PL179341B1 - Diphenylmethylpiperazine compounds - Google Patents

Abstract

1. Diphenylmethylpiperazine compounds of formula 1, wherein A is a phenyl group having a Y substituent on one ring carbon atom, which is a carboxamide, sulfonamide or aminomethyl group, Z is a hydride group, G is a nitrogen atom, R2 is a hydrogen atom, R3 and R5 are a methyl group, R4 is a hydrogen atom, R6 is a -CH2-CH=CH2 group, R7 is a hydrogen atom.

Description

The present invention provides diphenylmethylpiperazine compounds useful as receptor binding agents, particularly as agonist/antagonist conjugate pairs used to correct and/or assay receptor and neurotransmitter function. The present invention includes benzhydrylpiperazines useful as compounds binding to μ (mu) and/or δ (delta) opioid receptors mediating anesthesia, and as compounds useful in combating drug addiction, alcohol addiction, recovery from overdose, mental illness, urinary incontinence, cough, pulmonary edema, diarrhea, depression, cognitive disorders, respiratory and digestive disorders.

Studies of opioid biochemistry have identified numerous endogenous and non-endogenous opioid substances. Research into the mechanisms of action of opioid compounds, particularly in relation to cellular and differentiated tissue receptors, has been crucial to these efforts.

Opioid drugs are typically classified based on their binding selectivity for the cellular opiate receptors and the diverse tissue receptors to which a specific drug binds as a ligand. These receptors include the mu (μ), delta (δ), sigma (σ), and kappa (k) receptors.

Known opioid drugs such as morphine and its analogues are selective for the mu opioid receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal motility. Kappa receptors mediate analgesia and sedation. Sigma receptors mediate numerous biological processes.

The existence of the delta opioid receptor is a relatively recent discovery, following the isolation and characterization of endogenous enkephalin peptides, which are ligands for this delta receptor. Research over the past decade has yielded significant knowledge of the delta receptor, but a clear picture of its function has not yet emerged. Delta receptors mediate analgesia, but they do not appear to inhibit gastrointestinal motility in the manner characteristic of mu receptors.

Opioid agents are often characterized as agonists or antagonists. Both agonists and antagonists are substances that recognize and bind to a given receptor, influencing (either initiating or blocking) biochemical/physiological pathways. This process is called transduction. Agonists inhibit or suppress neurotransmitter release in receptor-containing tissues, for example, by inhibiting the pain response or affecting other processes related to neurotransmitter release. 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.

Regarding receptor-specific ligands, the distinction between delta receptor agonists and antagonists is made based on their activity in the mouse vas deferens test, which is generally considered to be

179 341 suitable diagnostic tissue for the delta receptor. Mu receptor agonists are characterized on the basis of activity demonstrated in a test of electrical stimulation of the guinea pig ileum.

Few essentially pure, delta-selective agents are known, and with the exception of the delta-opioid receptor antagonists disclosed by Portoghese in U.S. Patent No. 4,816,586, all known delta-selective opioid compounds are peptides, including endogenous enkephalins and other endorphins as well as exogenous peptide analogs. Previously synthesized exogenous peptide analogs have various drawbacks related to their peptide structure, including stability, potential suitable routes of delivery as drugs, and in vivo tissue distribution.

Various physiological effects of known peptide opioid ligands have been studied so far, including analgesic activity, respiratory depression, action on the digestive system, on mental and emotional functions, cognition processes, as well as mediating and modulating other physiological processes.

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

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

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

S. Goenechea et al. in their 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 of the metabolism of the drug meclozine in humans.

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

T. Iwamoto et al. in the paper: "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 action of a polyarylpiperazine with a defined structure 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) disclosed racemic mixtures and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives.

The publication of the European patent application EP 458.160 describes substituted diphenylmethane derivatives as analgesics and anti-inflammatory agents, including compounds in which the bridging 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. 8604522 discloses N-substituted arylalkyl- and arylalkylene-substituted aminoheterocyclic compounds, including piperidine derivatives, described as being useful as cardiological, antihistaminic and antisecretory agents.

European Patent Application EP No. 133,323 discloses diphenylmethylpiperazine compounds useful as non-sedating antihistamines.

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There is a continuing need for improved opioid compounds, especially compounds that lack the addictive properties and other undesirable side effects exhibited by conventional opiates such as morphine and peptidyl.

The invention relates to diphenylmethylpiperazine compounds of formula 1, wherein Ar is a phenyl group having on one ring carbon atom a substituent Y, which is a carboxamide, sulfonamide or aminomethyl 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 a hydrogen atom, R ⁶ is a -CH 2 -CH=CH 2 group, R ⁷ is a hydrogen atom.

Preferably, Y is a carboxamide, sulfonamide or aminomethyl group.

The invention also relates to diphenylmethylpiperazine compounds of formula 1, wherein Ar is a phenyl group having a Y substituent on one ring carbon atom, which is ^a carboxamide group of formula ^CONR9R10 , located in the para or meta position on the attached phenyl ring, wherein ^R9 is a hydrogen atom or a C1-C8-alkyl group and ^R10 is a C1-C8-alkyl, phenyl group, Z is a hydroxyl group, G is a nitrogen atom, ^R2 is a hydrogen atom, ^R3 and ^R5 are a methyl group, ^R4 is a hydrogen atom, ^R6 is a -CH-CH=CH2 group, ^R7 is a hydrogen atom.

The invention also includes 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*)-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-{a-[4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl}-N,N-diethylbenzamide;

N,N-diethyl-4-{3-hydroxy-a-[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}-N-ethyl-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*)-α-[(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-diethylbenzenesulfonamidamide;

(±)-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)-N-ethyl-N-methyl-benzamide;

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

(±)-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 thereof.

The invention also includes 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.

With respect to enantiomeric forms, the compounds of the invention include individual enantiomers of the compounds of formula 1, both in the form of single forms substantially free of the other enantiomer and in mixtures (in mixtures of enantiomeric pairs and/or in mixtures of multiple enantiomeric forms).

The compounds of the invention exhibit receptor selectivity. Depending on the structure and stereospecificity of the particular compound, they may exhibit binding to receptors belonging to the delta, mu, kappa, sigma receptor classes, and combinations thereof.

Many compounds of the invention exhibit delta receptor agonist activity, which is associated with mediating analgesia. Other compounds of the invention exhibit delta receptor antagonist activity, as described in more detail below. Still other compounds of the invention exhibit mu receptor activity, and particularly, in some cases, mixed mu and delta receptor activity.

Examples of compounds of the invention are synthesized compounds. To facilitate their identification, each compound is given a serial number associated with its chemical name in the following 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-dnethyl-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-aihlo-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-pipera2ynyl](4-bromo-2-thienyl)methylphenol (+)-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-N-ethyl 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)-N-ethylbenzamide

40. (±)-3-{(aR*)-a[(2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenz}do)-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 1 and the listed exemplary compounds (1-41) demonstrate utility as exogenous combination compounds that bind to a receptor, i.e., compounds useful for binding to a receptor such as the delta receptor, the mu receptor, the sigma receptor, the kappa receptor, or two or more of these receptors. Such a combination compound may be an agonist/antagonist conjugate pair used in studies of neurotransmitter function in appropriate cellular systems or differentiated tissue systems. In addition to receptor assays, differential binding, and specific applications for monitoring and evaluation purposes at the cellular, tissue, and systemic levels, the compounds of the invention variously exhibit specific biological activity, which renders them useful as therapeutic agents in various physiological and pathological conditions.

179 341

The compounds of the invention include various types of agonists that mediate analgesia and those that are useful for treating diarrhea, depression, urinary incontinence, mental illness, cough, pulmonary edema, digestive disorders, spinal injuries, and drug addiction.

The compounds of the invention also exhibit antagonist activity that may prove useful in their use as agonist conjugates for neurotransmitter assays and in the treatment of alcoholism and opiate drug overdose; these compounds also include other types of agonists.

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

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

Regarding the non-peptide opioid agents encompassed by the invention, the structure-activity relationships of the various compounds encompassed by general formula 1 are very diverse, and even minor differences, such as changes in stereochemistry, can result in different effects on transduction. Thus, formula 1 encompasses agonist-type compounds and antagonist-type compounds. Furthermore, empirical experiments using the compounds of the invention provide strong evidence for the existence of a delta receptor subtype in the brain that differs from the delta receptor in the mouse spermatic cord.

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

As for the mu receptor agonists, their activity can in principle be distinguished and measured by electrical stimulation of the guinea pig ileum.

Particularly preferred compounds from the above-mentioned list of 41 exemplary compounds include compounds 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 represented by formulas 2 (compound "A"), 3 (compound "B"), and 4 (compound "C"). These compounds A, B, and C are highly selective opioid receptor ligands.

Compound A, 3-{(R)-[(2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(2-thienyl)methyl}phenol, is a predominantly mu receptor agonist and may be used, for example, 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 receptor agonist and can be used for epidural analgesia.

Compound C, 3-{(aR)-a-[(2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl}N,N-diethylbenzamide, is a mixed mu and delta receptor agonist used in analgesia, especially for surgical and/or postoperative anesthesia.

The above compounds are preferably prepared in substantially enantiomeric pure 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. Enantiomeric excess values provide a quantitative measure of the excess percentage of a major isomer over the percentage of a minor isomer present. 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.

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The mixed affinity properties of Compound C for the mu and delta receptors and other and related compounds encompassed by the invention are a potential significant advantage over various known mu receptor binding compounds currently used as analgesics.

The vast majority of currently used potent analgesics, such as morphine, fentanyl, meperidine, sufentanil, and codeine, are compounds that bind to the mu receptor. It is well known that these compounds, although highly effective in pain control, are associated with side effects, including confusion, decreased mental acuity, muscle rigidity, and respiratory depression, as well as rejection-related symptoms such as nausea, vomiting, tremors, seizures, and sweating. Such side effects are generally absent or at least less pronounced with agents that bind to the delta receptors mediating analgesia. Thus, the use of compounds of the invention that bind to mixed mu and delta receptors may reduce or even eliminate the side effects normally associated with the use of compounds that bind to the mu receptor.

Compound A, prepared as its pure enantiomer, exhibits potent mu-receptor analgesic activity comparable to fentanyl, the leading mu-opiate analgesic used for surgical anesthesia. Comparative studies of compound A and fentanyl in rats, examining their effects on respiration and anesthesia, have demonstrated similar activity and duration profiles. Furthermore, compound A has been shown to be significantly safer than fentanyl at higher (equivalent) doses.

Compound B is a delta opioid receptor agonist. Agents of this type produce analgesia at the spinal cord level. Spinal analgesics such as lidocaine and morphine pose a risk of side effects due to leakage from the spinal chamber to the periphery. In contrast, compound B does not produce significant side effects when administered peripherally to rats and mice. The absence of such side effects makes compound B and related derivatives of the invention more useful in spinal anesthesia.

Compound C, as noted above, is an enantiomerically pure analgesic exhibiting agonism at both mu and delta opioid receptors. In rodent experiments, compound C demonstrated analgesic potency comparable to the mu analgesic morphine but induced significantly less pronounced muscle rigidity and respiratory depression. Furthermore, rodent studies have shown that compound C is devoid of the proconvulsive activity that may be associated with structurally related pure delta agonists.

