 2H). Calculated for C23H28N2O3 1.25 H2O: C, 68.55; H, 7.63; N, 6.95. Found C, 68.61; H, 7.66; N, 7.02. Mass spectrum (CI-CH4): m / z 381 (M + 1.44%), 153 (100%), 227 (17%).

Example VIII. (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) benzyl) phenol

Solution of (±) -3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol (example Π) (35 0.00 g, 0.0843 mol) in 400 ml of anhydrous tetrahydrofuran was cooled to -78 ° C. N-Butyllithium (1.6 M in hexane, 126 mL, 0.20 mol) was added dropwise. The mixture was stirred for 30 minutes at -78 ° C and then quenched with saturated ammonium chloride. After warming to room temperature, the reaction mixture was poured into a mixture of 1000 ml of ethyl acetate and 1000 ml of water. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The solvent was removed to give 27.6 g of a pink solid. The solid was recrystallized from ethyl acetate to give 19.4 g (68%) of (±) -3 - ((aR *) a - ((2R *, 5S *) -1-allyl-2,5-dimethyl-1- piperazinyl) benzyl) phenol as a white solid, mp 172.5-175.5 ° C. NMR (200 MHz, DMSO-d6): δ 0.96 (d, J = 6 Hz, 3H); 1.08 (d, J = 6 Hz, 3H); 1.85 (t, J = 11Hz, 1H); 2.09 (t, J = 11Hz, 1H); 2.5-2.9 (m, 5H); 3.15 (dd, J = 5.4 Hz and 15 Hz, 1H); 4.9 (s. 1H); 5.1-5.2 (2d, 2H); 5.7-5.9 (m, 1H); 6.55 (d, J = 8 Hz, 1H); 6.8 (d, J = 8 Hz, 1H); 6.85 (s. 1H); 7.07 (ζ J = 8 Hz, 1H); 7.2-7.4 (m, 5H); 9.3 (s, 1H). The free amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.8 with ethanolic hydrogen chloride. The salt was precipitated from ethanol with diethyl ether, yielding 15.82 g of product as a white solid. Calculated for C22H28N2O HCl 0.5 H ₂ O: C, 69.18; H, 7.92; N, 7.33; Cl, 9.28. Found C, 69.55; H, 8.03; N, 7.31; Cl, 9.27

Example IX. cis4- (a- (4 - ((Z) -2-Butenyl) -3,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide

A mixture of 4-carboxybenzaldehyde (100 g, 0.66 mol), 1l dimethylformamide and 2l dichloromethane was cooled in an ice-cooling bath. Thionyl chloride (53 mL, 0.73 mol) was added dropwise while stirring. After 18 hours at room temperature, the mixture was cooled again and diethylamine (275 mL, 2.6 mol) was added dropwise. After stirring at room temperature for 1 hour, the solvent was evaporated, and the residue was dissolved in aqueous 0.1 M sodium hydroxide and extracted with ethyl acetate. Organic layers

Was washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil, chromatography on silica gel with dichloromethane: ethanol (0-2%) gave 44.2 g (32%) of 4-formyl-N, N -Diethylbenzamide in the form of a yellow oil.

3-Bromophenoxy-tert-butyldimethylsilane (61.7 g, 0.21 mol), prepared as in Example 1, was dissolved in 500 ml of dry tetrahydrofuran under a nitrogen blanket and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (132 mL, 0.21 mol) was added dropwise at such a rate as to keep the temperature below -70 ° C. This was stirred for 30 minutes after the addition was complete and the cold solution was transferred via cannula to a second vessel containing a cold (-78 ° C) solution of the above 4-formyl-N, N-diethylbenzamide (44.1 g, 0.21 mol) in 500 ml of dry tetrahydrofuran under nitrogen blanket. The transfer rate was controlled so as to keep the temperature below 70 ° C. After stirring for 1 hour at -78 ° C, the reaction was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and diluted with diethyl ether. The ether layer was washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane: ethanol (0-1%) gave 45.4 g (52%) of 4- (3- (tert-butyldimethylsilyloxy) -ahydroxybenzyl) -N, N-diethylbenzamide as a white solid.

Thionyl chloride (12 mL, 0.17 mol) was added to a solution of the above benzhydryl alcohol (45.4 g, 0.11 mol) in 300 mL of dichloromethane. After stirring for 1 hour at room temperature, the solvent was evaporated, the residue was redissolved in toluene and re-evaporated to drive off the excess thionyl chloride.

A mixture of the crude benzhydryl chloride (about 0.11 mol), cis-2,6-dimethylpiperazine (43.97 g, 0.39 mol) and 10 ml of toluene was refluxed under nitrogen for 2 hours. The reaction mixture was partitioned between aqueous 1N hydrochloric acid and diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous 5M sodium hydroxide and extracted with dichloromethane. The extracts were washed with water, dried over sodium sulfate and evaporated to give 36.69 g of a yellow glass.

A mixture of the product (36.5 g, 72 mmol), 38.2 g (360 mmol) of anhydrous sodium carbonate 9.8 g (74 mmol) of 1-bromo-2-butyn prepared from 2-butyn-1-ol (L. Brandsma "Preparative Acetylene Chemistry", 2nd edition, Elsevier, 1988, p. 248) in 400 ml of dry tetrahydrofuran was refluxed under nitrogen for 48 hours. The solvent was evaporated, and the residue was taken up in dichloromethane and filtered to remove inorganic salts. The filtrate was evaporated, the residue was dissolved in acetonitrile and 21 g (about 0.11 mol) of tetraethylammonium fluoride hydrate were added. After stirring at room temperature for 3 hours, the solvent was removed and the residue was purified by chromatography on silica gel with a mixture of dichloromethane: ethanol (0-4%), yielding 12.5 g (31%) of cis-4- (α- (4- (-2-butynyl) -3,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a light yellow glassy substance.

The above butynylamine (12.5 g, 28 mmol) was dissolved in 400 mL of toluene with 7.9 g of Lindlar catalyst from Engelhard Industries and reduced in an atmospheric hydrogenation apparatus with magnetic stirring. The reaction was complete in 2 hours as judged by thin layer chromatography (dichloromethane: ethanol: ammonium hydroxide / 90: 10: l). The catalyst was filtered off through Celite and the filtrate was evaporated to give a brown solid. Chromatography on silica gel (Waters Prep 500 using a mixture of dichloromethane: ethanol: triethylamine / 100: 0.5-2: 0.1) gave 5.47 g (43%) cis-4- (α- (4 ((( Z) -2-butenyl) -3,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide in the form of a white solid. NMR (CDCfi is 0.9-1.3 (m, 12H); 1.65 (m, 3H); 1.8 (t, 2H); 2.6-2.9 (m, 7H); 3.2 (m, 4H); 3.5 (br m, 4H); 4.05 (s, IH); 5.6 (m, 2H); 6.75 (m, IH); 6.9 (m, 2H ); 7.05 (t, IH); 7.25 (d, 2H); 7.4 (d, 2H) The product was dissolved in anhydrous ethanol and titrated to pH 4.5 with ethanolic hydrochloric acid. The solution was concentrated and ether was added of diethyl to precipitate 4.36 g (82%) of the monohydrochloride salt Calculated for C28H38N3O7 HCl H ₂ O: C, 66.85; H, 8.21; N, 8.35; Cl, 7.05. C, 66.79; H, 8.40; N, 8.36; Cl, 7.00 Mass spectrum (CI-CH4): m / z 450 (M + 1.100%), 282 (9%) . 167 (29%).

179 341

Example X. (+) - N, N-Diethyl-4- (3-hydroxy) - (aR) -a - ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide

A mixture of 15.65 g (36 mmoles) of N, N-diethyl-4- (3-tert-butyldimethylsilyloxy) -achlorobenzyl) benzamide, prepared as described in Example 9, 7.22 g (65 mmoles) (+) - ( 2S, 5S) -dimethylpiperazine prepared from L-Ala-L-Ala-diketopiperazine from Bachem Chemicals, Philadelphia, PA as described by Jung and Rohloff (J. Org. Chem., 50, 4909-13 (1985)) and 3 ml of toluene was heated as in Example I. The product was purified by chromatography on silica gel (Waters Prep 500 with dichloromethane containing 1% ethanol and 0.1% triethylamine) to give 4.06 g (22%) of N, N-diethyl-4 - (3-tert-butyldimethylsilyloxy) -a - ((2S, 5S) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide in the form of a beige foam.

A mixture of the above benzhydryl piperazine (4.06 g, 8.0 mmol), 80 ml of dry tetrahydrofuran, 4.24 g (40 mmol) of anhydrous sodium carbonate and 1.56 g (8.4 mmol) of methyl tosylate was heated under reflux for 40 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and filtered to remove inorganic salts. After evaporation of the filtrate, 6.7 g of brown oil was obtained. Chromatography on silica gel (Waters Prep 500 using dichloromethane containing 0.5% ethanol and 0.1% triethanolamine) gave 1.17 g (28%) of N, N-diethyl-4- (3- (tert-butyldimethylsilyloxy) - (aR) -a - ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide as a yellow oil. The a-S isomer (1.37 g, 33%) was also isolated.

The above aR isomer (1.17 g, 2.2 mmol) was treated with tetraethylammonium fluoride as described in Example 1 to give 0.82 g (90%) of (+) - N, N-diethyl-4- (3-hydroxy - (aR) -a ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide as a beige solid. NMR (CDCl ₃ ): δ 0.95 (d, J - 6 Hz, 3H); 1.05 (d, J = 7Hz, 3H); 1.2 (br m, 6H); 2.05-2.6 (m, 5H); 2.2 (s. 3H); 3.05 (m, 1H); 3.25 (br m, 2H); 3.5 (br m, 2H); 4.4 (s. 1H); 6.6 (m, 1H); 6.9 (m, 2H); 7.05 (t, J = 8 Hz, 1H); 7.25 (d, J = 8Hz); 7.45 (d, J = 8Hz, 2H). Titration to pH 4 in ethanolic solution with ethanolic hydrochloric acid followed by precipitation with diethyl ether gave 0.28 g (56%) of the monohydrochloride salt as a white powder. Calcd for C25H35N3O2 HC1 1,25H ₂ O: C, 64.09; H, 8.29; N, 8.97; Cl, 7.57. Found C, 64.12; H, 8.29; N, 8.92; Cl, 7.65. [a] ² ° D = + 22 ° (anhydrous ethanol, 7 mg / ml). Compound stereochemistry was determined by X-ray crystallography (Molecular Structure Corp., College Station, Texas).

Example XI. (+) - N, N-Diethyl-4- (3-hydroxy- (aR) -a - ((2R, 5R) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide

The procedure described in Example 10 was followed with 11.62 g (27 mmol) of N, N-diethyl-4- (3- (tert-butyldimethylsiloxy) -a-chlorobenzyl) benzamide prepared as in Example 9 and 9.42 g. g (82 mmol) of (-) - (2R, 5R) -2-5-dimethylpiperazine, prepared from D-Ala-D-Ala-diketopiperazine from Bachem Chemicals Philadelphia, PA, as described by Jung and Rohloff (J. Org. Chem. 50,4909-13 (1985)). The crude product was dissolved in 100 ml of acetonitrile and 8.07 g (40 mmol) of tetraethylaminium fluoride hydrate were added. The solution was stirred overnight at room temperature. The solvent is evaporated off and the residue is treated with 100 ml of aqueous 1N hydrochloric acid and extracted with 200 ml of diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous 5M sodium hydroxide and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated to give 8.03 g (75%) of N, N-diethyl-4- (3-hydroxy-α - ((2R, 5R) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide in the form of a light brown solid.

The above benzhydryl piperazine (4.1 Ig, 10.4 mmol) was mixed with 1.6 ml (41.6 mmol) of 96%. formic acid and 2.3 ml (31.2 mmol) of 37%. aqueous formaldehyde. The mixture was kept at 80 ° C for 18 hours, cooled to room temperature, treated with 6 ml of 6 M aqueous hydrochloric acid and extracted with diethyl ether. The aqueous layer was diluted with water, and its pH was adjusted to 8 with 10 N aqueous sodium hydroxide. The resulting suspension was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 3.71 g of a beige solid. By silica gel chromatography using

179 341 mixtures of dichloromethane: methanol (1 to 7%) yielded 3.01 g (70%) of N, N-diethyl-4- (3-hydroxy-α - ((2R, 5R) -2,4,5-trimethyl-1 -piperazinyl) benzyl) benzamide in the form of a beige solid.

The above product (2.44 g, 5.9 mmol) was dissolved in 20 mL of dimethylformamide with tert-butylchlorodimethylsilane (1.33 g, 8.9 mmol) and imidazole and stirred overnight at room temperature. The reaction mixture was poured into cold water and extracted with diethyl ether. The combined ether layers were washed with water, dried over sodium sulfate and evaporated to give 2.99 g (96%) of a yellow oil. The two diastereoisomers of the product were separated by silica gel chromatography with a mixture of dichloromethane: ethanol (0.5 to 1%). The less mobile isomer (Rf = 0.61) was separated on silica gel with a mixture of dichloromethane: ethanol: ammonium hydroxide / 90: 10: l, yielding 0.79 g (25%) of N, N-diethyl-4- (3-tert) -butyldimethylsiloxy (ccR) -a - ((2R, 5R) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide as a beige solid. NMR (CDCl ₃ ): δ 0.15 (s, 6H); 0.95 (s, 9H); 0.9-1.3 (m, 12H); 2.0-2.3 (m, 2H); 2.2 (s. 3H); 2.35-2.6 (m, 3H); 3.0 (m, 1H); 3.2 (br m, 2H); 3.5 (br m, 2H); 4.45 (s. 1H); 6.65 (m, 1H); 6.9-7.05 (m, 2H); 7.1 (t, J = 8 Hz, 1H); 7.3 (d, J = 8Hz, 2H); 7.45 (d, J = 8Hz, 2H).