Compounds 1 to 41 given above as examples of compounds of the invention include compounds showing significant potency in the receptor binding assay (rat brain), compounds active predominantly at one or other of the delta receptor subtypes, and compounds showing affinity for both mu and delta receptors.

The receptor binding and analgesia assays demonstrate that the compounds of the invention differentially mediate analgesia under a wide variety of stimuli and physiological perturbations. This, in turn, demonstrates the high degree of complexity of the stimulus-dependent neural conduction responses associated with various opioid receptors, including mu, delta, and delta receptor subtypes.

As is apparent from the foregoing description, the compounds of the invention have broad utility in treating a wide variety of physiological conditions and disorders. The compounds of the invention are therefore useful in the preparation of medicaments for the treatment or prevention of such physiological conditions and disorders. In addition to the therapeutic uses listed above, 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 central nervous system disorders, such as compulsive behaviors, depression, psychosis, and the like. Agonists and antagonists containing the compounds of the invention are useful in combating such disorders.

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The various types of agonists and antagonists of the compounds of the invention may also find use in the treatment of drug (opioid/narcotic) addiction and may therefore replace methadone or other conventional agents used in drug treatment programs, as conventional agents used in drug treatment have side effects and other disadvantages that contraindicate or limit their use.

With respect to the treatment of drug addiction with effective compounds encompassed by the broad scope of this invention, it should be noted that methadone is an opioid that binds to the mu receptor and has effects similar to morphine, meaning that methadone itself poses a risk of addiction. This drug is used in "maintenance therapy" for opiate addicts, allowing these patients to remain functional while satisfying their drug needs through a safer, non-criminal route. In this regard, the compounds of this invention may find use as a replacement or complement to current drug addiction treatments involving the administration of naltrexone, methadone, clonidine, and similar medications.

Some compounds within the scope of the invention have utility in local anesthesia, such as spinal anesthesia, and some may be useful in appetite suppression and similar applications.

The compounds of the invention include a wide variety of compounds that are agonists of the delta opioid receptor subset in the mouse sperm test, as well as compounds that are antagonists of this delta receptor subtype. The compounds of the invention also include compounds that are agonists or antagonists of delta receptors in the brain, which, based on empirical studies, appear to be a different delta receptor subtype than the delta receptors in the mouse spermatic cord. A significant number of the compounds of the invention, having the general formula I, exhibit either agonist or antagonist activity at both subtypes of these receptors. Many of these compounds exhibit high activity at the mu opioid receptor, either binding exclusively to the mu receptor or exhibiting promiscuous binding activity at both the mu and delta receptors. Still other compounds of the invention exhibit significant affinity for sigma receptors.

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

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

Compound H (formula 5) exhibits delta receptor agonist activity, which indicates that this compound should participate in analgesia processes with the same effectiveness as delta-opioid peptide compounds.

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

Compound J (formula 7) has potent delta receptor agonist activity.

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

A method of obtaining an analgesic response in an animal requiring such treatment is to administer to the animal a compound of formula 1 at a dose that produces analgesia.

Furthermore, various compounds of the invention having suitable therapeutic utility may be successfully used to treat conditions such as: drug and alcohol addiction/overdose conditions, mental, emotional and cognitive disorders, cough, pulmonary edema, and digestive disorders. Accordingly, the use of the compounds of the invention enables the treatment of animals suffering from the above-mentioned conditions and in need of such treatment; this method comprises administering

179,341 to an animal an effective amount of a compound of the invention having a therapeutic effect on the disease state in question.

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

Depending on the specific condition requiring treatment, animals are administered compounds of formula 1 in an appropriate, therapeutically effective and safe dose, which can be easily determined by known methods that do not require excessive experimental testing.

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

The route of administration and formulation of the drug will, of course, influence the therapeutic amounts of compounds required and effective for a given therapeutic application.

For example, for the same active ingredient, oral doses are typically at least two to ten times greater than parenterally administered doses. When administered orally for pain relief, dosage levels for the mu-binding compounds of the invention range from 5 to 200 mg/70 kg body weight/day. Intrathecally administered drug dosage levels are generally about 10% of the parenterally administered dose levels. In tablet dosage forms, a typical dose of the analgesic active agent is in the range of 10 to 100 mg/tablet.

The compounds of formula 1 are administered as such and in the form of their pharmaceutically acceptable salts.

Examples of pharmaceutically acceptable salts of the compounds of formula 1 include salts 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 a C1-C4-alkyl group. Pharmaceutically acceptable salts of an amino group include salts of: organic carboxylic acids such as acetic, lactic, tartaric, malic, lactobionic, and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, isethionic, benzenesulfonic, and p-toluenesulfonic acids; and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, and sulfamic acids. 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 NΧ/ (where X is, for example, a C1-C4-alkyl group).

For therapeutic purposes, salts of compounds of formula 1 will be pharmaceutically acceptable, that is, they will be salts derived from a pharmaceutically acceptable acid or base. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, 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.

In veterinary and human medicine, pharmaceutical compositions containing one or more compounds of the invention as an active ingredient are also used, and compounds of the invention, such as those covered by formula 1 described above, are also used for the preparation of medicaments intended to treat or prevent the conditions and disorders described above.

179 341

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

Dosage forms include those adapted for parenteral and non-parenteral use; specific routes of administration include: oral, rectal, topical, intranasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intraarterial, subarachnoid, intrabronchial, intralymphatic, and intravaginal. Dosage forms adapted for parenteral administration are preferred.

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

If the active ingredient is administered directly in powder form, oral administration is a convenient route. Alternatively, it can be administered intrabronchially by nebulizing the powder in a carrier gas, which creates a gaseous dispersion that the patient inhales along with the flow delivered from a suitable nebulizer.

For some applications, it may be advantageous to administer the active ingredient in a "targeted" form, obtained by encapsulating the active ingredient in liposomes or another encapsulating medium, or by linking the active ingredient, e.g., covalently, chelated, or coordinately, to a suitable biological molecule such as a protein, lipoprotein, glycoprotein, or polysaccharide.

Formulations containing the compounds of the invention as the active agent are conveniently prepared in unit dosage forms prepared by methods known in the pharmaceutical art. Generally, these methods include the step of bringing the active compound into association with a carrier that consists of one or more excipients. In general, these formulations 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 may be presented as discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient in the form of powder or granules; suspensions in aqueous or non-aqueous media, such as syrups, elixirs, emulsions or decoctions, may also be prepared.

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

The syrup is prepared by adding the active compound to a concentrated aqueous solution of sugar, e.g. sucrose, to which solution are further added additional ingredients such as flavoring agents, suitable preservatives, agents retarding the crystallization of sugar and agents facilitating the solubility of other ingredients, such as polyhydric alcohols, e.g. glycerol or sorbitol.

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

179 341, and liposomes or other microparticulate systems designed to deliver the compound to blood components or one or more organs. These forms are prepared in unit-dose or multi-dose forms.

Nasal sprays contain purified aqueous solutions of the active ingredient with preservatives and isotonic agents. These formulations are adjusted to a pH and isotonicity compatible 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 formulations are manufactured similarly to nasal sprays, except that the pH and isotonicity values are adjusted so as not to irritate the eye.

Topical formulations are prepared by dissolving or suspending the active ingredient in one or more media such as mineral oil, petroleum, polyols or other bases used for topical pharmaceutical formulations.

Transdermal forms are prepared by incorporating the active agent into a thixotropic or gelatinous carrier, such as a cellulosic carrier, e.g. based on methylcellulose or hydroxyethylcellulose, and placing the resulting mass in a transdermal material adapted for skin contact.

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

The compound of formula 1 as defined above, wherein G is nitrogen, or pharmaceutically acceptable salts, is prepared by a method comprising the following steps:

(A) alkylating a piperazine of formula 10 with an alkylating agent of formula 9, wherein Ar, R ² -R ⁷ , Y and Z are as defined in the definition of formula 1, and further, if desired, Z may be protected by a suitable protecting group such as a tert-butyldimethylsilyl group and X ¹ is a suitable readily leaving group such as chloride, bromide, toluenesulfonate ([CH ₃ (C ₆ H 4 )SO 3 -], methylsulfonate (CH ₃ SO ₃ -) or other known groups of this type, or (B) transforming a compound of formula 11, wherein the meaning of Y as defined in the definition of formula 1 is limited to a reactive halogen (e.g., bromine or iodine) and Ar, R ² -R ⁶ , Z are as defined in the definition of formula 1, and further, if desired, Z may be protected by a suitable protecting group such as a tert-butyldimethylsilyl group to a compound of formula 1, where G is nitrogen, ^R7 is hydrogen and Y can be all groups given in the definition of formula 1, consistent with the transformation carried out by metal substitution reactions to form intermediate metal aryl compounds, which allows the introduction of new Y substituents in the place occupied by 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 the compound of formula 10 may initially be hydrogen, and after reaction to form a compound of formula 1 where G is nitrogen and R ⁶ is hydrogen, the compound of formula 1 can be alkylated with a suitable alkylating agent R ⁶ -X\ where R ⁶ is -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 alkylating agent R ⁶ -X ² , 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 to introduce the desired R ⁶ group.

A compound of formula 1 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, to obtain

179 341 by forming the corresponding compound of formula 1, where Y is a nitrile. This compound can then be hydrolyzed in an alkaline medium or in an aqueous solution of an inorganic acid to the compound of formula 1, where Y is a carboxylic acid residue. This carboxylic acid can then be converted to a compound of formula 1 wherein 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 mixed anhydride formation (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(dimethylamino)phosphonium hexafluorophosphate); each of these activated intermediates can be converted to the desired carboxamide by reaction with the appropriate amine (NHR ⁹ R ¹⁰ or NHR ⁹ ANR ⁹ H) in a suitable solvent such as dichloromethane or dimethylformamide. Similarly, reaction of these activated intermediates with a peptide gives compounds of formula 1, where Y is a peptide carboxamide conjugate.

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

The organometallic intermediate prepared from the compound of formula 11 can be treated with ^the appropriate carbamoyl chloride ( ^C1CONR9R10 ) to produce a compound of formula 1, where Y is ^CONR9R10 . The 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 produce a compound of formula 1, where Y is ^CONR9R10 .

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

The compound of formula 1 may be obtained as a pure single enantiomer by classical resolution with an enantiomerically pure acid such as mandelic acid, or by preparing readily separable diasteromers by treatment with an enantiomerically pure derivatizing agent or by chiral chromatography, or by enzymatic resolution of the compound of formula 1 or a suitable derivative thereof, or by preparing the compound of formula 1 from enantiomerically pure precursors which themselves may be obtained as 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 a suitable protecting group, by methods such as halogenation with thionyl chloride or a triphenylphosphine/carbon tetrabromide reagent or by reaction with methanesulfonyl chloride or toluenesulfonyl chloride in a solvent such as dichloromethane.

Piperazines of formula 10 are commercially available or can be prepared by methods published in the literature or by modification of these methods, where ^R6 is changed by appropriate alkylation with agents ^R6 - ^Xr .

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

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

179,341 compounds of formula 15 where X ² is a reactive halogen (e.g., iodine or bromine) by the methods described above, to Z-protected benzaldehydes of formula 16 including compounds where R ⁷ is hydrogen, to give compounds of formula 14.

Compounds of formula 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 which case compounds of formula 14 are obtained) to arylaldehydes of formula 17.

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

The compound of formula 1 is converted into a pharmaceutically acceptable form in a conventional manner, e.g., by treatment with a suitable acid. A salt of a compound of formula 1 can be converted into the parent compound, e.g., by hydrolysis.

Based on the above description and general synthetic principles, various synthetic routes can be used to prepare the diphenylmethylpiperazine compounds of the invention, as will readily become apparent to those skilled in the art.

Illustrative synthetic methods for preparing compounds of the invention are provided below by way of example only. It is understood that these compounds may be prepared by many other synthetic routes and methods.

If the synthetic procedures used to prepare the compounds of the invention give racemic mixtures as reaction products, such racemic mixtures may be resolved by suitable known methods, e.g., by formation of diastereomeric salts with enantiomerically pure carboxylic acids, by chiral chromatographic separation, by enzymatic resolution or by any other suitable conventional method.

Scheme 1 provides an exemplary synthetic route for (±)-4-{(aR*)-a[(2S*, 5R*)-4-allyl)-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl)-N,N-diethylbenzamide, hereinafter referred to as compound L, and its resolution into individual enantiomers, which is described in more detail in Example 6. This synthetic scheme and resolution methodology may be used to synthesize and resolve other compounds of the invention, or alternatively, those skilled in the art may utilize other synthetic and/or resolution methodologies.

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

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

Other alternative routes for preparing intermediates involve the condensation of an appropriately substituted piperazine with a carbonyl compound. Condensation with benzaldehyde should yield an ammonium salt that binds the aryllithium 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).

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

Compound L can also be synthesized via the alternative synthetic routes shown in Schemes 7 and 8.

The N-allyl-trans-2,5-dimethylpiperazine reagent used in synthetic scheme 8 is conveniently prepared by the method shown in scheme 9.

The chiral synthetic route used to prepare benzhydrylpiperazines 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 diastereomers is formed, which can be separated by conventional methods such as chromatography or fractional crystallization.

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

Compound L is also synthesized via a nitrile synthesis. Cuprous cyanide is used as the nitriling agent. This synthesis is depicted in Scheme 12, where the BOP reagent is the compound of formula 19.

Alternative methods for preparing compound L from the corresponding halogen compound are given in Scheme 13.

The methods described above are illustrated by examples of synthetic techniques successfully used to prepare compounds such as compound L and other diphenylmethylpiperazines of the invention via suitable or analogous reagents. Of the synthetic methods for preparing compound L presented above, the nitrile route is preferred for practical reasons, as it is somewhat more convenient than the other methods described.

Selected compounds of the invention, identified below by the example numbers in which their synthesis is described, were assayed in in vitro pharmacological assays for activity at opioid receptors. Various receptor systems were used, including brain tissue (delta receptor IC50 and Mu receptor IC50), mouse vas deferens (ED50), and guinea pig ileum (ED50). The assay procedures are provided below.

In vitro assays: Seminal vas were dissected from mice and suspended between platinum electrodes with a tension of 0.5 g in bath chambers containing modified Krebs buffer with the following composition (in millimoles): NaCl, 118; KC1 4.75; CaCl 2.6; KH2PO4 1.2; NaHCO3 _24.5 ; glucose 11. This buffer was saturated with a gas composed of 95% oxygen and 5% carbon dioxide and maintained at 37°C. The tissues were stimulated with an electric current at a supramaximal voltage, with trains of pulses at a frequency of 10 Hz for 400 milliseconds, with the interpulse time being 10 seconds and the pulse duration being 0.5 milliseconds.

The entire ileum (approximately 3 cm long) was dissected from a guinea pig and suspended under 1g tension in a bath similar to that used for the mouse vas deferens experiments. Modified Krebs buffer also contained MgSO4 (1.20 mM). The ileum was stimulated with square-wave electric current pulses at a frequency of 0.1 Hz. The pulse duration was 0.5 milliseconds at supramaximal voltage. The percentage inhibition of electrically induced muscle contractions was determined for individual compounds and various cumulative concentrations. ED50 values were extrapolated from concentration-response curves (J.A.H. Lord, A.A. Waterfield, J. Hughes, H.W. Kosterlitz: Nature 267, 495, 1977). Receptor Binding Inhibition Assay: After preparation of Sprague-Dawley rat brain membranes, receptor 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".

Delta receptor binding assays were performed against the highly selective mu receptor agonist [N- ^MePhe3 , D- ^Pro4 ]morphiceptin to attenuate cross-reactivity to the mu receptor using ^125- labeled J[D- ^Ala2 , D- ^Leu5 ]-enkephalin at a concentration of 0.24 nM.

Binding assays to the mu receptor were performed using ^125- labeled J[D-Ala ² , NMePhe ⁴ , Met(O) ^{W 5} ]-enkephalin at a concentration of 0.1 nM. Nonspecific binding was determined against 1μM of the corresponding unlabeled ligand.

The potency of the tested compounds in inhibiting the binding of ^125J -labeled enkephalin analogues was expressed as the concentration that reduced the binding of these labeled compounds by 50% (IC50). The test results are given in the table.

179 341

Representative examples of opioid receptor activity of compounds of the invention in in vitro ^assays

Example Receptor delta; IC50 (nM) Mouse ED _J0 spermatic cord (nM) Receptor mi IC ₅₀ (nM) Guinea pig ileum 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 > 10,000 (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 > 10,000 (4) >10,000 3700 (4) 19th 11 37(4) 0.8 8.0 (4) XXI 1.3 42(4) 40 5600 (4) XXV 6.5 0 30(12) 20 86(4) XXX 27 20 (8) 0.3 2.1 (8) XXXVI 1.6 8.6 (8) 3.0 10(8)

^and the values given are the average of a number (n) of experiments, or if no number (n) is given in parentheses, then they represent one determination.

^b Antagonist potency ( _pA2 value) determined by the Schild method (Arunlakshana O., Schild HO; Brit. J. Pharmacol, 1959, 14, 48-58): data for blockade of the inhibitory action of [D- ^Ala2 , D- ^Leu5 )-enkephalin in the test of electrically stimulated contraction of the mouse vas deferens muscle.

Preferred compounds of the invention (prepared by one of the convenient synthetic routes, e.g., by nitrile formation) are compounds selected from the group designated by numbers 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 thereof. The compounds of the invention find use in the treatment of conditions and disorders such as physiological pain, diarrhea, urinary incontinence, mental disorders, drug and alcohol overdose and dependence, pulmonary edema, cough, depression, asthma, emphysema and apnea, cognitive disorders, and digestive disorders. For example, the compounds of the invention are administered in a pharmaceutically safe and effective dose and in an appropriate dosage form to an animal, including a human, to relieve pain in the individual.

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

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

A 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 mu and delta opioid receptor agonist, 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 examples of chemical synthesis are given below:

179 341

Melting points were determined on a Thomas-Hoover melting point apparatus and are uncorrected. Except for some chemicals 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) analyses were performed on Perkin-Elmer R-24 and Varian XL-200 or XL-300 instruments. HPLC analyses were performed in a Waters liquid chromatography system equipped with a 700 Satellite WISP 600E System Controller and a 991 Photodiode Array detector with a 4.6 x 250 mm Cyclobond column (supplied by Advanced Separations Technologies, Whippany, New Jersey) 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. X-ray crystallographic determinations were performed by Molecular Structure Corporation, College Station, Texas. Thin-layer chromatographic analyses were performed on Analtech glass slides precoated with GF silica gel (250 μ). Preparative thin-layer chromatography was performed on Analtech Uniplates coated with silica gel GF (1000 μ and 2000 μ). Elemental analyses 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-butyldimethylsilane as a light yellow liquid. NMR (300 MHz, _CDCl3 ):δ 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 nitrogen and cooled to -78°C. A solution of 1.6 M n-butyllithium in hexane (318 ml, 0.51 mol) was added dropwise at a rate to maintain the temperature below -70°C. After the addition was complete, the reaction mixture was stirred for 30 min, and the cold solution was transferred 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. The rate of transfer was controlled to maintain the reaction temperature below -70°C. The reaction mixture was stirred for an additional 45 min 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 ethereal solution was dried over sodium sulfate, and the solvent was removed, yielding 197.2 g of crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as a yellow oil. NMR (200 MHz, CDCl3): 0.2 (s, 6H); 0.9 (s, 6H); 5.7 (s, 1H); 6.75 (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).

Crude benzhydryl 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 remove excess thionyl chloride, giving crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl chloride as a dark oil. NMR (200 MHz, _CDCl3 ): δ 0.2 (s, 6H); 1.0 (s, 9H); 6.0 (s, 1H); 6.78 (dd, Ji = 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 benzhydryl chloride (approximately 135 mmol) was combined with 46.3 g (405 mmol) of trans-2,5-dimethylpiperazine (purified by recrystallization from toluene to m.p. 115-119°C) and 30 ml of toluene and heated at reflux overnight under nitrogen. The toluene was removed under reduced pressure and the residue was redissolved.

179 341 in 2000 ml of diethyl ether and washed with 500 ml of 1.0 M sodium hydroxide and 1000 ml of water. The ethereal solution was dried over sodium sulfate and the solvent removed to yield a dark oil. The product was purified by chromatography on silica gel with 10% ethanol in dichloromethane to yield 41.0 g (62%) of (±)-trans-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers. NMR (300 MHz, CDCl3): δ 0.15 (s, 6H); 0.9 (m, 12H); 1.2 (d, J = 6 Hz, 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).

Purified benzhydrylpiperazine (41.0 g, 83.7 mmol) was dissolved in 500 mL of dry tetrahydrofuran with 7.3 mL (84 mmol) allyl bromide and 22 g (200 mmol) sodium carbonate and heated under reflux overnight under nitrogen. The cooled reaction solution was filtered, and the solvent was removed to give 44.1 g of crude (±)-trans-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a brown oil. NMR (200 MHz, _CDCl3 ): δ 0.15 (s, 6H); 0.95 (m, 12H); 1.15 (2 overlapping d, J = 6 Hz, 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 product, a brown oil (44.1 g, 83.3 mmol), was dissolved in 200 mL of acetone with 20 g (approximately 130 mmol) of tetraethylammonium fluoride hydroxide and stirred for 1 h 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 residue. The product was purified by chromatography on silica gel (Waters Prep 500) using 0.5-1% ethanol in dichloromethane containing 0.1% triethylamine. Both diastereomers 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 dichloromethane:ethanol:ammonium hydroxide/95:5:1) gave 7.3 g (21%) of (±)-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, Ji = 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, Ji = 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, Ji = 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 2HCl 0.33 H ₂ O: C, 53.46; H, 6.05; N, 5.67; total halogen calculated as Cl, 21.43. Assayed: C, 53.65; H, 6.39; N, 5.53; total halogen as Cl, 20.98. Assignment of relevant stereochemistry made from X-ray crystallographic structure determination.