The purified product (0.79 g, 1.51 mmol) was dissolved in 40 ml of acetonitrile with 0.45 g (2.26 mmol) of tetraethylammonium fluoride hydrate and stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water at pH 8. After drying over sodium sulfate, the solvent was evaporated and the residue was dissolved in anhydrous ethanol. After titration of this solution to pH 4.4 with ethanolic hydrochloric acid and subsequent precipitation with diethyl ether, 0.61 g (87%) of (+) - N, N-diethyl-4- (3-hydroxy- (aR) -a- monohydrochloride was obtained. ((2R, 5R) -2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide as a beige powder. Calcd for C25H35N3O2 HC1 0.75H ₂ O: C, 65.34; H, 8.23; N, 9.14; Cl, 7.71. Found C, 65.18; H, 8.33; N, 8.94; Cl, 7.52. Mass spectrum (CI-CH4) m / z 410 (M + 1.100%). [a] ²⁰ _D = +10.9 (anhydrous ethanol, c = 19.7 mg / ml). The benzhydryl carbon stereochemistry was assigned by comparison to the diastereoisomer from Example X by TLC and NMR methods.

Example XII. (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N, N-diethylbenzamide (±) -4 - ((aR *) -a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) N, N-diethylbenzamide prepared from the compound of Example VII by the procedures described in Example VI, method A. NMR (200 MHz, DMSO-cU): δ 0.9 (d, J = 6 Hz, 3H); 1.1 (d, J = 6Hz, 3H); 1.1-1.3 (br m, 6H); 1.8 (dd, Jj = 5Hz, J ₂ = 14.5 Hz, 1H); 3.1-3.6 (br m, 4H); 5.0 (s. 1H); 5.1 (d, J = 10Hz, 1H); 5.15 (d, J = 17Hz, 1H); 5.8 (m, 1H); 6.6 (d, J - 7.5 Hz, 1H); 6.8 (d, J = 7.5 Hz, 1H); 6.85 (s. 1H); 7.1 (t, J - 8Hz, 1H); 7.3 (s. 4H); 9.3 (s, 1H). Calculated for C27H37N3O2 HCl H ₂ O: C, 66.17; H, 8.23; N, 8.57; Cl, 7.23. Found C, 66.00; H, 8.24; N, 8.57; Cl, 7.20.

Example ΧΠΙ. (±) -4 - ((aR *) - a - ((2R *, 5S *) - 2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (±) -4 - (( aR *) - a - ((2R *, 5 S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (example Π) (21.75 g 0.0499 mol) was dissolved in a mixture of 330 ml of methanol and 90 ml of water. Trifluoroacetic acid (3.9 mL, 0.0499 mol) was added followed by 14.5 g of 5% palladium on carbon. The solution was refluxed for 3 days and filtered through celite. The solvent was removed and the residue was purified by chromatography on silica gel with ethanol (0-20%) in dichloromethane containing 1% triethylamine. The solvent was removed and the residue was redissolved in dichloromethane and washed with water at pH 8. The organic layer was dried over sodium sulfate and dried to dryness. The resulting solid was triturated with ethyl acetate overnight. Filtration gave 9.09 g (46%) (±) -4 ((aR *) - a - ((2R *, 5S *) - 2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N , N-Diethylbenzamide in the form of a yellow-brown solid. Calculated for C24H33N3O2 0.5H2O: C, 71.26; H, 8.47; N, 10.39. Found C, 71.12; H, 8.47; N, 10.49. NMR (300 MHz, CDCl ₃ ): δ 0.9 (d, J = 6 Hz, 3H); 1.2 (d br, tr, 9H); 1.5 (t, J = 10Hz, 1H); 2.2 (br m, 1H); 2.5 (m, 1H); 2.6 (d, Ji = 9Hz, 1H); 2.8 (m, 2H); 3.1-3.5 (br m, 5H); 5.3 (s. 1H); 6.6 (d, J = 8 Hz, 1H); 6.7 (d, J = 8 Hz, 1H); 6.8 (s. 1H); 7.1 (t, J = 8 Hz, 1H); 7.2 and 7.3 (ABq, J = 8Hz, 4H); 9.0 (br s, 1H).

Example XIV. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl) -N, N-diethylbenzamide, mp 178-180 ° C made from Example 6 by the methods described in Example 1. Calculated for C24H33N3O2: C, 72.87, H, 8.41, N, 10.62 Found: C, 72.72, H, 8.41, N, 10.47. NMR (200 MHz, DMSO-d /,): δ 0.85 (d, J = 6 Hz, 3H); 1.1 (d, J = 6 Hz, 3H); 1.0-1.3 (br m, 6H); 1.5 (t, J = 10Hz, 1H); 2.3 (br m, 1H); 2.45-2.6 (m, 2H); 2.7-2.9 ( m, 2H); 3.1-3.5 (br m, 5H); 5.25 (s, 1H); 6.6 (s, 1H); 6.6 (d, J = 8Hz, 1H) ; 6.7 (d, J = 8 Hz, 1H); 7.2 (t, J = 8 Hz, 1H); 7.3 and 7.4 (ABq, J = 8 Hz, 4H); 9.2 (br s, 1H).

Example XV. N- (4 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) benzoyl) -L-phenylalanil-L-leucine

Solution of carbobenzyloxy-L-phenylalanine (5.00 g, 16.7 mmol), L-leucine tert-butyl ester hydrochloride (3.74 g, 16.7 mmol), benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (7.39 g, 16.7 mmol) and triethylamine (4.66 ml, 33.4 mmol) in 250 ml of acetonitrile was stirred for 1.5 hours. The reaction mixture was taken up in 750 ml of ethyl acetate and washed successively with 500 ml of 5% citric acid, 500 ml of saturated sodium bicarbonate and 250 ml of brine. The organic layer was dried over sodium sulfate and the solvent was removed. The crude material was purified by silica gel chromatography with hexane: ethyl acetate to give 6.52 g of tert-butyl N - ((benzyloxy) caronyl) L-phenylalanyl-L-leucinate as a white crystalline solid.

A portion of the protected dipeptide (0.50 g, 1.1 mmol) was mixed with 10% palladium on carbon (0.10 g) in 100 mL of methanol and reduced with hydrogen on a Parr hydrogenator for 3 hours. The mixture was filtered and concentrated to dryness to give 0.35 g (98%) of tert-butyl L-phenylalanil-L-leucinate.

Crude lithium salt of (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) 3- (tert-butyldimethylsilyloxy) benzyl) benzoic acid (0.52 g, 1.0 mmol) (Example 7, below) was converted to the free acid using ethanolic hydrogen chloride. After removal of the solvent, the carboxylic acid was mixed with tert-butyl L-phenylalanyl-L-leucinate, benzatriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (0.47 g, 1.0 mmol) and triethylamine (0.16 mL, 1.0 mmol) in 20 ml of acetonitrile. After 2 hours, the reaction mixture was taken up in 20 ml of ethyl acetate, washed twice with 20 ml of saturated sodium bicarbonate and filtered. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel with a mixture of dichloromethane: ethanol, yielding 0.45 g (53%) of N- (4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2, Tert-Butyl 5-dimethyl-1-piperazinyl) 3 - ((tert-butyldimethylsilyloxy) benzyl) benzoyl) -L-phenylalanil-L-leucinate as a white solid.

A portion of the benzhydryl piperazine above (0.36 g, 0.44 mmol) was mixed with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 hour. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane: ethanol, yielding 0.180 g (58%) N- (4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2) Tert-Butyl 5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoyl) -L-phenylalanil-Lleucinate as a white solid.

Part of the tert-butyl ester (0.17 g, 0.25 mmol) was stirred for 1 hour in 10 ml of trifluoroacetic acid. The solvent was removed and the resulting solid was dried in vacuo to give 0.190 g (86%) N- (4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1 - piperazinyl) -3-hydroxybenzyl) benzoyl) -L-phenylalanil-L-leucine in the form of the trifluoroacetic acid salt. Calculated for C38H48N4O5 2C2HF3O2 H2O: C, 56.88; H, 5.91; N, 6.32. Found C, 57.15; H, 5.80; N, 6.23.

Example XVI. (±) -N- (4 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzoyl) glycylglycine

N-Carbobenzyloxyglycine (2.1 g, 10 mmol) was coupled to glycine tert-butyl ester (1.3 g, 10 mmol) using benzotriazole-1-yloxyltris (dimethylamino) phosphonium hexafluorophosphate (4.4 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in acetonitrile using the method described in Example 15 to give 2.5 g (79%) of N-carbobenzyloxyglycylglycine tert-butyl ester after chromatography on silica gel.

179 341

The carbobenzyloxy group was removed from the dipeptide (1.0 g, 3.1 mmol) using palladium on carbon as described in Example 15 to give glycylglycine tert-butyl ester (0.57 g, 3.0 mmol, 99%).

The dipeptide (0.41 g, 2.1 mmol) was coupled with the lithium salt of (±) -4 - ((aR *) - a - ((2S *, 5R *) 4-allyl-2,5-dimethyl-1 -piperazinyl) -3-hydroxybenzyl) benzoic acid (1.1 g, 2.1 mmol) from Example 6, Method B, and the tert-butyl ester and silyl ether were removed by the methods described in Example 15, yielding 0.64 g (34%) (±) -N- (4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-tert-butyldimethylsilyloxy) benzyl) benzoyl) glycylglycine in the form of a salt, trifluoroacetate. Calculated for C27H34N4O5 3.5CF3COOH: C, 45.70; H, 4.23; N, 6.27. Marked C, 45.55; H, 4.50; N, 6.08.

A small amount was converted to free amine for NMR analysis. NMR (300 MHz, DMSO-d6): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.9 (m, 1H); 2.1 (dd, J = 6.5 Hz and J = 10 Hz, 1H); 2.4-2.7 (m, 3H); 2.7 (d, J = 10Hz, 1H); 2.8 (dd, J = 7 Hz, and J = 10 Hz, 1H); 3.15 (dd, J = 4 Hz and J = 13.5 Hz, 1H); 3.3 (d, J = 4 Hz, 2H); 3.8 (d, J = 5 Hz, 2H); 5.0 (s. 1H); 5.1 (d, J = 10Hz, 1H); 5.15 (d, J = 17Hz, 1H) 5.8 (m, 1H); 6.8 (2d, J = 8Hz, 2H); 6.8 (s. 1H); 7.1 (t, J = 8 Hz, 1H); 7.25 (br t, J = 3 Hz, 1H); 7.45 and 7.8 (ABq, J = 8Hz, 4H); 8.8 (br t, J = 5 Hz, 1H).

Example XVII. (±) -4- (3-Hydroxy) -a- (cis-3,4,5-trimethyl-1-piperazinyl) benzyl) N, N-diethylbenzamide

A mixture of (±) -4- (3 - ((tert-butyldimethylsilyloxy) -a- (cis-3,5-dimethyl-1-piperazinyl) benzyl) -N, N-diethylbenzamide (18.5 g, 36.5 mmol ) (from Example 9), 88% formic acid (5.1 g, 110 mmol) and 37.6% formaldehyde (2.8 g, 95 mmol) were heated overnight at 80 ° C. The reaction mixture was cooled to temperature room and 20 ml of 7.2 M hydrochloric acid were added slowly. The mixture was washed 3 times with 40 ml of dichloromethane. The pH of the aqueous layer was adjusted to 8 with saturated sodium bicarbonate solution and then extracted with 3 x 40 ml of dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness, yielding 12.6 g (84%) of (±) -4- (3-hydroxy) -a- (cis-3,4,5-trimethyl-1-piperazinyl) benzyl) -N, N-diethylbenzamide as yellow-brown foam. NMR (300 MHz, CDCl 3): δ 1.0-1.3 (br m, 2d, J = 6 Hz and J = 6 Hz, 12H); 2.3 (br dd, 2H); 2.6 (s. 3H); 2.7-3.0 (br m, 4H); 3.2-3.6 (br m, 4H); 4.2 (s. 1H); 6.7 (d, J = 7Hz, 1H); 6.8 (d, J = 8 Hz, 1H); 6.9 (s. 1H); 7.1 (t, J = 8.1H); 7.25 and 7.40 (ABq, J = 8 Hz, 4H). Part of the product was dissolved in a mixture of dichloromethane and ethanol and converted to the dihydrochloride salt with excess ethereal hydrogen chloride. The solvent was removed and the residue was re-dissolved in a minimum amount of dichloromethane. Diethyl ether was added to give an oily solid which solidified with stirring. After filtration, the hydrate of the dihydrochloride salt was obtained. Calculated for C25H35N3O2 2HCl 1.5H2O: C, 58.93; H, 7.91; N, 8.25; Cl, 13.92. Found C, 58.84; H, 7.89; N, 8.09; Cl, 13.69.

Example XVIII. (±) -3 - ((R *) - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) (4-bromo-2-thienyl) methyl) phenol

Trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been previously recrystallized from toluene, mp 115-119 ° C, and 600 ml water, was added to a 12 liter three-necked round bottom flask. The flask was cooled in an ice-water bath and a solution of methanesulfonic acid (1290 g, 13.4 mol) in 600 mL of water was slowly added with stirring and cooling to keep the temperature below 40 ° C. The solution was cooled to 20 ° C and 800 ml of ethanol were added. A 500 mL dosing dropping funnel was charged with 60% aqueous potassium acetate from a 2 liter solution tank and potassium acetate was added to the reaction flask to adjust the pH to 4.0. A solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of tetrahydrofuran was added to the second dosing dropping funnel. The ethyl chloroformate solutions and potassium acetate were added dropwise simultaneously with the addition rate adjusted so as to maintain the reaction solution at pH 4.0 0.1 and with cooling required to maintain the temperature at 25 ° C. After the chloroformate addition was complete, the contents of the flask were stirred for 1 hour while the potassium acetate solution was added to maintain the pH at 4.0. The organic solvents were removed by distillation under reduced pressure. The residual aqueous solution was washed with 1500 mL of ethyl acetate to remove the biscarbamate impurities. The ethyl acetate wash was extracted with two

500 ml portions of 1 M hydrochloric acid each to recover the desired product. The acid extracts were combined with the initial aqueous solution and the pH was adjusted to 11 by the addition of 10 M sodium hydroxide while cooling. To keep the temperature below 40 ° C. The aqueous solution was extracted with two 1500 mL portions of ethyl acetate, the combined extracts were dried over magnesium sulfate and the solvent was removed to yield 927 g (74%) of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl bromide (328 ml, 3.80 mol) and sodium carbonate (440 g, 4.15 mol) in 2500 ml acetonitrile heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The residue was dissolved in 4000 ml of dichloromethane and washed with two 500 ml portions of 1M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) to a 87% solution of granular potassium hydroxide (2970 g, 46 mol) in 4300 ml 95% ethanol and refluxed at within 1.5 hours. Evolution of carbon dioxide was found during the first period (0.5 to 1 hour) of heating. The reaction mixture was cooled below the reflux temperature and 2000 ml of toluene was carefully added. The ethanol was removed by azeotropic distillation at 105 ° C while a further 4000 ml of toluene was added during this distillation to the reaction flask. After 9,000 mL of distillate was collected, the reaction mixture was cooled to 100 ° C and 1,000 mL of toluene was carefully added. The solution was slowly cooled to 5 ° C and held at that temperature for 30 minutes. The solution was filtered, the filter cake was washed with additional 1500 ml of toluene. The filtrate was then washed with 1000 ml of water, dried over magnesium sulfate and the solvent was removed to give 296 g (69%) of the trans-1-allyl-2,5-dimethylpiperazine as a dark liquid.

3-Bromophenoxy-tert-butyldimethylsilane (30.2 g, 0.105 mol), prepared as in Example 1, was dissolved in 300 ml of dry tetrahydrofuran under a nitrogen blanket and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (66 ml, 0.105 mol) was added dropwise at such a rate as to keep the temperature below -65 ° C. The mixture was stirred for 30 minutes after the addition was complete and the cold solution was transferred to a second vessel containing the solution at room temperature. megnesium bromide (20.2 g, 0.11 mol) in 400 mL of dry tetrahydrofuran under nitrogen blanket. The resulting solution was allowed to warm to 15 ° C while stirring. After 1 hour, a solution of 4-bromo-2-thiophenecarboxyidehydrate (20.0 g, 0.105 mol) in 100 ml of dry tetrahydrofuran was slowly added at such a rate as to keep the temperature below 25 ° C. The resulting solution was stirred for 3 hours at room temperature, then washed three times with aqueous ammonium chloride, dried over sodium sulfate and evaporated to yield a yellow oil. Chromatography on silica gel using dichloromethane: hexane / 50:50 gave 20.23 g (48.2%) of the alcohol α- (4-bromo-2-thienyl) -3 - ((tert-butyldimethylsilyl) oxy) benzyl as a viscous yellow oil.

Thionyl chloride (19.5 mL, 0.27 mol) was added to a solution of the alcohol (71.3 g, 0.18 mol) in 600 mL of dichloromethane. After stirring for 16 hours, the solvent was evaporated, the residue was redissolved in toluene and evaporated again to remove excess thionyl chloride.

A mixture of the crude diarylchloromethane (about 0.18 mol), N-allyl-trans-2,5-dimethylpiperazine and 1000 ml of acetonitrile was refluxed under nitrogen for 40 hours. The solution was cooled to room temperature, filtered and evaporated. The residue was partitioned between diethyl ether and 0.1 M aqueous sodium hydroxide. The ether layer was washed three times with 0.1 M aqueous sodium hydroxide, dried over potassium carbonate and evaporated to give 145 g of a black oil. Chromatography on silica gel with ethyl acetate removed the excess of N-allyl-trans-2,5-dimethylpiperazine, yielding 86 g of a black oil which was purified by chromatography on silica gel with dichloromethane: ethyl acetate / 95: 5, yielding 63.1 g ( 66%) of dark oil.

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A mixture of the product (63.1 g, 0.118 mol), tetraethylammonium fluoride hydrate (37 g, about 0.2 mol) and 100 ml of acetonitrile was stirred at room temperature under nitrogen blanket for 1 hour. The solvent was removed by evaporation, the residue was dissolved in dichloromethane, washed three times with water (adjusted to pH 8 with 1M aqueous sodium hydroxide), dried over sodium sulfate and evaporated to a yellow-brown solid. The two diastereoisomers of the product were separated by chromatography on silica gel using a 75:25 mixture of dichloromethane: ethyl acetate. Elution of the first isomer gave 15.84 g (32%) (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (4-bromo 2-thienyl) methyl) phenol. 1 H-NMR (300 MHz, DMSO-d 6): δ 0.93 (d, J = 6.0 Hz, 3H); 1.09 (d, J = 6.3 Hz, 3H); 2.00 (m, 2H); 2.40 (m, 2H); 2.65-2.90 (m, 3H); 3.30 (m, 1H); 5.14 (m, 2H); 5.44 (s. 1H); 5.80 (m, 1H); 6.65-6.81 (m, 3H); 7.05 (s. 1H); 7.12 (t, J = 8.0 Hz, 1H); 7.66 (s. 1H); 9.35 (s, 1H). A 500 mg portion was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.6 with ethanolic hydrochloric acid. The solvent was removed by evaporation and the salt was dissolved in dichloromethane and then precipitated with diethyl ether to give 300 mg (55%) of a white solid, mp 128-132 ° C. Calculated for C ₂ oH _{25 BrN 2} OS HCl 0.25 H ₂ O: C, 51.96; H, 5.78; N, 6.06; Br 17.28; Cl, 7.67; S, 6.93. Found C, 51.94; H, 5.80; N, 6.04; total halogen, calculated as chlorine, 15.33; S, 7.02.

Example XIX. (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thienyl) methyl) phenol

A mixture of (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) - (4-bromo-2-thienyl) methyl) phenol (example XVUI 4.0 g, 9.5 mmol), tert-butyldimethylsilyl chloride (1.66 g, 11.0 mmol) and imidazole (1.63 g, 24.0 mmol) were dissolved in 20 ml dry dimethylformamide under nitrogen blanket and stirred for 72 hours at room temperature. The mixture was diluted with 200 ml of ethyl acetate, washed three times with 0.1 M aqueous sodium hydroxide and once with water, dried over sodium sulfate and evaporated to give 5.4 g (100%) of a yellow-brown oil.

A solution of the product (5.4 g, 9.5 mmol) in 150 mL of dry tetrahydrofuran under nitrogen blanket was cooled to -70 ° C. A solution of 1.6 M n-butyllithium in hexane (6.4 mL, 10.0 mmol) was added by syringe at a rate that kept the temperature below 60 ° C. The solution was cooled to -78 ° C and carbon dioxide gas was introduced from the cannula below the surface of the solution over 15 minutes. The solution was allowed to warm to room temperature while stirring. The solvent was evaporated and the residue was re-dissolved in toluene and evaporated again to remove the butyl bromide. The resulting viscous oil was dissolved in 500 ml of dichloromethane and cooled to 0 ° C under nitrogen blanket. Thionyl chloride (1.0 mL, 14.0 mmol) was added slowly from the syringe. The resulting mixture was stirred for 2 hours at 0 ° C before a solution of diethylamine (5.1 mL, 50 mmol) in 60 mL of dichloromethane was added dropwise. The mixture was stirred for 16 hours at room temperature, washed three times with water, dried over sodium sulfate and evaporated to give an orange-brown oil. Chromatography on silica gel with dichloromethane: ethyl acetate (gradient from 90:10 to 0: 100) gave four products in the order they appeared during elution: 970 mg (21.2%) (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thienyl) methyl) phenol, as tert-butyldimethylsilyl ether; 550 mg (8.7%) (±) -5 ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -2-hydroxybenzyl-3 -bromo-N, N-diethyl-2-thiophenecarboxamide as tert-butyldimethylsilyl ether; 1050 mg (18.9%) (±) -5 - ((aR *) - a - ((2S *, 5R *) - 4-alkyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-2-thiophenecarboxamide as tert-butyldimethylsilyl ether; and 880 mg (15.8 g) (±) -5 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-3-thiophenecarboxamide as tert- ether butyldimethylsilyl.

The first eluting substance, (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thienyl) methyl) phenol as tert- of butyldimethylsilyl (1.06 g, 2.32 mmol) was combined with tetraethylammonium fluoride hydrate (750 mg, about 4 mmol) and 100 ml of acetonitrile and stirred for 16 hours at room temperature under the cover.

179,341 nitrogen. The solvent was removed by evaporation and the residue was dissolved in dichloromethane, washed three times with a pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glass. Chromatography on silica gel with a mixture of dichloromethane: acetonitrile / 2: 1 gave 610 mg (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1). -piperazinyl) (2-thienyl) methyl) phenol as a white solid. 1-NMR (300 MHz, DMSO-d ₆ ): δ 0.92 (d, J = 5.9 Hz, 3H); 1.10 (d, J = 5.8 Hz, 3H); 2.02 (q, 2H); 2.40 (m, 2H); 2.74 (m, 2H); 2.85 (m, 1H); 3.30 (m, 1H); 5.14 (m, 2H); 5.48 (s, IH); 5.80 (m, 1H); 6.60 (d, J = 7.8 Hz, IH); 6.79 (d, J = 7.8 Hz, IH); 6.85 (s, IH); 7.0-7.2 (m, 3H); 7.52 (d, J = 4.9 Hz, IH); 9.31 (s, IH). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.7 with ethanolic hydrochloric acid. The solvent was removed by evaporation and the salt was dissolved in dichloromethane then precipitated with diethyl ether to give 500 mg (56%) of a white solid, mp 115-121 ° C. Calculated for C20H26N2OS HCl 0.4 H ₂ O: C, 62.21; H, 7.26; N, 7.25; Cl, 9.18; S, 8.30. Found C, 62.21; H, 7.21; N, 7.23; Cl, 9.19; S, 8.22.

Example XX. (±) -5 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 2-hydroxybenzyl) -3-bromo-N, N- diethyl-2-thiophenecarboxamide

Method A

The second material eluted from the column in Example 19 (620 mg, 0.98 mmol) was deprotected with tetraethylammonium fluoride hydrate as in Example 19. Chromatography on silica gel with dichloromethane: acetonitrile / 1: 1 gave 280 mg of a colorless glass. H-NMR (300 MHz, DMSO-d ₆ ): δ 0.93 (d, J = 5.8 Hz, 3H); 1.13 (m, 9H); 1.90-2.20 (m, 2H); 2.40 (m, 2H); 2.65-3.00 (m, 3H); 3.30 (m, 5H); 5.14 (m, 2H); 5.47 (s, IH); 5.80 (m, 1H); 6.65 (d, J = 7.8 Hz, IH); 6.80 (d, J = 7.8 Hz, IH); 6.83 (s, Jul; 7.06 (s, IH); 7.14 (t, J = 7.8 Hz, IH); 9.41 (s, IH) The amine was dissolved in ethanol and converted to salt , monohydrochloride was titrated to pH 3.6 with ethanolic hydrochloric acid The solvent was removed by evaporation and the salt was dissolved in dichloromethane and then precipitated with diethyl ether to give 150 mg (27%) of a white solid, mp 114-124 ° C. Calculated for C ₂ 5H34BrN3O ₂ S HCl: C, 53.91; H, 6.33; N, 7.55; Br, 14.35; Cl, 6.37; S, 5.76 Marked: C, 53.80 ; H, 6.38; N, 7.59; total halogen based on chlorine, 12.72; S, 5.71.

Method B

A mixture of (±) -3 - ((R *) - ((2S *, 5R *) - 4-alkyl-2,5-dimethyl-1-piperazinyl- (4-bromo-2-thienyl) methyl) phenol (7.7 g, 0.0183 mol), Example 18), tert-butyldimethylsilyl chloride (3.17 g, 0.021 mol), imidazole (3.13 g, 0.046 mol) and 50 ml of dry dimethylformamide were stirred at room temperature under a nitrogen blanket for a 16 hours. The solution was diluted with 500 ml of ethyl acetate, washed three times with 0.1 N NaOH, dried over sodium sulfate and evaporated to give 10.3 g (105%) of crude tert-butyldimethylsilyl ether (±) -3 - ((R *) - (( 2S *, 5R * plallyl-2,5-dimethyl-1-piperazinyl) (4-bromo-2-thienyl) methyl) phenol as a dark oil.