The above compound could also be prepared by fractional crystallization of a mixture of isomers, which was partially enriched in the desired isomer by chromatography on a short silica gel column with a 1:1 dichloromethane:ethyl acetate mixture. Thus, a mixture (115 g) of (±)-3-((aR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol (70%) and (±)-3-((aR*)-α-((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 while hot. The filtrate was cooled to 42°C and seeded with crystals of (±)-3-((aR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenyl)phenol. The solution was cooled to 34°C and filtered to give 18.8 g of (±)-3-((aR*)-α((2S*, 5R*)-4-allyl-2,5-dimethylpiperazinyl)-4-bromobenzyl)phenol with an isomeric purity of 95%. Additional harvests gave 22.2 g of material of similar purity. The total amount of 40.0 g was recrystallized in the same way, obtaining 32.7 g of (±)-3-((aR*)-a-((S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol with isomeric purity above 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, mp 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 = 11 Hz, 1H); 5.13 (s, 1H); 5.18 (d, J = 16 Hz, 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 = 8 Hz, 4H); 9.3 (s, 1H). A portion was converted into the dihydrochloride salt using 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 2HCl 0.5H ₂ O: C, 53.14; H, 6.08; N, 5.63; total halogen expressed as Cl, 21.39. Assayed: C, 53.23; H, 6.40; N, 5.50; total halogen expressed as Cl, 21.04.

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

Example 1P. (±)-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 1) (32.6 g, 0.0786 mol) and cuprous cyanide (14.1 g, 0.157 mol) in 500 ml of dimethylformamide was heated at reflux for 3 days under nitrogen. The reaction mixture was cooled to room temperature and then poured into a mixture of 2000 ml of 30% sodium cyanide and 1500 ml of diethyl ether. The diethyl ether was washed with 600 ml of water and then with 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 _C27H36N3O : C, 76.42; H, 7.53; N, 11.62. Found: C, 76.31; H, 7.54; N, 11.55. NMR (200 MHz, DMSO- _d6 ): δ 0.95 (d, J = 6 Hz, 3H); 1.08 (d, J = 6 Hz, 3H); 1.77 (dd, J = 8 Hz, i 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 (p, 2d. 3H); 7.15 (t, J = 8 Hz, 1H); 7.6 and 7.8 (ABq, J = 8 Hz, 4H); 9.4 (s, 1H).

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

(±)-3-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol (0.30 g, 0.72 mmol) from 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 of a 1.6 M solution in hexane) and carbon dioxide as described in Example 6, Method B to give 0.35 g of a colorless vitreous.

Thionyl chloride (78 μA, 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 h at 0°C, this mixture was added dropwise to cold concentrated ammonium hydroxide (1.5 mL), stirred for 1 h 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 to give 0.21 g (58%) of (±)-4-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzamide as a yellow oil. NMR ( _CDCl3 ): 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 acetonitrile solution. The solvent was removed, the residue 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 give 97.4 mg (60%) of a white solid. Calculated for C23H29N3O2 HC10.5 _H2O : C, 64.34; H, 7.65; N, 9.38; Cl, 7.91. Assayed: C, 64.44; H, 7.93; N, 9.30; Cl, 7.94, mass spectrum (Cl-CH4) m/z 380 (M+1, 100%), 153 (9%), 226 (10%). A portion of the crude product was purified by chromatography on silica gel using dichloromethane:ethanol (2-10%) to give a light yellow foam. NMR (CDCl3): δ 1.0 (d, J - 6 Hz, 3H); 1.1 (d, J = 6 Hz, 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 - 8 Hz, 1H); 7.5 (d, J = 9 Hz, 2H); 7.6 (d, J = 9 Hz, 2H).

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

A solution of (±)-4-(((xR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzonitrile (Example 1P) (20.81 g, 0.0575 mol) and sodium hydroxide pellets (16.1 g, 0.402 mol) in 200 ml of 95% ethanol was heated under reflux overnight. The solution was cooled to room temperature, adjusted to pH 6 with 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-((αR*)-α-((2S*, 5R*)-4-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzonitrile (Example 1P) (20.81 g, 0.0575 mol) and sodium hydroxide pellets (16.1 g, 0.402 mol) in 200 ml of 95% ethanol ... (5R*)-4-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 isolated by filtration and dried under vacuum at 55°C. A suspension 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 again 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-hydroxybenzyl) benzoic acid as a brown solid. Calculated for C23H28N2O3 1.5H2O: C, 67.78: H, 7.67; N, 6.87. Assayed: C, 67.78; H, 7.38; N, 6.90. NMR (200 MHz, _D2O /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

A solution of crude (±)-4-((ccR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid (Example V, from 7.1 mmol from Example I), benzothiazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.1 g, 14 mmol) and diethylamine (3.7 ml, 35 mmol) in 100 ml of dimethylformamide was stirred overnight at room temperature. 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 aqueous layer was adjusted to pH 8 with 10 M sodium hydroxide and then extracted with 350 ml of dichloromethane. The dichloromethane layer was dried over sodium sulfate. The solvent was evaporated to give 3.59 g of a brown oil. The oil was chromatographed on silica gel using ethyl acetate:hexane to give 1.24 g (40%) of (±)-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 (58% total yield) of the amide as white needles, mp 170-171°C. Calculated for C27H27N3O2: C, 74.45; H, 8.56; N, 9.65. Marked: 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 = 11 Hz, 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 = 8 Hz, 4H); 9.35 (s, 1H).

Method B (±)-3-(<xR*)-α-((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) tert-butylchlorodimethylsilane and 2.05 g (30 mmol) imidazole and 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 ethereal solution was dried over sodium sulfate and the solvent removed to give 7.4 g of an oil, which was purified by chromatography on silica gel using 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 as a light yellow oil. NMR (200 MHz, CDCl3): δ 0.15 (s, 6H); 0.96 (s, 9H); 0.97 (d, J = 6 Hz, 3H); 1.15 (d, J = 6 Hz, 3H); 1.87 (dd, Ji = 9.5 Hz, J ₂ - 10 Hz, 1H); 2.12 (dd, Ji = 9.5 Hz, J ₂ = 10.5 Hz, 1H); 2.35-2.65 (m, 3H); 2.75-2.95 (m, 2H); 3.36 (dd, Ji = 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 = 7.7 Hz, 1H); 7.31 and 7.39 (ABq, J - 8.8.5 Hz, 4H).

Silyl ether (6.55 g, 12.4 mmol) was dissolved in 60 mL of dry tetrahydrofuran and cooled to -78°C under nitrogen. A solution of 1.35 M n-butyllithium in hexane (9.2 mL, 12.4 mmol) was added dropwise at such a rate as to maintain the temperature below -70°C. The orange solution was stirred for an additional 30 min at low temperature, and then anhydrous carbon dioxide gas was introduced into the reaction solution at such a rate as to maintain the temperature below -60°C. The addition of carbon dioxide was stopped when the reaction solution turned light yellow. The reaction mixture was allowed to warm to room temperature with stirring, and the solvent was removed under reduced pressure. The residue was redissolved in 50 ml of toluene and the solvent was again removed in vacuo to remove n-bromobutane. The reaction gave 6.2 g of (±)-4-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoic acid, lithium salt. 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 h 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 using 1-3 percent ethanol in dichloromethane to give 2.15 g (32%) of (±)-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, CDCl3): δ 0.15 (s, 6H); 0.95 (s, 9H); 0.97 (d, J = 6 Hz, 3H); 1.12 (br m, 3H); 1.18 (d, J = 6 Hz, 3H); 1.23 (br m, 3H); 1.87 (dd, Ji = 9 Hz, J ₂ = 11 Hz, 1H);2.21 (dd, Ji = 9 Hz, J ₂ = 11 Hz, 1H); 2.45 (m, 1H); 2.56 (dd, Ji = 2.5 Hz, J ₂ = 11 Hz, 1H); 2.58 (m, 1H); 2.79 (dd, Ji = 3 Hz, J ₂ = 11 Hz, 1H); 2.85 (dd, Ji = 8 Hz, J ₂ = 14 Hz, 1H); 3.25 (br m, 2H); 3.36 (dd, Ji = 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 - 8 Hz, 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 removed, yielding 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 to give 1.45 g (72%) of (±)-4-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride as a hygroscopic solution.

179,341 scopic white powder. Calculated for C27H37N3O2 2HCl 0.5 H2O: C, 62.66; H, 7.79; N, 8.12; Cl, 13.70. Assayed: C, 62.47; H, 7.91; N, 8.02; Cl, 13.49). A portion was converted to the free amine by adjusting the aqueous solution to pH = 8 and extracting with dichloromethane, to give a sample for spectral analysis. NMR (300 MHz, CDCl3): δ 1.00 (d, J = 6 Hz, 3H); 1.12 (br m, 3H); 1.16 (d, J = 6 Hz, 3H); 1.25 (br m, 3H); 1.90 (dd, Jj = 9 Hz, J ₂ = 11 Hz, 1H); 2.14 (dd, Ji = 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, Ji = 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 = 8 Hz, 4H). Mass spectrum (Cl-CH4) m/e: 436 (m+l, 48%), 284 (100%), 153 (57%).

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

A solution of crude lithium salt of 4-((aR*)-a-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-tert-butyldimethylsiloxybenzyl)benzoate (11.5 g, from 23 mmol from 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 dilution 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 off, washed with water and dried under reduced pressure (60°C) to give 2.65 g (30%) of (±)-4((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid as 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 = 11 Hz, 1H); 2.9 (dd, Ji = 7 Hz, J ₂ = 14 Hz); 3.1 (dd, Ji = 14 Hz, J ₂ = 5 Hz, 1H); 4.9-5.2 (m, 3H); 5.6-5.8 (m, 1H); 6.5 (dd, Ji = 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 = 8 Hz, 2H); 7.9 (d, J = 8 Hz, 2H). Calculated for C23H28N2O3 1.25 H2O: C, 68.55; H, 7.63; N, 6.95. Marked: C, 68.61; H, 7.66; N, 7.02. Mass spectrum (Cl-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

A solution of (±)-3-((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol (Example Π) (35.00 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 min 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*)^-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 = 11 Hz, 1H); 2.09 (t, J = 11 Hz, 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 into the monohydrochloride salt by titration to pH 3.8 with ethanolic hydrogen chloride. The salt was precipitated from ethanol with diethyl ether, giving 15.82 g of the 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. Assayed: C, 69.55; H, 8.03; N, 7.31; Cl, 9.27

Example 9. 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), 1 L dimethylformamide, and 2 L dichloromethane was cooled in an ice-cooling bath. Thionyl chloride (53 ml, 0.73 mol) was added dropwise with 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. The organic layers

179,341 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 as 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 nitrogen and cooled to -78° C. A solution of 1.6 M n-butyllithium in hexane (132 ml, 0.21 mol) was added dropwise at a rate to maintain the temperature below -70° C. Stirring was continued 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. The rate of transfer was controlled to maintain the temperature below 70° C. After stirring for 1 hour at -78°C, the reaction was quenched with saturated aqueous ammonium chloride, 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 using dichloromethane:ethanol (0-1%) afforded 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 h at room temperature, the solvent was evaporated, the residue was redissolved in toluene, and evaporated again to remove excess thionyl chloride.