A solution of the product (2.2 g, 4.1 mol) in 250 ml of dry tetrahydrofuran under a nitrogen blanket was cooled to -78 ° C. A solution of 1.5 M lithium diisopropylamide in cyclohexane (2.8 mL, 4.1 mmol) was added via the syringe at a rate to keep the temperature below -70 ° C. The resulting solution was stirred for 1 hour at -78 ° C, then carbon dioxide gas was introduced below the surface of the solution via a cannula for 10 minutes. The solution reached room temperature while stirring. The solvent was evaporated and the residue was redissolved in toluene and evaporated again. The resulting viscous oil was dissolved in 250 ml of dichloromethane and stirred at room temperature under a blanket of nitrogen. Thionyl chloride (0.42 mL, 5.75 mmol) was added and the resulting mixture was stirred for 1 hour before adding diethylamine (2.1 mL, 20.6 mmol). The mixture was stirred for 16 hours at room temperature, washed three times with water, dried over sodium sulfate and evaporated to a dark oil. Chromatography on silica gel with diochloromethane: ethyl acetate / 9: 1 gave 1.57 g (60%) of tert-butyldimethylsilyl ether (±) -5 - ((aR *) - a - ((2S *, 5R *) - 4 -allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl) -3-bromo-N, N-diethyl-2-thiophenecarboxamide.

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The product was deprotected using tetraethylammonium fluoride hydrate as in Example 19. Chromatography using ethyl dichloromethamacetate / 1: 1 gave 940 mg of (±) -5 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) ) -3-hydroxybenzyl) -3-bromo-N, N-diethyl-2-thiophenecarboxamide as light yellow brown foam. Ή-NMR (300 MHz, DMSO-cU): δ 0.91 (d, J = 6.0 Hz, 3H); 1.10 (m, 9H); 1.90-2.20 (m, 2H); 2.40 (m, 2H); 2.65-3.00 (m, 3H); 3.30 (m, 5H); 5.13 (m, 2H); 5.47 (s. 1H); 5.76 (m, 1H); 6.63 (d, J = 8.1 Hz, 1H); 6.78 (d, J = 7.8 Hz, 1H); 6.82 (s. 1H); 7.04 (s. 1H); 7.13 (t, J = 7.8 Hz, 1H); 9.38 (s. 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.7 with ethanolic hydrochloric acid. The solvent was removed and the salt was dissolved in dichloromethane and then precipitated with diethyl ether to give 780 mg (57%) of a white solid, mp 147-150 ° C. Calcd for C25H ₃ 4BrN ₃ O2S HC1: C, 53.91; H, 6.33; N, 7.55; Br, 14.35; Cl, 6.37; S, 5.76. Found C, 53.82; H, 6.30; N, 7.50; total halogen based on chlorine, 12.72; S, 5.71.

Example XXI. (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 4-methylsulfonyl) benzyl) phenol

A solution of 3-hydroxybenzaldehyde (183.6 g, 1.50 mol), tert-butylchlorodimethylsilane (227.6 g, 1.50 mol) and imidazole (255.4 g, 3.75 mol) in 700 ml of dimethylformamide was stirred overnight. in room temperature. The reaction solution was poured into 1700 ml of water and extracted with three 350 ml portions of diethyl ether. The combined ether extracts were washed with two 350 mL portions of 1.0 M sodium hydroxide, 350 mL of water and 350 mL of saturated aqueous sodium chloride. The ether solution was dried over sodium sulfate and the solvent was removed to give 268 g (76%) of 3- (tert-butyldimethylsilyloxy) benzaldehyde as a yellow oil.

A solution of 4-bromothioanisole (10.0 g, 49.0 mmol) in 60 ml of anhydrous tetrahydrofuran was cooled to -78 ° C under nitrogen blanket and 32 ml (49 mmol) of 1.55 M n-butyllithium in hexane was added dropwise at this rate. to keep the temperature below -60 ° C. The mixture was stirred for an additional 15 minutes after the addition was complete, and a solution of crude 3- (tert-butyldimethylsilyloxy) benzaldehyde (11.6 g, 49 mmol) in 50 mL of dry tetrahydrofuran was added dropwise over 20 minutes. Stir for an additional 30 minutes and quench the reaction at -78 ° C with saturated aqueous ammonium chloride. After warming to room temperature, it was diluted with 200 ml of diethyl ether and washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride. After drying over sodium sulfate, the solvent was removed to yield 17.5 g (99%) of crude (4-methylthiophenyl) (3-tert-butyldimethylsilyloxyphenyl) methanol as an orange oil.

A solution of the alcohol (16.97 g) in 100 ml of dichloromethane was stirred at room temperature while a solution of m-chloroperbenzoic acid (28.74 g, 141 mmol) in 400 ml of dichloromethane was added dropwise. After stirring for 1 hour, the reaction mixture was filtered. The filtrate was washed with 200 ml of 1.0 M sodium bisulfite and three 200 ml portions of 1.0 M sodium hydroxide and dried over sodium sulfate. After evaporation of the solvent, 8.76 g of crude (4-methylsulfonylphenyl) (tert-butyldimethylsilyloxyphenyl) methanol was obtained as a yellow oil.

The alcohol was then treated with thionyl chloride, trans-2,5-dimethylpiperazine, and allyl bromide following the procedure described in Example 1 to give 1.68 g of crude (±) -trans-4-alkyl-1- (ct) -3 -tert- butyldimethylsilyloxyphenyl) -4-methylsulfonylbenzyl) 2,5-dimethylpiperazine as a mixture of diastereoisomers. The isomers were separated by chromatography on silica gel (Watres Prep 500A) with 0 - 0.75% ethanol in dichloromethane containing 0.1% triethylamine. The first eluted isomer (0.68 g) was deprotected by dissolving in 10 ml of tetrahydrofuran containing 2.0 ml of a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The solvent was removed and the residue was purified by chromatography on silica gel with 2.5% methanol in dichloromethane to yield (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2.5 -dimethyl-1-piperazinyl) -4 (methylsulfonyl) benzyl) phenol. ¹ H-NMR (300 MHz, DMSO-ds): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.8 (dd, J = 5 Hz. Ti = 9 Hz, 1H); 2.1 (dd, you = 5 Hz, J ₂ = 9 Hz, 1H); 2.2-2.4 (m, 3H); 2.7 (dd, you = 3 Hz, J ₂ = 11 Hz, 1H); 2.85 (dd, Jj = 6 Hz, J ₂ = 11 Hz, 1H);

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3.1 (m, 1H); 7.6 and 7.85 (ABq, J = 8Hz, 4H). The product was dissolved in ethanol and converted to its dihydrochloride salt with excess ethanolic hydrochloric acid. The salt was precipitated with diethyl ether and then hexane to afford the salt as a hygroscopic white powder. Calcd for C 3 H ₃ oN ₂ 0 ₃ S ₂ 2HC1 0.5 H ₂ O: C, 55.64; H, 6.70; N, 5.64. Found C, 55.70; H, 6.97; N, 5.50. Mass spectrum (EI): (m / e) 414 (M +, 1.0%); 261 (18%); 153 (100%).

Example ΧΧΠ. (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide.

A 25% aqueous solution of dimethylamine (420 mL, 2.3 mol) was diluted with 1000 mL of tetrahydrofuran and added dropwise to a solution of p-bromobenzenesulfonyl chloride (200 g, 0.78 mol) in 700 mL of tetrahydrofuran. The mixture was diluted with diethyl ether, and the organic layer was washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. After evaporation of the solvent, 195.4 g (95%) of 4-bromo-N, N-dimethylbenzenesulfonamide as white crystals were obtained, mp 90-92 ° C (according to literature 94 ° C, J.Am.Chem. Soc. 45.2696 (1923)).

The sulfamide (97.45 g, 0.37 mol) was then treated with n-butyllithium and 3- (tert-butyldimethylsilyloxy) benzaldehyde as described in Example 21, and the product was purified by chromatography on silica gel using hexane: ethyl acetate to afford 89. 5 g (57%) 4- (3-tert-butyldimethylsilyloxy) -a-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide as a yellow oil which crystallized on storage. A portion was recrystallized from ethanol: water to give white crystals, mp 100-103 ° C. NMR (CDCl ₃ , 60 MHz): 0.1 (s, 6H); 0.9 (s, 9H); 2.6 (s, 6H); 3.5 (br s, 1H); 5.7 (s. 1H); 6.5-7.7 (m, 8H).

Alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4- (3-tert-butyldimethylsilyloxy) -a-chlorobenzyl) -N, N-dimethylbenzenesulfonamide in the form of brown oil. Crude benzhydryl chloride (93.7 g, 0.21 mol) was mixed with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 ml of dimethylformamide and heated at 140 ° C for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1 M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel chromatography with dichloromethane: methanol to give 28.9 g (27%) of trans-4- (α- (2,5-dimethyl-1-piperazinyl) -3- (tert-butyldimethylsilyloxy) ) benzyl) -N, N-dimethylbenzenesulfonamide as a brown oil.

Benzhydryl piperazine was treated with allyl bromide as in Example 1 and purified by silica gel chromatography (Waters Prep 500) with 0.3-0.5% ethanol dichloromethane containing 0.1% triethylamine to give 17.34 g of a light brown glassy substance. The product was treated with tetrabutylammonium fluoride as in Example 21. The two product stereoisomers were separated by silica gel chromatography (Waters Prep 500) with 0.3-3.0% ethanol in dichloromethane containing 0.1% triethylamine. Elution of the more mobile isomer gave 4.94 g (36%) (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3 -hydroxybenzyl) -N, N-dimethylbenzenesulfonamide as a white solid, mp 205-207 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.05 (d, J = 6 Hz, 3H); 1.2 (d, J = 6Hz, 3H); 1.9 (br m, 1H); 2.2 (br m, 1H); 2.5-2.75 (m, 3H); 2.7 (s, 6H); 2.85 (dd, Jj = 9 Hz, J ₂ = 10 Hz, 1H); 2.95 (br m, 1H); 3.35 (br m, 1H); 5.15-5.3 (m, 3H); 5.9 (m, 1H); 6.7 (dd, J = 8 Hz, J ₂ = 2 Hz, 1H); 6.85 (d, J = 8 Hz, 1H); 6.9 (s. 1H); 7.15 (t, J = 8 Hz, 1H); 7.4 and 7.75 (ABq, J = 9Hz, 4H). Mass spectrum (CI-CH4) m / e 444 (M + 1.100%); 292 (15%); 153 (52%). The product was treated with excess ethanolic hydrochloric acid and the salt, dihydrochloride, diethyl ether and hexane precipitated to yield 3.19 g (66%) of a hygroscopic white powder. Calculated for C ₂₄ H ₃₃ N ₃ O ₃ S 2HCl 1.5H ₂ O: C, 53.03; H, 7.05; N, 7.73; S, 5.90; Cl, 13.04. Found C, 53.09; H, 7.07; N, 7.73; S, 5.94; Cl, 13.11. ,

Example XXIII. (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-Allyl-2,5-dimethyl-l-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzenesulflonamide

The procedure of Example 11 was followed, starting with 4-bromobenzenesulfonyl chloride and diethylamine. The final mixture of diastereoisomers was separated by method

179,341 chromatography in a similar manner. Elution of the more mobile isomer gave a light brown glassy material. 1 H-NMR (300 MHz, DMSO-d6): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.05 (t, J = 7Hz, 3H); 1.8 (m, 1H); 2.1 (m, 1H); 2.4-2.6 (m, 6H); 2.7 (m, 1H); 2.9 (m, 1H); 3.1 (q, J = 7Hz, 4H); 3.1 (m, 1H); 5.0-5.2 (m, 3H); 5.8 (m, 1H); 6.6 (d, J = 8 Hz, 1H); 6.75 (d, J = 8 Hz, 1H); 6.8 (s. 1H); 7.05 (t, J = 8 Hz, 1H); 7.5 and 7.75 (ABq, J = 8Hz, 4H). The dihydrochloride salt was obtained as a hygroscopic solid. Calcd for C26H37N3O3S 2HC1H ₂ O: C, 55.51; H, 7.35; N, 7.47, S, 5.70; Cl, 12.60. Found C, 55.42; H, 7.41; N, 7.39; S, 5.73; Cl, 12.73. Mass spectrum (EI) m / e: 471 (Μζ 1.03%); 318 (9.2%); 153 (100%).

Example XXIV. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzenesulflonamide

Elution of the less mobile isomer from the chromatography of example ΧΧΠΙ gave a light brown glassy material. 1-NMR (300 MHz, CDCl 3): δ 1.05 (d, J = 6 Hz, 3H); 1.15 (t, J = 7Hz, 3H); 1.2 (d, J = 6Hz, 3H); 1.9 (dd, Jj = 10 Hz, J ₂ = 12 Hz, 1H); 2.35 (dd, J = 10 Hz, J ₂ = 12 Hz, 1H); 2.5 (m, 2H); 2.65 (m, 1H); 2.9 (dd, J = 9 Hz, J ₂ = 12 Hz, 2H); 3.25 (q, J = 7 Hz, 4H); 3.45 (m, 1H); 5.15-5.3 (m, 3H); 5.9 (m, 1H); 6.55 (d, J = 8 Hz, 1H); 6.55 (s. 1H); 6.6 (d, J - 8Hz, 1H); 7.15 (t, J = 8 Hz, 1H); 7.55 and 7.7 (ABq, J = 8Hz, 4H). The dihydrochloride salt was obtained as a hygroscopic white solid. Calcd for C26H37N3O3S 2HC1H ₂ O: C, 55.51; H, 7.35; N, 7.47, S, 5.70; Cl, 12.60. Found C, 55.48; H, 7.45; N, 7.39; S, 5.77; Cl, 12.56. Mass spectrum (EI) m / e 471.