A mixture of crude benzhydryl chloride (approximately 0.11 mol), cis-2,6-dimethylpiperazine (43.97 g, 0.39 mol), and 10 mL of toluene was heated under reflux under nitrogen for 2 h. The reaction mixture was partitioned between aqueous 1N hydrochloric acid and diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous 5 M 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 and 9.8 g (74 mmol) of 1-bromo-2-butyne prepared from 2-butyne-1-ol (L. Brandsma, "Preparative Acetylene Chemistry", second edition, Elsevier, 1988, p. 248) in 400 ml of dry tetrahydrofuran was heated under reflux 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 was added. After stirring at room temperature for 3 hours, the solvent was removed and the residue was purified by chromatography on silica gel using dichloromethane:ethanol (0-4%) to give 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 Engelhard Industries Lindlar catalyst and reduced in an atmospheric pressure hydrogenator with magnetic stirring. The reaction was complete in 2 hours as judged by thin-layer chromatography (dichloromethane:ethanol:ammonium hydroxide/90:10:1). The catalyst was filtered through Celite, and the filtrate was evaporated to give a brown solid. Chromatography on silica gel (Waters Prep 500 using dichloromethane:ethanol:triethylamine/l 00:0.5-2:0.1) gave 5.47 g (43%) of cis-4-(a-(4((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide as a white solid. NMR (CDCfijto 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); 7.25 (d, 2H) was added to precipitate 4.36 g (d, 2H). Calculated for C28H38N3O7 HCl _H2O : C, 66.85; H, 8.21; N, 8.35; Cl, 7.05. Marked: C, 66.79; H, 8.40; N, 8.36; Cl, 7.00. Mass spectrum (Cl-CH4): m/z 450 (M+1, 100%), 282 (9%), 167 (29%).

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

A mixture of 15.65 g (36 mmol) N,N-diethyl-4-(3-tert-butyldimethylsilyloxy)-achlorobenzyl)benzamide, prepared as described in Example 9, 7.22 g (65 mmol) (+)-(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 were heated as in Example 1. The product was purified by chromatography on silica gel (Waters Prep 500 using dichloromethane containing 1% ethanol and 0.1% triethylamine) to give 4.06 g (22%) N,N-diethyl-4-(3-tert-butyldimethylsilyloxy)-α-((2S, 5S)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide in the form of a beige foam.

A mixture of the above benzhydrylpiperazine (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 h. The solvent was evaporated. The residue was dissolved in dichloromethane and filtered to remove inorganic salts. Evaporation of the filtrate gave 6.7 g of a brown oil. Silica gel chromatography (Waters Prep 500 using dichloromethane containing 0.5% ethanol and 0.1% triethanolamine) afforded 1.17 g (28%) of N,N-diethyl-4-(3-(tert-butyldimethylsilyloxy)-(αR)-α-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide as a yellow oil. The α-S isomer was also isolated (1.37 g, 33%).

The αR isomer from above (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-(αR)-α((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide as a beige solid. NMR ( _CDCl3 ): δ 0.95 (d, J - 6 Hz, 3H); 1.05 (d, J = 7 Hz, 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 = 8 Hz); 7.45 (d, J = 8 Hz, 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. Calculated for C25H35N3O2 HCl 1.25H ₂ O: C, 64.09; H, 8.29; N, 8.97; Ćl, 7.57. Assayed: C, 64.12; H, 8.29; N, 8.92; Cl, 7.65. [a] ² °D = +22° (anhydrous ethanol, 7 mg/ml). The stereochemistry of the compound was determined by X-ray crystallography (Molecular Structure Corp., College Station, Texas).

Example 11. (+)-N,N-Diethyl-4-(3-hydroxy-(aR)-a-((2R, 5R)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide

The procedure described in Example 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 tetraethylamine fluoride hydrate were added. The solution was stirred overnight at room temperature. The solvent was evaporated and the residue was treated with 100 ml of aqueous 1 N hydrochloric acid and extracted with 200 ml of diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous 5 M 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 as a light brown solid.

The above benzhydrylpiperazine (4.1 µg, 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 heated at 80°C for 18 hours, cooled to room temperature, treated with 6 ml of aqueous 6 M hydrochloric acid, and extracted with diethyl ether. The aqueous layer was diluted with water and the pH was adjusted to 8 with aqueous 10 N 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. Chromatography on silica gel using

179,341 of dichloromethane:methanol (1 to 7%) gave 3.01 g (70%) of N,N-diethyl-4-(3-hydroxy-α-((2R, 5R)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide as 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 diastereomers of the product were separated by chromatography on silica gel using dichloromethane:ethanol (0.5 to 1%). The less mobile isomer (Rf =0.61) was separated on silica gel using dichloromethane:ethanol:ammonium hydroxide/90:10:1 to give 0.79 g (25%) of N,N-diethyl-4-(3-tert-butyldimethylsiloxy(ccR)-α-((2R,5R)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide as a beige solid. NMR ( _CDCl3 ): 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 = 8 Hz, 2H); 7.45 (d, J = 8 Hz, 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 to pH 8. After drying over sodium sulfate, the solvent was evaporated and the residue was dissolved in anhydrous ethanol. Titration of this solution to pH 4.4 with ethanolic hydrochloric acid and subsequent precipitation with diethyl ether gave 0.61 g (87%) of (+)-N,N-diethyl-4-(3-hydroxy-(aR)-a-((2R,5R)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide monohydrochloride as a beige powder. Calculated for C25H35N3O2 HCl _0.75H2O : C, 65.34; H, 8.23; N, 9.14; Cl, 7.71. Determined: C, 65.18; H, 8.33; N, 8.94; Cl, 7.52. Mass spectrum (Cl-CH4) m/z 410 (M+1, 100%). [a] ²⁰ _D = +10.9 (anhydrous ethanol, c = 19.7 mg/ml). The stereochemistry of the benzhydryl carbon was assigned by comparison with the diastereoisomer of Example X by TLC and NMR.

Example XII (±)-4-((aR*)-α-((2R*, 5S*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (±)-4-((aR*)-α-((2R*, 5S*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was 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 = 6 Hz, 3H); 1.1-1.3 (br m, 6H); 1.8 (dd, Jj = 5 Hz, J ₂ = 14.5 Hz, 1H); 3.1-3.6 (br m, 4H); 5.0 (s, 1H); 5.1 (d, J = 10 Hz, 1H); 5.15 (d, J = 17 Hz, 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 - 8 Hz, 1H); 7.3 (s, 4H); 9.3 (s, 1H). Calculated for C27H37N3O2 _HC1H2O : C, 66.17; H, 8.23; N, 8.57; Cl, 7.23. Marked: C, 66.00; H, 8.24; N, 8.57; Cl, 7.20.

Example ΧP1. (±)-4-((aR*)-α-((2R*, 5S*)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (±)-4-((aR*)-α-((2R*, 5S *)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example ΧP) (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 heated at reflux for 3 days and filtered through Celite. The solvent was removed, and the residue was purified by chromatography on silica gel using 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 overnight with ethyl acetate. Filtration afforded 9.09 g (46%) of (±)-4((aR*)-a-((2R*, 5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide as a yellow-brown solid. Calculated for C24H33N3O2 0.5H2O: C, 71.26; H, 8.47; N, 10.39. Marked: C, 71.12; H, 8.47; N, 10.49. NMR (300 MHz, CDCl ₃ ): δ 0.9 (d, J = 6 Hz, 3H); 1.2 (di br tr, 9H); 1.5 (t, J = 10 Hz, 1H); 2.2 (br m, 1H); 2.5 (m, 1H); 2.6 (d, Ji = 9 Hz, 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 = 8 Hz, 4H); 9.0 (br s, 1H).

Example XIV. (±)-4-((aR*)-a-((2S*, 5R*)-2,5-Dimethyl-1-piperazinyl-3hydroxybenzyl)-N,N-diethylbenzamide, mp 178-180°C, was prepared from Example 6 by the methods described in Example ΧΠΙ. Calculated for C24H33N3O2: C, 72.87; H, 8.41; N, 10.62. Calculated: C, 72.72; N, 10.47; 1.5 (t, J = 10 Hz, 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 = 8 Hz, 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-phenylalanyl-L-leucine

A solution of carbobenzyloxy-L-phenylalanine (5.00 g, 16.7 mmol), L-leucine tert-butyl ester hydrochloride (3.74 g, 16.7 mmol), benzotriazol-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 h. The reaction mixture was poured into 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 using 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 in a Parr hydrogenator for 3 h. The mixture was filtered and concentrated to dryness to afford 0.35 g (98%) of tert-butyl L-phenylalanyl-L-leucinate.

Crude (±)-4-((aR*)-a-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoic acid lithium salt (0.52 g, 1.0 mmol) (Example VII, 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 h, the reaction mixture was poured into 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 using dichloromethane:ethanol to give 0.45 g (53%) of tert-butyl N-(4-((aR*)-a-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-((tert-butyldimethylsilyloxy)benzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.

A portion of the benzhydrylpiperazine as above (0.36 g, 0.44 mmol) was stirred with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 h. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:ethanol to give 0.180 g (58%) of tert-butyl N-(4-((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.

A portion of the tert-butyl ester (0.17 g, 0.25 mmol) was stirred in 10 mL of trifluoroacetic acid for 1 hour. The solvent was removed, and the resulting solid was dried under vacuum to give 0.190 g (86%) N-(4-((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucine as the trifluoroacetic acid salt. Calculated for C38H48N4O5 2C2HF3O2 H2O: C, 56.88; H, 5.91; N, 6.32. Assayed: 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 with 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.

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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 (±)-4-((aR*)-α-((2S*, 5R*)4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid lithium salt (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 to give 0.64 g (34%) of (±)-N-(4-((aR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-tert-butyldimethylsilyloxy)benzyl)benzoyl)glycylglycine as the trifluoroacetate salt. Calculated for C27H34N4O53.5CF3COOH: C, 45.70; H, 4.23; N, 6.27. Assayed: C, 45.55; H, 4.50; N, 6.08.

A small amount was converted to the 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 = 10 Hz, 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 = 10 Hz, 1H); 5.15 (d, J = 17 Hz, 1H) 5.8 (m, 1H); 6.8 (2d, J = 8 Hz, 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 = 8 Hz, 4H); 8.8 (br t, J = 5 Hz, 1H).

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

A mixture of (±)-4-(3-((tert-butyldimethylsilyloxy)-α-(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) was heated overnight at 80°C. The reaction mixture was cooled to room temperature and 20 ml of 7.2 M hydrochloric acid was added slowly. The mixture was washed 3 times with 40 ml of dichloromethane. The aqueous layer was adjusted to pH 8 with saturated sodium bicarbonate solution and then extracted 3 x with 40 ml of dichloromethane. The organic extracts were dried over 20 ml of 7.2 M hydrochloric acid. magnesium sulfate and evaporated to dryness, yielding 12.6 g (84%) of (±)-4-(3-hydroxy)-α-(cis-3,4,5-trimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a yellow-brown foam. NMR (300 MHz, CDCl3): 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 = 7 Hz, 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 using excess ethereal hydrogen chloride. The solvent was removed and the residue was redissolved in a minimum amount of dichloromethane. Diethyl ether was added, and an oily precipitate was obtained, which solidified on stirring. Filtration gave the dihydrochloride salt hydrate. Calculated for C25H35N3O2 2HCl 1.5H2O: C, 58.93; H, 7.91; N, 8.25; Cl, 13.92. Assayed: 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

To a 12-L three-necked round-bottom flask was added trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been previously recrystallized from toluene to a mp of 115-119°C, and 600 mL of water. 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 maintain the temperature below 40°C. The solution was cooled to 20°C, and 800 mL of ethanol was added. A 500-mL dosing funnel was filled with 60% aqueous potassium acetate from a 2-L solution reservoir, 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 a second addition funnel. The ethyl chloroformate and potassium acetate solutions were added simultaneously, adjusting the addition rate to maintain the reaction solution at pH 4.0 ±0.1 and with cooling as necessary to maintain the temperature at 25°C. After the chloroformate addition was complete, the flask contents were stirred for 1 hour while potassium acetate solution was added to maintain pH 4.0. The organic solvents were removed by distillation under reduced pressure. The remaining aqueous solution was washed with 1500 ml of ethyl acetate to remove biscarbamate impurities. The ethyl acetate used for the washes was extracted with two