Example XXV. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3- (hydroxybenzyl) -N-ethyl-N- (hydroxyethyl) benzamide

The compound was synthesized by the method of Example 6, method A, using N- (2-hydroxyethyl jethylamine to form the amide. 1 H-NMR (200 MHz, DMSO-d 6): δ 0.96 (d, J - 6 Hz, 3H); 1, 0-1.2 (br m, 3H), 1.09 (d, J = 6 Hz, 3H), 1.85 (dd, J = 7.6 Hz, J ₂ = 11.4 Hz, 1H); 2.10 (dd, J = 7.4 Hz, J ₂ = 10.4 Hz, 1H); 2,52-2,6 (br m, 3H), 2.74 (d, J = 11 Hz, 1H ); 2.86 (dd, Ji = 7 Hz, J ₂ = 14 Hz, 1H); 3.18 (dd, Ji = 5 Hz, J ₂ = 15 Hz, 1H); 3.1-3.7 ( br m, 6H); 4.78 (t, J = 5 Hz, 1H); 5.00 (s, 1H); 5.11 (d, J - 10 Hz, 1H): 5.18 (d, J = 17 Hz, 1H); 5.8 (m, 1H); 6.88 (d, J = 8 Hz, 1H); 6.70 (s, 1H); 6.72 (d, J = 17 Hz, 1H ); 7.16 (t, J = 8 Hz, 1H); 7.31 and 7.43 (ABq, J = 8 Hz, 4H) The product was dissolved in ethanol and titrated to pH 3.8 with ethanolic hydrochloric acid to give the salt monohydrochloride. Calculated for ^ 7 ^ 7X303 HC1 1,25H ₂ O: C, 63.51; H, 7.99; N, 8.23; Cl, 6.94. Found: C, 63.62; H, 8.02; N, 8.09; Cl, 7.01.

Example XXVI. (±) -3 - ((R * or S *) - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-l-piperazinyl) (2-thiazolyl) methyl) phenol

A solution of 1.6 M n-butyllithium in hexane (206 mL, 0.33 mol) was cooled to -45 ° C under nitrogen blanket. A suspension of 2-bromothiazole (50 g, 0.30 mol) in 75 ml of diethyl ether was added portionwise while maintaining the temperature between -35 ° C and -45 ° C. The resulting dark brown solution was stirred for an additional 15 minutes before the addition of 3- (tert-butyldimethylsilyloxybenzaldehyde (70.9 g, 0.30 mol, Example 21 below) dropwise from a syringe at a rate such as to maintain the temperature between -25 ° C and -35 ° C. then poured onto a mixture of 1 liter of ice with 600 ml of 1 M HCl. The organic phase was dried over sodium sulfate and evaporated to give a brown oil. By chromatography on silica gel with hexane: ethyl acetate (gradient from 90:10 to 80:20) yielded 25.5 g (26.4%) of α- (2-thiazolyl) -3 - ((tert-butyldimethylsilyl) oxy) benzyl alcohol as a sticky yellow oil.

Thionyl chloride (0.33 mL, 4.58 mmol) was added to a solution of the alcohol (1.0 g, 3.27 mmol) in 50 mL of dichloromethane. After stirring for 16 hours, the solvent was evaporated, the residue was redissolved in toluene and evaporated again to drive off the excess thionyl chloride.

A mixture of the crude diarylchloromethane (about 3.27 mmol), N-allyl-trans-2,5-dimethylpiperazine (1.26 m, 8.2 mmol, Example 18) and 50 ml of acetonitrile was refluxed under nitrogen for 16 hours. The solution was evaporated and the residue was partitioned between ethyl acetate and 0.1 M aqueous sodium hydroxide. The organic layer was washed twice with 0.1 M aqueous sodium hydroxide, and once with water, dried over

Sodium sulfate and evaporated to give 1.1 g of a reddish brown oil. Chromatography on silica gel with hexane: ethyl acetate (gradient from 80:20 to 50:50) gave two products in the order of elution: 300 mg (20.0%) tert-butyldimethylsilyl ether (±) -3 ((R * or S * H (2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thiazolyl) methyl) phenol and 280 mg (18.7%) tert-butyldimethylsilyl ether (±) -3 - ((S * or R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-piperazinyl) (2-thiazolyl) methyl) phenol.

The first eluting substance, tert-butyldimethylsilyl ether (±) -3 - ((R * or S *) ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thiazolyl) methyl) phenol (2.65 g, 5.79 mmol) was mixed with tetraethylammonium fluoride hydrate (1.86 g, about 9.8 mmol) and 200 ml of acetonitrile and stirred at room temperature for 16 hours under a nitrogen blanket. The solvent was evaporated and the residue was dissolved in dichloromethane, washed three times with a pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glassy material. Chromatography on silica gel with a mixture of dichloromethane: methanol 95: 5 gave 620 mg (±) -3 - ((R * or S *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1- piperazinyl) (2-thiazolyl) methyl) phenol as a yellow-brown solid. H-NMR (300 MHz, DMSO-d /: δ 0.88 (d, J = 5.9 Hz, 3H); 1.17 (d, J = 6.0 Hz, 3H); 1.65 (m , 1H); 2.00 (m, 1H); 2.40 (m, 1H); 2.60 (m, 2H); 2.78 (m, 2H); 3.25 (m, 1H); 5 . 13 (m, 2H); 5.36 (s, 1H); 5.80 (m, 1H); 6.69 (m, 3H); 7.15 (t, J = 7.8 Hz, 1H) ; 7.63 (d, J = 3.2, 1H); 7.69 (d, J = 3.3 Hz, 1H); 9.34 (s, 1H) The amine was dissolved in ethanol and converted to salt, monohydrochloride was titrated to pH 3.7 with ethanolic hydrochloric acid The solvent was evaporated and the salt was dissolved in a mixture of dichloromethane / ethanol then precipitated with diethyl ether to give 400 mg of a yellow brown solid, mp 127-130 ° C. Calculated for C19H25N3OS HCl 0. 25H ₂ O: C, 59.36; H, 6.95; N, 10.93; Cl, 9.22: S, 8.34 Found C, 59.23; H, 6.97; N, 10.81; Cl, 9.17; S, 8.28.

Example XXVII. (±) -3 - ((S * or R *) - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-l-piperazinyl) (2-thiazolyl) methylphenol

Second eluting material from the column in Example XXVI, (±) -3 - ((S * or R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thiazolyl) methyl) phenol tert-butyldimethylsilyl ether mixed with tetraethylammonium fluoride hydrate (860 mg, about 4.5 mmol) and 250 ml of acetonitrile and stirred at room temperature for 16 hours under a nitrogen blanket. The solvent was evaporated and the residue was dissolved in dichloromethane, washed three times with a pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glassy material. Chromatography on silica gel using a mixture of dichloromethane: methanol / 94: 6 gave 480 mg (±) -3 - ((S * or R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethyl -1-piperazinyl) (2-thiazolyl) methyl) phenol as a yellow-brown solid. H-NMR (300 MHz, DMSOd6): δ 0.90 (d, J = 5.8 Hz, 3H); 1.11 (d, J = 6.1 Hz, 3H); 2.00 (m, 1H); 2.14 (m, 1H); 2.38 (m, 1H); 2.43 (m, 1H); 2.60 (m, 1H); 2.70 (m, 1H); 2.78 (m, 1H); 3.25 (m, 1H); 5.18 (m, 2H); 5.61 (s. 1H); 5.80 (m, 1H); 6.63 (sd, J = 1.1, 7.8); 6.71 (d, J = 7.8, 1H); 7.10 (t, J = 7.9 Hz, 1H); 7.74 (d, J = 3.2, 1H); 7.87 (d, J = 3.3 Hz, 1H); 9.34 (s. 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.7 with ethanolic hydrochloric acid. The solvent was evaporated and the salt was dissolved in a mixture of dichloromethane / ethanol and then precipitated with diethyl ether to give 150 mg of a tan solid, mp 124-128 ° C. Calcd for C ₉ H ₂₅ N HC1 ₃ = S 0.25H ₂ O: C, 59.36; H, 6.95; N, 10.93; Cl, 9.22: S, 8.34. Found C, 59.21; H, 6.98; N, 10.85; Cl, 9.18; S, 8.28.

Example XXVIII. (±) -3 - ((R *) - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-l-piperazinyl) (3-thienyl) methyl) phenol

3-Bromophenoxy-tert-butyldimethylsilane (57.5 g, 0.20 mol, Example 1 above) was dissolved in 300 ml of dry tetrahydrofuran under a nitrogen blanket and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (125 mL, 0.20 mol) was added dropwise at such a rate to keep the temperature below -70 ° C. The mixture was stirred for 30 minutes after completion of the dropwise addition, and the cold solution was transferred to a second vessel containing a -40 ° C solution of magnesium bromide (37.8 g, 0.205 mol) in 600 ml of dry tetrahydrofuran under nitrogen blanket. The resulting solution was stirred and allowed to warm to -15 ° C. After 1 hour, a solution of thiophene-3-carboxaldehyde (22.4 g,

179 341

0.20 mol) in 200 ml of dry tetrahydrofuran at such a rate as to keep the temperature below 25 ° C. The resulting solution was stirred for 30 minutes at room temperature, then washed twice with aqueous ammonium chloride, dried over sodium sulfate and evaporated to yield a brown oil. Chromatography on silica gel using hexane: dichloromethane (3: 1 to 1: 1 gradient) gave 44.1 g (69%) of the 3 - ((tert-butyldimethylsilyl) oxy) - (3-thienyl) benzyl alcohol in the form of a sticky yellow oil.

To a solution of the alcohol (23.8 g, 0.074 mol) in 400 ml of dichloromethane was added thionyl chloride (7.6 ml, 0.104 mol). After stirring for 3 hours, the solvent was evaporated and the residue was re-dissolved in toluene and evaporated again to drive off the excess thionyl chloride.

A mixture of the crude diarylchloromethane (about 0.074 mol), N-allyl-trans-2,5-dimethylpiperazine (Example 18 above, 28.5 g, 0.185 mol,) and 400 ml of acetonitrile was refluxed under nitrogen for 24 hours. The solution was cooled to room temperature and evaporated. The residue was redissolved in dichloromethane and washed three times with a pH 8 aqueous buffer solution, dried over sodium sulfate and evaporated to a dark oil. The product was purified by chromatography on silica gel with 98: 2 dichloromethane: ethyl acetate to give two isomers.

The first isomer eluted was (±) -3 - ((R *) ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (3-thienyl) methyl) phenol tert-butyldimethylsilyl ether (12.27 g, 36%). Part of it was deprotected (3.1 g, 6.79 mol) with tetraethylammonium fluoride hydrate as in Example 19. Chromatography on silica gel using a mixture of dichloromethane: ethyl acetate / 3: 1 gave 1.6 g of (±) -3 - ((R *) - ((2S *, 5R *) - 4-allyl-2,5-dimethylol) -oiperazinyl) (3-thienyl) methyl) phenol in the form of a yellow foam. Ή-NMR (300 MHz, DMSO d from ₆ ): δ 0.91 (d, J = 6.2 Hz, 3H); 1.08 (d, J = 6.2 Hz, 3H); 1.79 (m, 1H); 2.00 (m, 1H); 2.45 (m, 1H); 2.62 (m, 2H); 2.80 (m, 1H); 3.21 (m, 1H); 3.32 (d, J = 7.0 Hz, 1H); 5.14 (m, 2H); 5.80 (m, 1H); 6.68 (m, 3H); 6.98 (d, J = 5.0 Hz, 1H); 7.15 (m, 2H); 7.45 (dd. J, = 4.9 Hz, J ₂ = 3.0 Hz, 1H); 9.31 (s, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.5 with ethanolic hydrochloric acid. The solvent was evaporated and the salt was dissolved in dichloromethane and then precipitated with diethyl ether, yielding 1.3 g (50%) of an off-white solid, mp 140-142 ° C. Calculated for C20H26N2OS HCl 0.25H2O: Calculated C, 62.65; H, 7.23; N, 7.31; Cl, 9.25; S, 8.36. Found C, 62.49; H, 7.27; N, 7.33; Cl, 9.25; S, 8.32.

Example XXIX. (-) - 3 - ((R - ((2S, 5R) -4-Allyl-2,5-dimethyl-1-piperazinyl) (4-bromo-2-thienyl) methyl) phenol

A solution of 6.33 g (16.4 mol) of (+) - p-ditoluoyl-D-vumic acid 15 ml of anhydrous ethanol was added to the suspension 3.46 g of (±) -3 - ((R *) - ((2S * , 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) (4-bromo-2-thienyl) methyl) phenol (Example 18) in 10 ml of anhydrous ethanol. The mixture was heated to reflux and then the resulting clear solution was allowed to crystallize at room temperature. After five recrystallizations, the salt was dissolved in 20 ml of IN aqueous sodium hydroxide and the solution was titrated to pH 8 with 6N hydrochloric acid. The precipitated amine was separated by filtration and recrystallized from anhydrous ethanol to give 0.50 g (15% of theoretical value for one enantiomer) (-) - 3 - ((R - ((2S, 5R) -4alkyl-2,5-dimethyl- l-piperazinyl) (4-bromo-2-thienyl) methyl) phenol as white crystals, mp 183-185 ° C, [a] ²⁰ D = 14.0 ° (tetrahydrofuran, c = 2.1). HPLC β-cyclodextrin using methanol: 0.1 M ammonium acetate / 1: 1 as eluent gave one peak at tR = 8.1 minutes Calculated for C20H25BrN ₂ OS: C, 57.00; H, 5.98; N , 6.65, Br, 18.96, S, 17.61 Found C, 56.90, H, 6.03, N, 6.57, Br, 18.92, S, 7.52.