179,341 with 500 ml portions of 1 M hydrochloric acid 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, with cooling. To maintain 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 afford 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 of acetonitrile was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature, filtered, and the solvent removed under reduced pressure. The residue was dissolved in 4000 ml of dichloromethane and washed with two 500 ml portions of 1 M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate, and the solvent was removed to afford 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) was added to an 87% solution of granular potassium hydroxide (2970 g, 46 mol) in 4300 ml of 95% ethanol and heated to reflux for 1.5 hours. Carbon dioxide evolution was observed during the first period (0.5 to 1 hour) of heating. The reaction mixture was cooled to below reflux temperature, and 2000 ml of toluene was carefully added. The ethanol was removed by azeotropic distillation at 105°C while an additional 4000 ml of toluene was added to the reaction flask during this distillation. After collecting 9000 ml of distillate, the reaction mixture was cooled to 100°C, and 1000 ml of toluene was carefully added. The solution was slowly cooled to 5°C and held at this temperature for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 ml of toluene. The filtrate was then washed with 1000 ml of water, dried over magnesium sulfate, and the solvent removed to yield 296 g (69%) of 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 nitrogen 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 maintain 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 a room temperature solution of magnesium bromide (20.2 g, 0.11 mol) in 400 ml of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to 15°C with stirring. After 1 hour, a solution of 4-bromo-2-thiophenecarboxaidehyde (20.0 g, 0.105 mol) in 100 ml of dry tetrahydrofuran was slowly added at a rate such that the temperature was maintained 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 afforded 20.23 g (48.2%) of α-(4-bromo-2-thienyl)-3-((tert-butyldimethylsilyl)oxy)benzyl alcohol as a viscous yellow oil.

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

A mixture of crude diarylchloromethane (ca. 0.18 mol), N-allyl-trans-2,5-dimethylpiperazine, and 1000 ml of acetonitrile was heated at reflux under nitrogen for 40 h. 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. Excess N-allyl-trans-2,5-dimethylpiperazine was removed by silica gel chromatography with ethyl acetate to give 86 g of a black oil, which was purified by silica gel chromatography with dichloromethane:ethyl acetate/95:5 to give 63.1 g (66%) of a dark oil.

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A mixture of the product (63.1 g, 0.118 mol), tetraethylammonium fluoride hydrate (37 g, ca. 0.2 mol) and 100 ml of acetonitrile was stirred at room temperature under nitrogen for 1 hour. The solvent was removed by evaporation, the residue was dissolved in dichloromethane, washed three times with water (pH 8 adjusted with 1M aqueous sodium hydroxide), dried over sodium sulfate and evaporated to a yellow-brown solid. The two diastereomers of the product were separated by chromatography on silica gel using dichloromethane:ethyl acetate/75:25. Eluting of the first isomer gave 15.84 g (32%) of (±)-3-((R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol. 1H-NMR (300 MHz, DMSO-d6): 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 with 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. Marked: 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 151, 4.0 g, 9.5 mmol), tert-butyldimethylsilyl chloride (1.66 g, 11.0 mmol) and imidazole (1.63 g, 24.0 mmol) was dissolved in 20 ml of dry dimethylformamide under nitrogen 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 was cooled to -70°C under nitrogen. A solution of 1.6 M n-butyllithium in hexane (6.4 mL, 10.0 mmol) was added by syringe at a rate to maintain the temperature below 60°C. The solution was cooled to -78°C, and carbon dioxide gas was introduced via cannula below the surface of the solution over 15 min. The solution was allowed to warm to room temperature with stirring. The solvent was evaporated, and the residue was redissolved in toluene and evaporated again to remove butyl bromide. The resulting viscous oil was dissolved in 500 mL of dichloromethane and cooled to 0°C under nitrogen. Thionyl chloride (1.0 ml, 14.0 mmol) was added slowly from a 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 using dichloromethane: ethyl acetate (gradient from 90:10 to 0:100) gave four products in the order of appearance 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*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-2-hydroxybenzyl-3-bromo-N,N-diethyl-2-thiophenecarboxamide in the form of the tert-butyldimethylsilyl ether; 1050 mg (18.9%) (±)-5-((aR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-2-thiophenecarboxamide in the form of the 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 in the form of a tert-butyldimethylsilyl ether.

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

179,341 nitrogen. The solvent was removed by evaporation and the residue was dissolved in dichloromethane, washed three times with pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glassy solid. Chromatography on silica gel using dichloromethane:acetonitrile /2:1 gave 610 mg of (±)-3-((R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thienyl)methyl)phenol as a white solid. 1H-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, IH); 3.30 (m, IH); 5.14 (m, 2H); 5.48 (s, IH); 5.80 (m, IH); 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 into the monohydrochloride salt by titration to pH 3.7 with ethanol hydrochloric acid. The solvent was removed by evaporation and the salt was dissolved in dichloromethane and then precipitated with _diethyl ether to give 500 mg (56%) of a white solid with mp 115-121°C. Calculated for C20H26N2OSHC10.4H2O: 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 substance eluted from the column in Example XIX (620 mg, 0.98 mmol) was deprotected with tetraethylammonium fluoride hydrate as in Example XIX. Chromatography on silica gel with dichloromethane:acetonitrile /1:1 gave 280 mg of a colorless glassy substance. 1B-NMR (300 MHz, DMSO- _d6 ): 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, 1H); 5.80 (m, 1H); 6.65 (d, J = 7.8 Hz, IH); 6.80 (d, J = 7.8 Hz, IH); 6.83 (s, lP; 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 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 150 mg (27%) of a white solid, mp 114-124°C. Calculated for _{C25H34BrN3O2SHCl} : C, 53.91; H, 6.33; N, 7.55; Br, 14.35; Cl, 6.37; S, 5.76. Assayed: C, 53.80; H, 6.38; N, 7.59; total halogen expressed as chlorine, 12.72; S, 5.71.

Method B

A mixture of (±)-3-((R*)-((2S*, 5R*)-4-alpha-2,5-dimethyl-1-piperazinyl-(4-bromo-2-thienyl)methyl)phenol (7.7 g, 0.0183 mol), Example XVIII), tert-butyldimethylsilyl chloride (3.17 g, 0.021 mol), imidazole (3.13 g, 0.046 mol) and 50 ml of dry dimethylformamide was stirred at room temperature under nitrogen for 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 (±)-3-((R*)-((2S*,5R*p-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol tert-butyldimethylsilyl ether as a dark oil.

A solution of the product (2.2 g, 4.1 mol) in 250 ml of dry tetrahydrofuran was cooled to -78°C under nitrogen. A solution of 1.5 M lithium diisopropylamide in cyclohexane (2.8 ml, 4.1 mmol) was added from a syringe at a rate sufficient to maintain the temperature below -70°C. The resulting solution was stirred for 1 hour at -78°C, then carbon dioxide gas was introduced via a cannula below the surface of the solution over a period of 10 minutes. While stirring, the solution warmed to room temperature. 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 nitrogen. Thionyl chloride (0.42 ml, 5.75 mmol) was added and the resulting mixture was stirred for 1 hour before the addition of 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 give a dark oil. Chromatography on silica gel using dichloromethane:ethyl acetate 9:1 gave 1.57 g (60%) of (±)-5-((aR*)-a-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl)-3-bromo-N,N-diethyl-2-thiophenecarboxamide tert-butyldimethylsilyl ether.

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The product was deprotected using tetraethylammonium fluoride hydrate as in Example 19. Chromatography using an ethyl dichlorometamocate/1:1 mixture obtained 940 mg of (±)-5-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3hydroxybenzyl)-3-bromo-N,N-diethyl-2-thiophenecarboxamide in a light yellow-brown form marshmallows. 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. Calculated for _{C25H34BrN3O2SHCl} : C, 53.91; H, 6.33; N, 7.55; Br, 14.35; Cl, 6.37; S, 5.76. Assayed: C, 53.82; H, 6.30; N, 7.50; total halogen calculated as 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 at 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 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, and 32 mL (49 mmol) of 1.55 M n-butyllithium in hexane was added dropwise at a rate to maintain the temperature below -60°C. The mixture was stirred for an additional 15 min 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 min. The mixture was stirred for an additional 30 min, and the reaction was quenched at -78°C with saturated aqueous ammonium chloride. After warming to room temperature, the mixture 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-chloroperoxybenzoic 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. Evaporation of the solvent gave 8.76 g of crude (4-methylsulfonylphenyl)(tert-butyldimethylsilyloxyphenyl)methanol as a yellow oil.

The alcohol was then treated with thionyl chloride, trans-2,5-dimethylpiperazine, and allyl bromide according to the procedures described in Example 1 to give 1.68 g of crude (±)-trans-4-allyl-1-(ct)-3-tert-butyldimethylsilyloxyphenyl)-4-methylsulfonylbenzyl)-2,5-dimethylpiperazine as a mixture of diastereomers. The isomers were separated by chromatography on silica gel (Watres Prep 500A) using 0-0.75% ethanol in dichloromethane containing 0.1% triethylamine. The first eluting 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 give (±)-3-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)phenol. ^1H -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, ty = 9 Hz, 1H); 2.1 (dd, ty = 5 Hz, J ₂ = 9 Hz, 1H); 2.2-2.4 (m, 3H); 2.7 (dd, ty = 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 = 8 Hz, 4H). The product was dissolved in ethanol and converted into its dihydrochloride salt using excess ethanolic hydrochloric acid. The salt was precipitated with diethyl ether and then hexane, affording the salt as a hygroscopic white powder. Calculated for C ₂ 3 H ₃ o N ₂ O ₃ S 2 HCl 0.5H ₂ O: C, 55.64; H, 6.70; N, 5.64. Assayed: 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*)-α-((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. Evaporation of the solvent gave 195.4 g (95%) of 4-bromo-N,N-dimethylbenzenesulfonamide as white crystals, mp 90-92°C (according to the literature 94°C, J. Am. Chem. Soc. 45, 2696(1923)).

The sulfonamide (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 give 89.5 g (57%) of 4-(3-tert-butyldimethylsilyloxy)-.alpha.-hydroxybenzyl)-N,N-dimethyl-benzenesulfonamide as a yellow oil which crystallized on storage. A portion was recrystallized from ethanol:water to give white crystals, mp 100-103°C. NMR ( _CDCl3 , 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).

The 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)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The 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 chromatography on silica gel 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.