Example XXX. (-) - 3 - ((R) - ((2S, 5R) -4-Allyl-2,5-dimethyl-1-piperazinyl) (2-thienyl) methyl) phenol

Z (-) - 3 - ((R) - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) (4-bromo-2-thienyl) methyl) phenol (0.53 g , 1.3 mmol, Example XXIX) bromine was removed with n-butyllithium as in Example VH [. The crude product was recrystallized from acetonitrile to give 0.33 g (77%) of (-) - 3 - ((R) - ((2S, 5R) 4-allyl-2,5-dimethyl-1-piperazinyl) (2-thienyl) ) methyl) phenol as beige crystals, mp 176-178 ° C, [a] d = -23.3 ° (ethyl acetate, c = 1.5). HPLC on β-cyclodextrin using

A mixture of methanol: 0.1 M ammonium acetate / 1: 1 as eluent gave one peak at a tR of 8.5 minutes. Calculated for C ₂ oH _{2 6} BrN 2 OS 0.25 H ₂ O: C, 69.23; H, 7.70; N, 8.07; S, 9.24. Found C, 68.86; H, 7.47; N, 8.27; S, 9.06. The product (0.30 g, 0.87 mmol) was treated with ethanolic hydrochloric acid as in Example 18 to yield 0.201 g (61%) of the monohydrochloride salt. Calculated for C ₂ oH _{2 6} BrN 2 OS HCl 0.75 H ₂ O: C, 61 21; H, 7.32; N, 7.12; S, 8.17; Cl, 9.03. Found C, 61.35; H, 7.01; N, 7.30; S, 9.11. [α] ^2σ _ο = -11.9 ° (ethanol, c = 1.05).

Example XXXI. (+) - 3 - ((aS) -a - ((2S, 5R) -4-Allyl-2,5-dimethyl-1-piperazinyl-4-bromobenzyl) phenol

A solution of (+) - di-p-toluoyl-D-tartaric acid (12.72 g, 31.4 mmol) in 100 ml of anhydrous ethanol was added to the suspension of (±) -3 - ((aR *) - a - (( 2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenyl (6.43 g, 15.5 mmol, Example 2) in 150 mL dry ethanol. 30 mL of water was added to the resulting clear solution and the mixture was concentrated to a total volume of 150 mL. After a few days at room temperature, the crystals were collected and recrystallized from 90% aqueous ethanol. The crystalline salt of di-p-toluolio-D-tartrate was dissolved in 1 N aqueous sodium hydroxide and titrated to pH 8 with 6 N hydrochloric acid. The resulting slurry was extracted with dichloromethane, the extracts were dried over sodium sulfate and evaporated to give 0.92 g (28% of theory for one enantiomer) of the free amine as a white solid, mp 209-212 ° C, [a] ² d ⁼ +7 .8 ° (tetrahydrofuran, c = 5). A portion was recrystallized (0.106 g) from anhydrous ethanol to give 25.8 mg of (+) - 3 - ((aS) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) - 4-bromobenzyl) phenol, mp 211-214 ° C. Calculated for C2 ₂ H ₂₇ BrN ₂ O: C, 63.61; H, 6.55; N, 6.74. Found C, 63.53; H, 6.53; N, 6.70. HPLC on β-cyclodextrin using methanol: 0.1 M ammonium acetate / 1: 1 as eluent gave one peak at tR = 8.9 minutes.

Example XXXII. (+> 3 - ((aS) -a - ((2S. 5R) -4-Allyl-2,5-dimethyl-1-piperazinyl) benzyl) phenol

The compound was prepared as in Example 8, starting from (±) -3 - ((aS) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -4-bromobenzyl) phenol ( example XXXI). The product was recrystallized from acetonitrile to give 0.26 g (48%) of (+) - 3 - ((aS) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) benzyl) phenol in beige crystals, mp 192-195 ° C. [a] ² ° D = + 3.7 ° (tetrahydrofuran, c = 3.5). HPLC on β-cyclodextrin with methanol: 0.1 M ammonium acetate / 1: 1 gave one peak at tR = 7.8 minutes. Calculated for C ₂ H ₂₈ N ₂ OO, 1 CH ₃ CN: C, 78.29; H, 8.37; N, 8.64. Found C, 77.98; H, 8.31; N, 8.53.

Example ΧΧΧΠΙ. (±) -3 - ((R *) - ((2R *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-pyridylmethyl) phenol

3-Bromopyridine (50.0 g, 0.316 mol) and 3- (tert-butyldimethylsiloxyloxy) benzaldehyde (74.8 g, 0.316 mol, Example 21 above), each dissolved in 500 ml of anhydrous diethyl ether under nitrogen blanket and cooled to -78 ° C in dry ice / acetone baths. Was added dropwise n-butyllithium (198 ml, 0.316 mol, 1.6 M in hexanes) to a cooled solution of pyridine at such a rate as to maintain _t temperature below -70 ° C. After the addition was complete, the mixture was stirred for 10 minutes. The aldehyde solution was then added via a cannula to the reaction mixture while maintaining the temperature below -70 ° C. The mixture was stirred at -78 ° C for 45 minutes and quenched with aqueous saturated ammonium chloride. The reaction mixture was then allowed to warm to room temperature and washed with water and brine. The ether extracts were dried over sodium sulfate and the solvent was removed to give 98.2 g of crude (3- (tert-butyldimethylsilyloxy) phenyl) (3-pyridyl) methanol. The crude alcohol was dissolved in 300 ml of dichloromethane and cooled in an ice bath. Thionyl chloride (34 mL, 0.74 mol) was dissolved in 30 mL of dichloromethane and added dropwise to the cooled alcohol solution. After stirring for three hours, the solvent was removed to give the salt, hydrochloride, (tert-butyldimethylsilyl) (3- (α-chloro-3-pyridylmethyl) phenyl ether as a tan solid. The crude alkyl chloride (about 0.311 mol) was stirred in 120 ° C. g (0.78 mol) of N-allyl-trans-2,5-dimethylpiperazine (Example 18 above) in 100 ml of acetonitrile and refluxed overnight. After cooling the reaction mixture to room temperature, 62 g (about 0.43) were added. mol) tetraethylammonium fluoride hydrate and stirred for 1 hour The solvent was removed and the product was purified by

Chromatography on silica gel with 0-20% ethanol in dichloromethane. The first isomer eluted was obtained as 14.7 g of a dark oil which crystallized from 100 ml of acetonitrile on storage at room temperature. 3.0 g of (±) -3 - ((R * X (2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-pyridylmethyl) phenol were obtained, mp 115-118 ° C. Calculated for C21H28N3O: C, 74.52; H, 8.34; N, 12.41. Found C, 74.78; H, 8.11; N, 12.47. NMR (200 MHz, DMSO-d 6): δ 0.95 (d, J = 6 Hz, 3H); 1.09 (d, J = 6 Hz, 3H); 1.84 (dd, J = 7.6 Hz, J ₂ = 11.7 Hz, 1H); 2.10 (dd, J = 6.8 Hz, J ₂ = 10.8 Hz, 1H); 2.5-2.8 (m, 4H); 2.86 (dd, L = 7.2 Hz, J ₂ = 14.0 Hz, 1H); 3.18 (dd, J = 5.3 Hz, J ₂ = 14 Hz, 1H); 5.05 (s. 1H); 5.8 (m, 1H); 6.7 (m, 3H); 7.16 (T, J = 7.6 Hz, 1H); 7.34 (dd, J = 4.9 Hz, J ₂ = 8.0 Hz, 1H); 7.75 (d, J = 7.9 Hz, 1H); 8.43 (d, J - 4.6 Hz, 1H); 8.57 (s. 1H); 9.41 (s, 1H).

Example XXXIV. (±) -3 - ((R *) - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-pyridylmethyl) phenol

The second isomer eluted from the column in Example 11 was obtained as an oil in an amount of 6.9 g. The product was crystallized from ethyl acetate to give 2.4 g of a tan solid, mp 158-160 ° C. NMR (200 MHz, DMSO-ds): 0.96 (d, J = 6 Hz, 3H); 1.10 (d, J = 6Hz, 3H); 1.79 (dd, J = 7.2 Hz, J ₂ = 10.6 Hz, 1H); 2.08 (dd, Ji = 7.2 Hz, J ₂ - 11.2 Hz, 1H); 2.3 - 2.75 (m, 4H); 2.85 (dd, J = 7.0 Hz, J ₂ = 13.9 Hz, 1H); 3.18 (dd, J = 5.2 Hz, J ₂ = 13.9 Hz, 1H); 5.08 (s. 1H); 5.10 (d, J = 9.9 Hz, 1H); 5.17 (d, J = 16.2 Hz, 1H); 5.7-5.9 (m, 1H); 7.10 (t, J = 7.8 Hz, 1H); 7.40 (dd, Jj = 4.9 Hz, J ₂ = 7.8 Hz, 1H); 7.66 (d, J = 8 Hz, 1H); 8.50 (d, J = 6 Hz, 1H); 8.52 (s. 1H); 9.32 (s, 1H). The free amine was dissolved in ethanol and converted to the monohydrochloride salt by titration to pH 3.4 with ethanolic hydrochloric acid. The solvent was removed and the residue was re-dissolved in dichloromethane. The salt was precipitated with ether: hexane and collected by filtration to give a white powder. Calculated for C _{2 and} H ₂₇ N ₃ O HCl 0.75 H ₂ O: C, 65.10; H, 7.67; N, 10.85; Cl, 9.15. Found C, 65.12; H, 7.68; N, 10.87; Cl, 9.20.

Example XXXV. (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4- (Cyanomethyl) -2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (± ) -4 - ((aR *) - a - ((2S *, 5R *) - 2,5-Dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (1.0 g, 2, 6 nunoles, Example 14) was mixed with tert-butyldimethylsilyl chloride (0.60 g, 3.9 nunol) and imidazole (0.50 g, 6.5 mmol) in 30 ml dimethylformamide and stirred overnight. The solvent was removed under reduced pressure and the residue was redissolved in dichloromethane (150 ml) and washed with 80 ml of aqueous 1 N sodium hydroxide. The organic layer was dried over sodium sulfate and the solvent was removed to give 0.70 g of the silyl ether.

The silyl ether (0.51 g, 1.0 mmol) was mixed with 2-chloroacetonitrile (0.07 ml, 1.1 mmol, Eastman Kodak, Rochester, NY) and sodium carbonate in anhydrous tetrahydrofuran. The reaction mixture was cooled in an ice bath and sodium iodide (0.16 g, 1.1 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed and the residue was redissolved in dichloromethane and washed with water. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethanol (0-3%) in dichloromethane. The product was dissolved in 20 ml of acetonitrile and stirred with tetraethylammonium fluoride hydrate (0.18 g) for 3 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethanol (0-3%) in dichloromethane. Crystallization of the acetonitrile product gave 37 g of a solid, mp 190-192 ° C. Calculated for C ₂₆ H 34 N ₄ O 4: C, 71.86; H, 7.88; N, 12.89. Found C, 71.83; H, 7.94; N, 12.95. NMR (200 MHz, CDCl 3): δ 0.93 (d, J = 6 Hz, 3H); 1.15 (d, J = 4.7 Hz, 3H); 1.0-1.2 (br m, 6H); 1.79 (t, J = 11Hz, 1H) 2.2-2.4 (m, 5H); 3.2-3.6 (br m, 4H); 3.36 and 3.76 (ABq, J = 17.4 Hz, 2H); 5.15 (s. 1H); 6.55 (s. 1H); 6.57 (d, J = 8.6 Hz, 1H); 6.73 (d, J = 8 Hz, 1H); 7.13 (t, J = 7.6 Hz, 1H); 7.28 and 7.42 (ABq, J = 8.2 Hz, 4H).

Example XXXVI. (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl-N, N-diethylbenzamide

A mixture of 300 g (1.7 mol) 3-bromophenol, 392.1 g (2.6 mol) tert-butylchlorodimethylsilane and 295.1 g (4.3 mol) imidazole in 1N, N-dimethylformamide was stirred at room temperature under with nitrogen blanket for 18 hours. The reaction mixture was poured into the cold

179 341 of water and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give 650 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as a brown oil. NMR (CDCl ₃ , 200 MHz): δ 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).