The benzhydrylpiperazine was treated with allyl bromide as in Example 1 and purified by chromatography on silica gel (Waters Prep 500) using 0.3-0.5% ethanol in dichloromethane containing 0.1% triethylamine to give 17.34 g of a light brown glassy material. The product was treated with tetrabutylammonium fluoride as in Example 21. The two stereoisomers of the product were separated by chromatography on silica gel (Waters Prep 500) using 0.3-3.0% ethanol in dichloromethane containing 0.1% triethylamine. Eluting of the more mobile isomer gave 4.94 g (36%) of (±)-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. ^1H -NMR (300 MHz, _CDCl3 ): δ 1.05 (d, J = 6 Hz, 3H); 1.2 (d, J = 6 Hz, 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, Ji = 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 = 9 Hz, 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 dihydrochloride salt _was precipitated with diethyl ether and hexane to give 3.19 g (66%) of _a hygroscopic white powder. Calculated for _{C24H33N3O3S2HCl1.5H2O} : C, _53.03 ; H, _7.05 ; N, 7.73; S, 5.90; Cl, 13.04. Assayed: 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-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzenesulfonamide

The procedure of Example 9 was used, starting from 4-bromobenzenesulfonyl chloride and diethylamine. The final mixture of diastereomers was separated by

179 341 chromatography in a similar manner. Elution of the more mobile isomer gave a light brown glassy substance. 1H-NMR (300 MHz, DMSO-d6): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.05 (t, J = 7 Hz, 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 = 7 Hz, 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 = 8 Hz, 4H). The dihydrochloride salt was obtained in the form of a hygroscopic solid. Calculated for C26H37N3O3S 2HC1H ₂ O: C, 55.51; H, 7.35; N, 7.47, S, 5.70; Cl, 12.60. Marked: C, 55.42; H, 7.41; N, 7.39; S, 5.73; Cl, 12.73. Mass spectrum (El) 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-diethylbenzenesulfonamide

Elution of the less mobile isomer from the chromatography of example ΧΧΠΙ gave a light brown glassy substance. 'H-NMR (300 MHz, CDCl3): δ 1.05 (d, J = 6 Hz, 3H); 1.15 (t, J = 7 Hz, 3H); 1.2 (d, J = 6 Hz, 3H); 1.9 (dd, Jj = 10 Hz, J ₂ = 12 Hz, 1H); 2.35 (dd, J i = 10 Hz, J ₂ = 12 Hz, 1H); 2.5 (m, 2H); 2.65 (m, 1H); 2.9 (dd, J i = 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 - 8 Hz, 1H); 7.15 (t, J = 8 Hz, 1H); 7.55 and 7.7 (ABq, J = 8 Hz, 4H). The dihydrochloride salt was obtained as a hygroscopic white solid. Calculated for C26H37N3O3S2HC1H2O: C, _55.51 ; H, 7.35; N, 7.47, S, 5.70; Cl, 12.60. Marked: 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)ethylamine to form the amide. 1H-NMR (200 MHz, DMS2-d6): 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, J = 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 = 17Hz, 1H); 7.16 (t, J = 8Hz, 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, obtaining the salt, monohydrochloride. Calculated for ^7^7X303 HC1 1.25H ₂ O: C, 63.51; H, 7.99; N, 8.23; Cl, 6.94. Marked: 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-1-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. A suspension of 2-bromothiazole (50 g, 0.30 mol) in 75 ml diethyl ether was added portionwise, maintaining the temperature between -35°C and -45°C. The resulting dark brown solution was stirred for a further 15 minutes before adding 3-(tert-butyldimethylsilyloxybenzaldehyde) (70.9 g, 0.30 mol, Example XXI below) dropwise from a syringe at such a rate as to maintain the temperature between -25°C and -35°C, and then poured into a mixture of 1 liter of ice and 600 ml of 1 M HCl. The organic phase was dried over sodium sulfate and evaporated to give a brown oil. Chromatography on silica gel using hexane:ethyl acetate (gradient from 90:10 to 80:20) gave 25.5 g (26.4%) of α-(2-thiazolyl)-3-((tert-butyldimethylsilyl)oxy)benzyl alcohol as a viscous yellow oil.

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

A mixture of crude diarylchloromethane (ca. 3.27 mmol), N-allyl-trans-2,5-dimethylpiperazine (1.26 mL, 8.2 mmol, Example XVIII) and 50 ml of acetonitrile was heated at reflux under nitrogen for 16 hours. The solution was evaporated and the residue 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 and dried over

179 341 sodium sulfate and evaporated to give 1.1 g of red-black oil. Chromatography on silica gel using hexane:ethyl acetate (gradient from 80:20 to 50:50) gave two products in the order of elution: 300 mg (20.0%) of (±)-3((R* or S*H(2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol tert-butyldimethylsilyl ether and 280 mg (18.7%) of (±)-3-((S* or R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol tert-butyldimethylsilyl ether.

The first eluted substance, (±)-3-((R* or S*)((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol tert-butyldimethylsilyl ether (2.65 g, 5.79 mmol), was mixed with tetraethylammonium fluoride hydrate (1.86 g, ca. 9.8 mmol) and 200 ml of acetonitrile and stirred at room temperature for 16 hours under nitrogen. The solvent was evaporated and the residue was dissolved in dichloromethane, washed three times with pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glassy substance. Chromatography on silica gel using dichloromethane:methanol 95:5 gave 620 mg of (±)-3-((R* or S*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol as a yellow-brown solid. ^-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, 1H); 5.13 (m, 1H); 5.80 (m, 3H); 3.3Hz, 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 dichloromethane/ethanol and then precipitated with diethyl ether to give 400 mg of a yellow-brown _solid , mp 127-130°C. Calculated for C19H25N3OSHC10.25H2O: C, 59.36; H, 6.95; N, 10.93; Cl, 9.22: S, 8.34. Assayed: 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-1-piperazinyl)(2-thiazolyl)methylphenol

The second eluted substance from the column in Example XXVI, (±)-3-((S* or R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol tert-butyldimethylsilyl ether, was mixed with tetraethylammonium fluoride hydrate (860 mg, approximately 4.5 mmol) and 250 ml of acetonitrile and stirred at room temperature for 16 hours under nitrogen. The solvent was evaporated and the residue dissolved in dichloromethane, washed three times with pH 8 buffer solution, dried over sodium sulfate and evaporated to give a brown glassy substance. Chromatography on silica gel using dichloromethane:methanol / 94:6 gave 480 mg of (±)-3-((S* or R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thiazolyl)methyl)phenol as a yellow-brown solid. 1D-NMR (300 MHz, DMS0d6): 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 (dd, 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 into the monohydrochloride salt by titration to pH 3.7 with ethanolic hydrochloric acid. The solvent was evaporated and the salt was dissolved in dichloromethane/ethanol and then precipitated with diethyl ether to give 150 mg of yellow-brown solid, mp 124-128°C. Calculated for C ₁₉ H ₂₅ N ₃ =S HCl 0.25H ₂ O: C, 59.36; H, 6.95; N, 10.93; Cl, 9.22; S, 8.34. Assayed: 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-1-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 nitrogen 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 as to maintain the temperature below -70°C. The mixture was stirred for 30 minutes after the addition was complete, and the cold solution was transferred to a second vessel containing a solution of magnesium bromide (37.8 g, 0.205 mol) in 600 ml of dry tetrahydrofuran at -40°C under nitrogen. 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 maintain 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 (gradient from 3:1 to 1:1) gave 44.1 g (69%) of 3-((tert-butyldimethylsilyl)oxy)-α-(3-thienyl)benzyl alcohol as a viscous 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 redissolved in toluene and evaporated again to remove excess thionyl chloride.

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

The first isomer to elute was (±)-3-((R*)((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol tert-butyldimethylsilyl ether (12.27 g, 36%). A portion of this was deprotected (3.1 g, 6.79 mol) using tetraethylammonium fluoride hydrate as in Example 19. Chromatography on silica gel using dichloromethane:ethyl acetate 3:1 gave 1.6 g of (±)-3-((R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol as a yellow foam. Ή-NMR (300 MHz, DMSOd 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. Ji = 4.9 Hz, _J2 = 3.0 Hz, 1H); 9.31 (s, 1H), The amine was dissolved in ethanol and converted into 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 to give 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. Assayed: 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-ditoluyl-D-vinyl acid in 15 ml of anhydrous ethanol was added to a suspension of 3.46 g of (±)-3-((R*)-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol (Example XVIII) in 10 ml of anhydrous ethanol. The mixture was heated to boiling and then the resulting clear solution was left to crystallize at room temperature. After five recrystallizations, the salt was dissolved in 20 ml of 1N 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 theory for one enantiomer) of (-)-3-((R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol as white crystals, mp 183-185°C, [α] ²⁰ D = 14.0° (tetrahydrofuran, c = 2.1). HPLC on β-cyclodextrin using methanol: 0.1 M ammonium acetate /1:1 as eluent gave one peak at tR = 8.1 minutes. Calculated for _C2oH25BrN2OS : C, 57.00; H, 5.98; N, 6.65; Br, 18.96; S, 17.61. Marked: 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

Bromine was removed from (-)-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) with n-butyllithium as in Example 5H[. 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, [α] d = -23.3° (ethyl acetate, c = 1.5). HPLC on β-cyclodextrin using

179 341 as the eluent mixture of methanol: 0.1 M ammonium acetate /1: 1 gave one peak at tR - 8.5 minutes. Calculated for C ₂ oH ₂ 6BrN ₂ OS 0.25H ₂ O: C, 69.23; H, 7.70; N, 8.07; S, 9.24. Marked: 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 give 0.201 g (61%) of the monohydrochloride salt. Calculated for C ₂ oH ₂ 6BrN ₂ OS HC1 0.75H ₂ O: C, 61 21; H, 7.32; N, 7.12; S, 8.17; Cl, 9.03. Marked: 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 a suspension of (±)-3-((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenyl (6.43 g, 15.5 mmol, Example II) in 150 ml of anhydrous 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 several days at room temperature, the crystals were collected and recrystallized from 90% aqueous ethanol. The crystalline di-p-toluol-D-tartrate salt was dissolved in 1 N aqueous sodium hydroxide and titrated to pH 8 with 6 N hydrochloric acid. The resulting suspension 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, [α] 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 _C22H27BrN2O : 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 by the method of Example 8, starting from (±)-3-((aS)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol (Example XXXI). The product was recrystallized from acetonitrile, yielding 0.26 g (48%) of (+)-3-((aS)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol in the form of beige crystals, mp 192-195°C. [α] ² °D = +3.7° (tetrahydrofuran, c = 3.5). HPLC on β-cyclodextrin using methanol: 0.1 M ammonium acetate / 1:1 gave one peak at tR = 7.8 minutes. Calculated for _{C22H28N2OO.1CH3CN} : C, _78.29 ; H, 8.37; N, _8.64 . Assayed: C, 77.98; H, 8.31; _N , 8.53.