The silyl ether (155.2 g, 0.54 mol) was dissolved in 600 mL of dry tetrahydrofuran, dried further on molecular sieves, then transferred to a reaction flask and diluted to 1200 mL with dry tetrahydrofuran and cooled to -78 ° C. N-Butyllithium (310 ml of a 1.6 M hexane solution) was added while stirring under nitrogen blanket at a rate that kept the temperature below -70 ° C. Stirring was continued for 45 minutes at -78 ° C. A solution of 3-bromobenzaldehyde (100.0 g, 0.54 mol) in 900 ml of dry tetrahydrofuran was added at such a rate that the temperature was kept below -70 ° C. After stirring for 30 minutes at -78 ° C, the reaction was quenched with 500 mL of saturated aqueous ammonium chloride and allowed to warm to room temperature. The mixture was diluted with water and diethyl ether and the ether layer was washed with brine, dried over sodium sulfate and evaporated to give 216.2 g of a yellow oil. Chromatography on silica gel with hexane: ethyl acetate (4-25%) provided 98.86 g (51%) of the α- (3-bromophenyl) - (3-tert-butyldimethylsiloxy) benzyl alcohol as a yellow oil. NMR (CDCl3, 200 MHz): δ 0.2 (s, 6H); 0.95 (s, 9H); 2.3 (br s, 1H); 5.7 (s. 1H); 6.75 (d, J = 8 Hz, 1H); 6.8 (s. 1H); 6.9 (d, J = 8 Hz, 1H) 7.2 (m, 2H); 7.3 (d, J = 8 Hz, 1H); 7.4 (d, J = 8 Hz, 1H); 7.5 (s, 1H).

Thionyl chloride (27.5 ml, 0.38 mol) was added dropwise to a solution of the above benzhydyl alcohol (98.9 g, 0.25 mol) in 500 ml of dichloromethane and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the residue was re-dissolved in toluene and the solvent was removed again under reduced pressure to remove excess thionyl chloride to yield 154 g of crude α- (3-bromophenyl) 3- (tert-butyldimethylsilyloxy) benzyl chloride as a brown oil. NMR (CDCl 3, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.0 (s. 1H); 6.8-7.0 (m, 3H); 7.2-7.6 (m, 5H).

A mixture of benzhydyl chloride as above (103.5 g, 0.25 mol) and N-allyl-2,5-dimethylpiperazine (96.9 g, 0.63 mol, Example XV1H below) in 50 ml of toluene was refluxed overnight . Acetonitrile (350 mL) and tetraethylammonium fluoride hydrate (75 g, 0.38 mol) were added to the cooled reaction mixture. After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure to yield 344 g of a crude mixture of diastereoisomers as a dark brown oil. Chromatography on silica gel with a mixture of dichloromethane: ethanol (99: 1) gave 31.15 g of a brown solid containing 95% less mobile diastereoisomer (Rf = 0.42) on silica gel with a mixture of dichloromethane: ethanol: anion hydroxide / 95 : 5: 1). As a result of crystallization from isopropanol, 28.6 g (55% of theoretical amount for one diastereoisomer) were obtained (±) - (3) - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2, 5-dimethyl-1-piperazinyl) -3-bromobenzyl) phenol as a white solid, mp 186-189 ° C. NMR (DMSO-dg, 200 MHz) δ: 0.95 (d, J = 6 Hz, 3H); 1.03 (d, J - 6Hz, 3H); 1.8 (dd, Π = 6 Hz, J ₂ = 10 Hz, 1H); 2.1 (dd, J = 6 Hz, J ₂ = 10 Hz, 1H); 2.4-2.6 (m, 3H); 2.7 (d, 11 Hz, 1H); 2.8 (dd, J = 7 Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, Jj = 6 Hz, J ₂ = 13 Hz, 1H); 4.9 (s. 1H); 5.1 (d, J = 10Hz, 1H); 5.2 (d, J = 18Hz, 1H); 5.7-5.9 (m, 1H); 6.6-6.8 (m, 3H); 7.0-7.4 (m, 4H); 7.55 (s. 1H); 9.35 (s, 1H).

Bromobenzene (3.22 g, 7.75 mmol) was dissolved in 25 ml of dimethylformamide with cuprous cyanide (1.39 g, 11.5 mmol) and refluxed for 3 days. The reaction mixture was cooled to room temperature and poured into 300 ml of aqueous 30% sodium cyanide. The mixture was extracted with 250 ml of ethyl acetate. The solvent was removed and the residue was purified by chromatography on silica gel with ethanol (0-20%) in dichloromethane, yielding 1.3 g (46%) (±) -3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-piperazinyl) -3-hydroxybenzyl) benzonitrile, mp 169-171 ° C. Calculated for C ^ H ^NjO: C, 76.42; H, 7.53; N, 11.62. Found C, 76.35; H, 7.54; N, 11.62.

Part of the benzonitrile (0.72 g, 1.99 mmol) was mixed with 0.56 g of granular sodium hydroxide in 8 ml of 95% ethanol and refluxed overnight. After cooling to room temperature, the reaction solution was adjusted to pH 5 with concentrated acid

179,341 salt. The solvent was removed under reduced pressure and the residue was suspended for 3 days. After filtration, 1.44 g of the carboxylic acid was obtained as a mixture with sodium chloride. This carboxylic acid was mixed with 1.8 g (4.0 mmol) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 1.0 ml (9.7 mmol) of diethylamine in 25 ml of acetonitrile and stirred overnight. The solvent was removed under reduced pressure and the residue was redissolved in 150 ml of 1 N aqueous hydrochloric acid and 150 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 8 with 10 N aqueous sodium hydroxide, and this layer was extracted with diethyl ether. The ether extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 0.4 g of a brown oil. The crude product was purified by preparative thin layer chromatography (silica gel, dichloromethane: ethanol: ammonium hydroxide / 95: 5: 1) giving 0.090 g (10% based on benzonitrile) (±) -3 - ((aR *) - a- ( (2S *, 5R *) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a white foam.

The free amine was converted to the monohydrochloride salt by dissolution in ethanol and titration with 0.2 M ethanolic hydrochloric acid to pH 3.45. The solvent was removed, the residue was redissolved in 10 ml of dichloromethane and the salt was precipitated with diethyl ether. After filtration, 0.070 g of the monohydrochloride salt was obtained as a white solid. Calculated for C27H37N3O2 HCl H ₂ O: C, 66.17; H, 8.23; N, 8.57; Cl, 7.23. Found C, 66.06; H, 7.97; N, 8.55; Cl, 7.31.

Example XXXVII. (+) - 3 - ((aR) -a - ((2S, 5R) -4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N, N-diethylbenzamide

(R) - (-) - Almond acid (11.50 g, 75.6 mmol) was added to the slurry 28.55 g (68.7 mmol) (±) -3 - ((aR *) - a - (( 2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-bromobenzyl) phenol (example XXXVI above) in 450 ml of anhydrous ethanol. The mixture was heated until complete dissolution of the ingredients and allowed to crystallize at room temperature. Crystals were collected and recrystallized from anhydrous ethanol. The crystalline mandelic acid salt was treated with an excess of 1 N aqueous sodium hydroxide and then titrated to pH 8 with 6 N hydrochloric acid. The precipitated free amine was recrystallized from anhydrous ethanol to give 6.25 g (44% based on the theoretical yield of one enantiomer) (+) - 3 - ((aS) -a - ((2S, 5R) -4-allyl2.5- dimethyl-1-piperazinyl) -3-bromobenzyl) phenol as a white solid, mp 205-206 ° C. [a] ²⁰ _D - + 20 ° (methanol c = 2). Calcd for C 22 H ₂ 7BrN ₂ O: C, 63.62; H, 6.55; N, 6.74; Br, 19.24. Found C, 63.63; H, 6.57; N, 6.68; 19.16.

A mixture of the above product (6.09 g, 14.7 mmol) and cuprous cyanide (2.63 g, 29.4 mmol) in 55 ml of N, N-dimethylphannamide was refluxed for 2 days. The reaction mixture was poured into 500 ml of 30% aqueous sodium cyanide, stirred for 20 minutes and then extracted with ethyl acetate. Combine the ethyl acetate extracts, wash them with brine and dry over sodium sulfate, and remove the solvent under reduced pressure. The resulting brown solid was purified by chromatography on silica gel with dichloromethane: ethanol / 95: 5, yielding 3.54 g (67%) of 3 - ((aR) -a - ((2S, 5R) -4-allyl-2 , 5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzonitrile as a beige solid. NMR (DMSOd6, 200 MHz): δ 0.96 (d, J = 6 Hz, 3H); 1.08 (d, J = 6 Hz, 3H); 1.8 (dd, J = 6.8 Hz, J ₂ = 11 Hz, 1H); 2.1 (dd, J = 6.6 Hz, J ₂ = 10.7 Hz, 1H); 2.4-2.7 (m, 3H); 2.75 (dd, J = 2.7 Hz, J ₂ = 10.9 Hz, 1H); 2.86 (dd, J = 7.0 Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, J = 5 Hz, J ₂ = 14 Hz, 1H); 5.0 (s. 1H); 5.1 (d, J = 11Hz, 1H); 5.2 (d, J = 17Hz, 1H); 5.7-5.9 (m, 1H); 6.68 (s. 1H); 6.7 (d, J = 8Hz, 2H); 7.16 (t, J = 8 Hz, 1H); 7.5 (t, J = 8 Hz, 1H); 7.7 (d, J - 8Hz, 2H); 7.8 (s. 1H); 9.4 (s, 1H).

Benzonitrile (3.54 g, 9.8 mmol) was dissolved in 40 mL 95% ethanol with 2.74 g (68.6 mmol) of granular sodium hydroxide and the mixture was refluxed overnight. Concentrated hydrochloric acid was added to adjust the pH to 5 and the solvent was removed under reduced pressure. The residue was mixed with 8.67 g (19.6 mol) benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 5.1 ml (49.0 mmol) diethylamine in 60 ml acetonitrile. After stirring overnight at room temperature under nitrogen blanket, the solvent was removed under reduced pressure, and the residue was dissolved in 100 ml of 6N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was adjusted to pH 8 with 10 N aqueous sodium hydroxide and extracted with ethyl acetate. Combine the acetate extracts,

Wash with pH 8 water, dry over sodium sulfate and evaporate the solvent to give 2.6 g of a beige solid. Chromatography on silica gel with dichloromethane: ethanol (1-4%) gave 1.76 g (41%) (+) - 3 - ((aR) -a - ((2S, 5R) -4-allyl-2 , 5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a beige solid, [a] d - + 15.0 ° (methanol, c = 1.9). NMR (DMSO-tk 200 Hz): δ 0.95 (d, J = 6 Hz, 3H); 1.1 (d, J = 6Hz, 3H); 1.0-1.2 (br m, 6H); 1.9 (dd, Jj = 8Hz, J ₂ = 12 Hz, 1H); 2.1 (dd, J = 7 Hz, _J2 - 11 Hz, 1H); 2.4-2.7 (m, 3H); 2.7 (dd, J = 3 Hz, J ₂ = 11 Hz, 1H); 2.9 (dd, Jj = 7 Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, J = 5 Hz, J ₂ = 14 Hz, 1H); 3.1-3.5 (m, 4H); 5.0 (s. 1H); 5.1 (d, J = 10Hz, 1H); 5.2 (d, J = 17Hz, 1H); 5.7-5.9 (m, 1H); 6.7 (d, J = 8 Hz, 1H); 6.69 (s. 1H); 6.7 (d, J = 8 Hz, 1H); 7.17.2 (m, 2H); 7.3-7.4 (m, 3H); 9.4 (s, 1H).

Mass spectrum: (Cl-CH4) m / z: 435 (Μζ 13%), 436 (M + 1.3%), 282 (47%), 153 (100%). The product was dissolved in anhydrous ethanol and titrated to pH 4 with ethanolic hydrochloric acid. The solution was concentrated and diethyl ether was added to precipitate the monohydrochloride salt (1.07 g, 56%) as a white solid. Calculated for C ₂₇ H 37 N _{3 O 2} HCl 1.25 H 2 O: C, 65.57; H, 8.25; N, 8.50; Cl 7.17. Marked: C, 65.26; H, 8.14; N, 8.82; Cl, 7.41.

Examples XXXVHI-XLIII were prepared in a similar manner to Example XXXVII.

Example XXXVHI: (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-methyl-N -propylbenzamide.

NMR (DMSO-d6, 200 MHz): δ 0.8-1.0 (br m, 3H); 0.95 (d, J = 6Hz, 3H); 1.1 (d, J = 6Hz, 3H); 1.5 (br m, 2H); 1.85 (br m, 1H); 2.1 (br m, 1H)); 2.4-3. 0 (m, 8H); 3.0-3.2 (br m, 3H); 5.0 (br s, 1H); 5.13 (d, J = 9Hz, 1H); 5.2 (d, J = 17Hz, 1H); 5.8 (m, 1H); 6.7 (m, 3H); 7.05-7.25 (m, 2H); 7.3-7.4 (m, 3H); 9.36 (s. 1H).

Example XXXIX: (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl-N-ethyl-N-methylbenzamide.

NMR (DMSO-d6, 200 MHz): δ 0.95 (d, J = 6 Hz, 3H); 1.1 (d, J = 6Hz, 3H); 1.0-1.2 (br m, 3H); 1.85 (br t, J = 9 Hz, 1H); 2.1 (br t, J = 8 Hz, 1H); 2.53 and 2.56 (2s, 3H); 2.6-3. 0 (m, 5H); 3.1-3.5 (m, 3H); 5.0 (br s, 1H); 5.1 (d, J = 10Hz, 1H); 5.17 (d, J = 17Hz, 1H); 5.8 (m, 1H); 6.7 (s. 1H); 6.6-6.75 (m, 2H); 7.1-7.25 (m, 2H); 7.3-7.5 (m, 3H); 9.4 (s, 1H).

Example XL: (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzamide.