Example ΧΧΠΙ. (±)-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-butyldimethylsiloxylyloxy)benzaldehyde (74.8 g, 0.316 mol, Example XXI above) were each dissolved in 500 mL of anhydrous diethyl ether under nitrogen and cooled to -78°C in a dry ice/acetone bath. n-Butyllithium (198 mL, 0.316 mol, 1.6 M in hexanes) was added dropwise to the cooled pyridine solution at _a rate to maintain the temperature below -70°C. After the addition was complete, the mixture was stirred for 10 min. The aldehyde solution was then added via cannula to the reaction mixture, maintaining the temperature below -70°C. The mixture was stirred at -78°C for 45 min 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 hydrochloride salt of (tert-butyldimethylsilyl)(3-(α-chloro-3-pyridylmethyl)phenyl ether) as a brown solid. The crude alkyl chloride (about 0.311 mol) was mixed with 120 g (0.78 mol) of N-allyl-trans-2,5-dimethylpiperazine (Example XVIII above) in 100 ml of acetonitrile and heated under reflux overnight. After cooling the reaction mixture to room temperature, 62 g (about 0.43 mol) of tetraethylammonium fluoride hydrate was added and the mixture was stirred for 1 hour. The solvent was removed and the product purified by

179,341 by chromatography on silica gel using 0-20% ethanol in dichloromethane. The first eluted isomer was obtained as 14.7 g of a dark oil which crystallized from 100 ml of acetonitrile on storage at room temperature. This gave 3.0 g of (±)-3-((R*X(2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-pyridylmethyl)phenol, mp 115-118°C. Calculated for C21H28N3O: C, 74.52; H, 8.34; N, 12.41. Assayed: C, 74.78; H, 8.11; N, 12.47. NMR (200 MHz, DMSO-dj): δ 0.95 (d, J = 6 Hz, 3H); 1.09 (d, J = 6 Hz, 3H); 1.84 (dd, Ji = 7.6 Hz, J ₂ = 11.7 Hz, 1H); 2.10 (dd, Ji = 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, Ji = 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 ΧΧΧΙΠ was obtained as an oil in the amount of 6.9 g. The product was crystallized from ethyl acetate, giving 2.4 g of yellow-brown solid, mp 158-160°C. NMR (200 MHz, DMSO-ds): 0.96 (d, J = 6 Hz, 3H); 1.10 (d, J = 6 Hz, 3H); 1.79 (dd, J = 7.2 Hz, J ₂ = 10.6 Hz, 1H); 2.08 (dd, J = 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, Ji = 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 redissolved in dichloromethane. The salt _was precipitated with ether: _hexane and collected by filtration, giving a white powder. Calculated for _{C2iH27N3OHCl0.75H2O} : C, _65.10 ; H, 7.67; N, 10.85; Cl, 9.15. Assayed: C, 65.12; H, 7.68; N, 10.87; Cl, 9.20.

Example XXXV. (±)-4-((aR*)-α-((2S*, 5R*)-4-(Cyanomethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (±)-4-((aR*)-α-((2S*, 5R*)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.0 g, 2.6 mmol, Example XIV) was mixed with tert-butyldimethylsilyl chloride (0.60 g, 3.9 mmol) and imidazole (0.50 g, 6.5 mmol) in 30 ml of 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 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 h. 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 _C26H34N4O4 : C, 71.86; H, 7.88; N, 12.89. Assayed: C, 71.83; H, 7.94; N, 12.95. NMR (200 MHz, CDCl3): 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 = 11 Hz, 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 1 1N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into cold

179,341 mL of water and extracted with diethyl ether. The ethereal 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, further dried on molecular sieves, then transferred to a reaction flask and diluted to 1200 ml with dry tetrahydrofuran and cooled to -78°C. n-Butyl lithium (310 ml of a 1.6 M solution in hexane) was added with stirring under nitrogen at a rate to maintain the temperature below -70°C. Stirring was continued for 45 min at -78°C. A solution of 3-bromobenzaldehyde (100.0 g, 0.54 mol) in 900 ml of dry tetrahydrofuran was added at a rate to maintain the temperature 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 using hexane:ethyl acetate (4-25%) gave 98.86 g (51%) of 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 benzhydriyl 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 redissolved in toluene, and the solvent was again removed under reduced pressure to remove excess thionyl chloride to give 154 g of crude α-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl chloride as a brown oil. NMR (CDCl3, 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 benzhydiyl 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 heated under reflux overnight. To the cooled reaction mixture was added acetonitrile (350 ml) and tetraethylammonium fluoride hydrate (75 g, 0.38 mol). After stirring at room temperature for 30 min, the solvent was removed under reduced pressure to give 344 g of the crude mixture of diastereomers as a dark brown oil. Chromatography on silica gel using dichloromethane:ethanol (99:1) gave 31.15 g of a brown solid containing 95% of the less mobile diastereoisomer (Rf = 0.42) on silica gel using dichloromethane:ethanol:hydroxide anion / 95:5:1). Crystallization from isopropanol gave 28.6 g (55% of theory for one diastereoisomer) of (±)-(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 - 6 Hz, 3H); 1.8 (dd, Π = 6 Hz, J ₂ = 10 Hz, 1H); 2.1 (dd, Ji = 6 Hz, J ₂ = 10 Hz, 1H); 2.4-2.6 (m, 3H); 2.7 (d, 11Hz, 1H); 2.8 (dd, Ji = 7Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, Jj = 6 Hz, J ₂ = 13 Hz, 1H); 4.9 (s, 1H); 5.1 (d, J= 10 Hz, 1H); 5.2 (d, J = 18 Hz, 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 heated under reflux 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 to give 1.3 g (46%) of (±)-3-((aR*)-a-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzonitrile, mp 169-171°C. Calculated for C^H^N^O: C, 76.42; H, 7.53; N, 11.62. Found: C, 76.35; H, 7.54; N, 11.62.

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

179,341 hydrochloric acid. The solvent was removed under reduced pressure and the residue was kept in suspension for 3 days. Filtration gave 1.44 g of the carboxylic acid 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) to give 0.090 g (10% from 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 redissolved in 10 ml of dichloromethane, and the salt was precipitated with diethyl ether. Filtration gave 0.070 g of the monohydrochloride salt as a white solid. Calculated for C27H37N3O2 HCl _H2O : C, 66.17; H, 8.23; N, 8.57; Cl, 7.23. Assayed: 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)-(-)-Mandelic acid (11.50 g, 75.6 mmol) was added to a suspension of 28.55 g (68.7 mmol) of (±)-3-((aR*)-a-((2R*, 5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)phenol (Example XXXVI above) in 450 ml of absolute ethanol. The mixture was heated until the components were completely dissolved and allowed to crystallize at room temperature. The crystals were collected and recrystallized from absolute ethanol. The crystalline mandelic acid salt was treated with excess 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 theoretical yield of one enantiomer) of (+)-3-((aS)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)phenol as a white solid, mp 205-206°C. [a] ²⁰ _D - +20° ( _methanol c = 2). Calculated for _C22H27BrN2O : C, 63.62; H, 6.55; N, 6.74; Br, 19.24. Assayed: 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-dimethylformamide was heated under reflux 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. The ethyl acetate extracts were combined, washed with brine, and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting brown solid was purified by chromatography on silica gel using dichloromethane:ethanol / 95:5 to give 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 1 = 6.6 Hz, J ₂ = 10.7 Hz, 1H); 2.4-2.7 (m, 3H); 2.75 (dd, Ji = 2.7 Hz, J ₂ = 10.9 Hz, 1H); 2.86 (dd, Ji = 7.0 Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, Ji = 5 Hz, J ₂ = 14 Hz, 1H); 5.0 (s, 1H); 5.1 (d, J= 11 Hz, 1H); 5.2 (d, J = 17 Hz, 1H); 5.7-5.9 (m, 1H); 6.68 (s, 1H); 6.7 (d, J = 8 Hz, 2H); 7.16 (t, J = 8 Hz, 1H); 7.5 (t, J = 8 Hz, 1H); 7.7 (d, J - 8 Hz, 2H); 7.8 (s, 1H); 9.4 (sec, 1H).

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

179 341 was washed with water at pH 8, dried over sodium sulfate and the solvent was evaporated, yielding 2.6 g of a beige solid. Chromatography on silica gel with dichloromethane:ethanol (1-4%) gave 1.76 g (41%) of (+)-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 = 6 Hz, 3H); 1.0-1.2 (br m, 6H); 1.9 (dd, Jj = 8 Hz, J ₂ = 12 Hz, 1H); 2.1 (dd, Ji = 7 Hz, J ₂ - 11 Hz, 1H); 2.4-2.7 (m, 3H); 2.7 (dd, Ji = 3 Hz, J ₂ = 11 Hz, 1H); 2.9 (dd, Jj = 7 Hz, J ₂ = 14 Hz, 1H); 3.2 (dd, Ji = 5 Hz, J ₂ = 14 Hz, 1H); 3.1-3.5 (m, 4H); 5.0 (s, 1H); 5.1 (d, J= 10 Hz, 1H); 5.2 (d, J = 17 Hz, 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 (Mζ 13%), 436 (M+1, 37%), 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 _{C27H37N3O2HCl1.25H2O} : C, _65.57 ; H, 8.25; N, 8.50; Cl, 7.17. Assayed: 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-dj, 200 MHz): δ 0.8-1.0 (br m, 3H); 0.95 (d, J = 6 Hz, 3H); 1.1 (d, J = 6 Hz, 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= 9 Hz, 1H); 5.2 (d, J = 17 Hz, 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-d, 200 MHz): δ 0.95 (d, J = 6 Hz, 3H); 1.1 (d, J = 6 Hz, 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= 10 Hz, 1H); 5.17 (d, J = 17 Hz, 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, 10 Hz, 1H); 5.1 (d, J = 17 Hz, 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= 10 Hz, 1H); 5.2 (d, J = 17 Hz, 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 (sec, 1H); 9.35 (sec, 1H).

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

NMR (DMSO-de, 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 (DMŚO-d6, 200 MHz): δ 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J - 6 Hz, 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 - 10 Hz, 1H); 5.1 (d, J - 17 Hz, 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

Pattern 1

OH CH ₃

CH ₃ V

CH2CH=CH ₂

Pattern 2

Et ₂ N

OH r ^N yCH ₃ CH ₃ ψ ch ₂ ch=ch ₂

Pattern ₃

ch ₂ -ch-ch ₂

Pattern 4

OH r ^N yCH ₃

CH/V ch ₂ -ch=ch ₂

Pattern 6

179 341

Pattern 7

Pattern 10

rNyR ³ _R 5 ÓpR ⁴

R ⁶

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

Pattern 8 '

Pattern 13

Pattern 9

Ar—X ²

Pattern 15

Pattern 16

Ar—CHO

Pattern 17

Pattern 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

continuation of 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

continuation of 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) _CO2

H

0SiMe ₂ t-Bu N-^CH ₃

1)SOCl2, _CH2Cl2

2)Et ₂ NH ³ ch ₂ ch=ch ₂

179 341

Scheme 1 continued /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} \A ^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

Bf reaction

Friedel-Crofts _| □citation

NaBHz,

Friedel-Crofts acylation reaction

Scheme 4

X=Br or

CONEta

CH3

-h ₂ o

H*

Y=C0 ₂ El or

CH ₂ -CH=CH 2

0SiMe ₂ t-Bu

Dn-BuLiJHF, -78°

Scheme 5

179 341

1)SOCl ₂ CH2C12.DMF

Et ₂ N^ ^C

2)Et ₂ NH

Scheme 7

Scheme 8 continued on next page

179 341 dc scheme 8

Compound L

Scheme 8

EtOCOCl pH=4

BrCH ₂ -CH=CH ₂

CU2tt U rM ³ nooh r ^N Y ³

CHFN ch; V

ĆHjCH-CHz CHzCH-CHj

Diagram

179 341

OSiMe ₂ t-Bu

CH3

ĆH 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) olyl bromide

BOC-D-Alo ^bo 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

ĆH3

L-A(a-0Me

Diagram 11 continued 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(uxing <Nγ*0Η3 CH/'V CH ₃ ^xx y ch ₂ ch=ch ₂ ch ₂ ch=ch ₂ Scheme 12 dc on the 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-Ć

1) neutralization /HCl

2)Regent 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-Ć

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 Patent Office of the Republic of Poland. 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. * * *