NMR (DMSO-d ₆ , 300 MHz): 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.85 (m, 1H); 2.1 (m, 1H)); 2.8 and 2.85 (2s, 3H); 2.4-3. 0 (m, 5H); 3.1 (m, 1H); 4.95 (s. 1H); 5.05 (d, 10Hz, 1H); 5.1 (d, J = 17Hz, 1H); 5.8 (m, 1H); 6.7 (m, 3ΉΥ, 7.1 (t, J - 8 Hz, 1H); 7.2 (d, J = 8 Hz, 1H); 7.3-7.45 (m, 5H); 9 . 35 (s, 1H).

Example XLI: (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N-ethylbenzamide.

NMR (DMSO-df, 200 MHz): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.05 (m, 3H); 1.85 (m, 1H); 2.1 (m, 1H)); 2.4-3. 0 (m, 4H); 3.1-3.5 (m, 4H); 4.95 (s. 1H); 5.1 (d, J = 10Hz, 1H); 5.2 (d, J = 17Hz, 1H); 5.8 (m, 1H); 6.7 (m, 3H); 7.1 (t, J = 8 Hz, 1H); 7.4 (t, J = 8 Hz, 1H); 7.65 (d, J = 8 Hz, 1H); 7.85 (s. 1H); 9.35 (s, 1H).

Example XLII: (±) -3 - ((aR *) - a ((2S *, 5R *) - 4-Allyl-2,5-dimethyl-1-piperazinyl) 3-hydroxybenzyl) -N-cyclopropyl-N- methylbenzamide.

NMR (DMSO-d6, 500 MHz): δ 0.4 (m, 3H); 0.95 (br s, 3H); 1.05 (br s, 3H); 1.85 (m, 1H); 2.1 (m, 1H)); 2.4-3. 0 (m, 5H); 2.9 (s, 3H); 3.1 (m, 1H); 4.95 for s, 1H); 5.0-5.2 (br m, 2H); 5.8 (br m, 1H); 6.65 (br m, 3H); 7.1 (br m, 1H); 7.2-7.5 (m, 5H); 9.35 (s, 1H).

Example XLIII: (±) -3 - ((aR *) - 4- (1-Pyrrolidinylcarbonyl) -a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) benzyl) phenol.

NMR (DMSO-d6, 200 MHz): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J - 6Hz, 3H); 1.8 (m, 5H); 2.1 (m, 1H)); 2.2-3. 0 (m, 7H); 3.1 (m, 1H); 3.4 (m, 2H); 4.95 (s. 1H); 5.05 (d, J - 10Hz, 1H); 5.1 (d, J - 17Hz, 1H); 5.8 (m, 1H); 6.65 (m, 3H); 7.3-7.5 (m, 4H); 9.35 (s, 1H).

179 341

R ⁷

R ⁶

Formula 1

OH CH ₃

CH ₃ V

CH 2 CH = CH ₂

Formula 2

Et ₂ N

OH r ^N yCH ₃ CH ₃ ψ ch ₂ ch = ch ₂

Formula ₃

ch ₂ -ch-ch ₂

Formula 4

OH r ^N yCH ₃

CH / V ch ₂ -ch = ch ₂

Pattern 6

179 341

Pattern 7

Formula 10

rNyR ³ _R 5 ÓpR ⁴

R ⁶

Formula 11 _r N ^ CH ₃ ch / ^ ch ₂ ch = ch ₂

Pattern 8 '

Formula 13

Formula 9

Ar-X ²

Formula 15

Pattern 16

Ar-CHO

Formula 17

Formula 18

Pattern 19

179 341

t-BuMe ₂ SiCty bA ^ OH omf ° ^z ° 'eAAsiMejt-Bu Βι-γ ^ SOCh _ B ® \ ®®OSiMe ₂ t-Bu CH2CI2 1) n-BuLi, THF, -78 ° 2) Br. ° Tl ^ CHO AA ΤΤγΧΙθ ^ Μθ ^ -θυ

OH U. ^ N ^ * CH3 CHr + f Cl Ϊ 1 11 ^ Y ^^ OSit ^ t-Bu ___ ^ NyCHa BrCH ₂ -CH = CH ₂ ~ cH ^ y ^u Π Scheme 1 dc on the next page

179 341

c.d scheme 1 / a

OSiMe ₂ t-Bu _r NyCH3 ^{L 3} ćh ₂ -ch = ch ₂

Et ^ NF

CH ₃ CN chromatography or selective crystallization

c.d scheme 1 / b

H.

Br

OH ŃyCH ₃ Λ CH-CHo bn ₂ ln-bn ₂ t-BuMejSiCl imidazole, DMF

OSiMe ₂ t-Bu

NyCH ₃

In Ψ

CH ₂ -CH = CH ₂

LiO

1) n-BuLi

2) CO ₂

H.

0SiMe ₂ t-Bu N- ^ CH ₃

1) SOCl2, CH ₂ Cl2

2) Et ₂ NH ³ ch ₂ ch = ch ₂

179 341

continuation of scheme 1 / c 0 Et ₂ N-Cy ^ _H ®yAU ^ OSiMe ₂ t-Bu ^ NyCH ₃ CHH ³ ch ₂ -ch = ch ₂ S ch ei 0 Et ₂ NC ^ _H ^{EUNF H} -ass—- i ^N r CH ₃ ^v V ³ ch ₂ -ch = ch ₂ Compound L mat 1

Dn-BuLiJHF, -78 °

Br ^ OSiMe ₂ t-Bu ^{21 Br,} N ^ CHO

Diagram

Br

OSiMe ₂ t-Bu

OH ²

1) n-BuLi, THF, -78 °

Br ^ OSiMezt-Bu ²¹

Br

CN

NqBH ₄

Br

Br

OSiMe ₂ t-Bu

OSiMe ₂ t-Bu OH

Scheme 3

179 341

Reaction Bf

Friedel-Crofts _| □ citation

NaBHz,

Friedel-Crofts reaction acylation

Sch e mat 4

X = Br or

CONEta

CH3

-h _{2 st}

H *

Y = C0 ₂ El or

CH ₂ -CH = CH2

0SiMe ₂ T-Bu

Dn-BuLiJHF, -78 °

Scheme 5

179 341

1) SOCl ₂ CH2C12.DMF

Et ₂ N 2 ^C

2) Et ₂ NH

Scheme 7

Diagram 8 cd on next page

179,341 dc scheme 8

Union L

Scheme 8

EtOCOCl pH = 4

BrCH ₂ -CH = CH ₂

CU2tt U rM ³ nooh r ^N Y ³

CHFN ch; V

CHjCH-CHz CHzCH-CHj

Diagram

179 341

OSiMe ₂ t-Bu

CH3

_{H 2} CH = CH ₂ racemic

X = e.g. Br or CONEt?

(2R, 5S)

1) CH ₃ CN, heat

2) Et ₄ NF

3) separation of isomers

xNyCH ₃ ^CHi Uh = ch ₂

Scheme at 10 ^H H

BOC-N ^ COOH

CH ₃

1) more than 2 equivalents of NaH

2) ollyl bromide

BOC-D-Alo ^because 5nXcooh

CH _f CH-CH ₂ X, ch ₃ ^Β ° 5Νφ0 ° 0Η +

CHrCH-CH ₂ T bn ₃

Η ₂ ΝχψΧΟ ₂ ΟΗ ₃ Me ₂ N- (CH ₂ ) ₃ -N = C = N-Et _r

Clh3

L-A (a-0Me

Diagram 11 cd on next page

179 341 c d Scheme 11

_HCOOH ° ² , Λή ₃ = -buoh 'BOC CH ₂ CH = CH ₂ CH3, N 0 0¼¼ ch ₂ ch = ch ₂

CH ₃ a Li Al H 4 UA γτΗ ₃ ch ₂ ch = ch ₂ Scheme 11 u NC ^^, μ iW1 TTikl ^ r ^ OH _CuCN L> ^ WoH DMF, ref (bias <Νγ * 0Η3 CH / 'V CH ₃ ^xx y ch ₂ ch = ch ₂ ch ₂ ch = ch ₂ Diagram 12 dc on next page NaOH

179 341 cd sch ema tu 12 h ₂ nc

OH

HO-C

OH Ńy * CH ₃

CH ₂ CH = CH ₂ ch ₃ ^v ch ₂ -ch = ch ₂

Et ₂ N-C

1) neutralization / HCl

2) Reogent BOP

Et ₂ NH, DMF

OH

Λ | γ · υΗ ₃ CH ₃ 'V 0Η2 · 0Η = 0Η2

Zwigzek L.

Diagram

Br

Br • Νγ * 0Η3 W 'Ψ CH ₂ CH = CH ₂

Et ₂ N-C

Pd ⁰ , CO

Et ₂ NH

OH N- ^ CH ₃

CH / 't-BuMe ₂ SiCl imidazole, DMF

0SiMe ₂ T-Bu

- ζΝγΟΗ ₃ ^CH3 'CH ₂ CH = CH ₂

Et ₄ NF

1) n-BuLi

Et ₂ NC

CH ₂ -CH = CH ₂

OSiMe ₂ t ~ Bu

Hy * CH ₃ ch ₂ -ch = ch ₂

Zwigzek L.

Diagram

Publishing Department of the Polish Patent Office. Circulation 70 copies Price PLN 6.00.

Claims (9)

Patent claims Difenylometylopiperazyny 1. Compounds of formula 1 wherein Ar is a phenyl group having one carbon atom of the ring Y, which represents a carboxamide, sulfonamide, or aminomethyl, Z is hydroxy, G is nitrogen, R ² is hydrogen, R ³ and R ' ^{is methyl, R 4} is hydrogen, R ⁶ is -CH 2 -CH = CH 2, R ⁷ is hydrogen. 2. A compound according to claim The process of claim 1, wherein Y is a carboxamide group. 3. The compound according to p. The process of claim 1, wherein Y is a sulfonamide group. 4. The compound of claim 1 The process of claim 1, wherein Y is an aminomethyl group. 5. The diphenylmethylpiperazine compounds of the formula I in which Ar is a phenyl group having a Y substituent on one ring carbon atom which is a para or meta position on the attached phenyl ring, a carboxamide group of the formula CONR ⁹ R ¹⁰ , wherein R ^{9 is} represents a hydrogen atom or a C 1 -C 6 -alkyl group, and R ¹⁰ is a C 1 -C 6 -alkyl or phenyl group, Z is a hydroxyl group, G is a nitrogen atom, R ² is a hydrogen atom, R ³ and R ⁵ are a methyl group, R ⁴ is hydrogen, R ⁶ is -CH-CH = CH 2, R ⁷ is hydrogen. 6. A compound selected from one of the following compounds: (±) -3 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -4- (methylsulfonyl) benzyl} -phenol; (±) N- {4 - [(aR *) - a- (2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3- (hydroxybenzyl) benzoyl} glycylglycine; (±) -4 - {(aR *) - a - [(2R *, 5S *) - 2,5-dimethyl-1-piperazinyl] -3 - (hydroxybenzyl} -N, N-diethylbenzamide; cis-4- {α- [4 - ((Z) -2-butenyl) -3,5-dimethyl-1-piperazinyl] -3- (hydroxybenzyl} -N, N-diethylbenzamide; N, N-diethyl-4- {3-hydroxy-α- [cis-3,4,5-trimethyl-1-piperazinyl] benzyl} benzamide; N, N-diethyl-4- {3-hydroxy- (aR) -a [(2S, 5S) -2,4,5-trimethyl-1-piperazinyl] benzyl} benzamide; N, N-diethyl-4- {3-hydroxy- (aR) -a [(2R, 5R) -2,4,5-trimethyl-1-piperazinyl] benzyl} benzamide; (±) -3- {(aR *) - a - [(2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol; (±) -4 - {(aR *) - a - [(2S *, 5R *) M-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} benzamide; (±) M - {(aR *) - a - [(2S *, 5R *) - 4-alhlo-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -Netyl-N- (2-hydroxyethyl ) -benzamide; (±) -5 - {(aR *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -3-bromo-N, N-diethyl -2-thiophenecarboxamide; (±) -3 - {(R *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] (2-thienyl) methyl} phenol; (±) -3- {(aS *) - a - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] benzyl} phenol; (±) -3 - {(R *) - a - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] (3-thienyl) methyl} phenol; (±) -4 - {(aR *) - a - [(2S *, 5R *) - 4- (cyanomethyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethylbenzamide (±) -3 - {(R *) - [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] (3-pyridylmethyl} phenol; (±) -4- {(aR *) - a [(2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl} -N, N-diethylbenzenesulfonamide; (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl)} - N-methyl-N-propylbenzamide; (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl)} - Netyl-N-methylbenzamide; 179 341 (±) -3- {(ClR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl)} -Netylbenzamide; (±) -3 - {(aR *) - a [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl)} - N-cyclopropyl-N-methylbenzamide; (±) -3 - {(aR *) - 4- (1-pyrrolidinylcarbonyl) -a - [(2S *, 5R *) - 4-allyl) -2,5-dimethyl-1-piperazinyl] -benzyl} phenol ; and a pharmaceutically acceptable salt of the compound. 7. 3 - {(R) - [(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl] - (2-thienyl) methyl} phenol or a pharmaceutically acceptable salt thereof. 8. 3 - {(aR *) - a [(2S *, 5R *) -4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethylbenzamide or a pharmaceutically acceptable salt this relationship. 9. 3 - {(aR) -a [(2S, 5R) -4-allyl) -2,5-dimethyl-1-piperazinyl] -3-hydroxybenzyl) -N, N-diethylbenzamide or a pharmaceutically acceptable salt thereof. * * *