Abstract:
The present invention relates to the use of derivatives of aryl (or heteroaryl) azolylcarbinols of general formula (1) of the specification, as well as their physiologically acceptable salts, in the manufacture of medicaments, useful in human and/or veterinary therapy, for the treatment of disorders that are mediated by an excess of substance P, and especially disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, and locomotive disorders.

Description:
This application is a 371 of PCT/ES99/00255 filed Aug. 5, 1999. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to the use of derivatives of aryl(or heteroaryl)azolylcarbinols of general formula (I), as well as their physiologically acceptable salts, in the manufacture of medicaments, useful in human and/or veterinary therapy, for the treatment of disorders that are mediated by an excess of substance P, and especially disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug addiction, cognitive disorders, locomotive disorders, etc. 
     BACKGROUND OF THE INVENTION 
     Substance P is a peptide, a tachykinin, that can be isolated from brain tissue and the gastrointestinal tract. In the brain, substantia nigra and the basal ganglions contain relatively high concentrations of substance P. 
     There is evidence suggesting that substance P functions as a neurotransmitter. In the basal ganglions, substance P is synthesised in the medium sized striatal neurones with spinae, which project the substantia nigra pars reticulate. Studies on the receptor distribution indicate that the receptors NK 1  are found in the striate at a relatively high density, but are to all extents and purposes absent from the substantia nigra. However, the substantia nigra contains one of the highest levels of tissue substance P in the central nervous system. Although this seems to indicate that receptor and ligand are unpaired, substance P can interact with the receptors in the striate by release of from collateral local axons of the striatonigral neurones. The terminals containing substance P have been shown to make synaptic contact with the cholinergic cell bodies in the striate. In the striate, the receptors NK 1  seem to be expressed mainly by cholinergic inter-neurones, although a small population of non-cholinergic striatal neurones can also express these receptors. Furthermore, stimulation of the NK 1  receptors by substance P has been shown to increase the release of acetylcholin (Ach), both in vitro and in vivo. As a consequence, an anatomical circuit has been described in which substance P, released locally in the striate from the collateral axons of the striatonigral neurones can bind to the NK 1  receptors of the striatal cholinergic inter-neurones to stimulate the release of acetylcholine (J. J. Anderson,  J.Pharmacol. Exp. Ther ., 1995, 274, 928-936). 
     Substance P has also been implicated in the pathophysiology of several neuropsychiatric disorders such as, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, or with depression (M. Bianchi,  Inflamm. Res ., 1995, 44 (11), 466-469). Similarly, a clear relation between depressive states and levels of substance P can be supposed, since the products that act as inhibitors of substance P have a clear anti-depressive component when studied in various laboratory animal models. 
     On the other hand, there is also a relation between the anxiety processes (anxiolisis/anxiogenesis) with the levels of substance P. It has been demonstrated that products that act as antagonists of the NK 1  receptor display anxiolytic activity in a social interaction trial (S. File,  Pharmacol. Biochem. Behav ., 1997, 58 (3), 747-752), with little tendency towards the development of tolerance. Similarly, administration of substance P is an anxiogenic agent when studied in the elevated-plus-maze trial (R. M. Teixeira,  Eur.J. Pharmacol ., 1996, 31 (1), 7-14), and substance P receptor blockers have the opposite effect. It can therefore be deduced that the levels of substance P play an important role in the expression of anxiety. 
     In our patents EP 289380 and ES 9800793 we have described carbinol derivatives of general formula (I)                           
     wherein Ar represents a benzene ring or a substituted or unsubstituted thiopheno ring, R1 represents a hydrogen atom or a lower alkyl group (C 1 -C 4 ); R2 represents a dialkylaminoalkyl or azahetercyclylalkyl radical and Het represents an azol, as well as their physiologically acceptable salts, which are claimed for the treatment of pain. 
     In our patents PCT/EP 96105596, ES 9701538, ES 9701728 and ES 9800793 we have also described several procedures for preparing enantiomerically pure compounds of general formula (I). 
     We have now discovered that the compound of general formula (I), as well as their physiologically acceptable salts, are especially useful in the manufacture of medicaments, useful in veterinary and/or human therapy, for the treatment of disorders that are mediated by an excess of substance P, especially certain disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, etc. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to the use of derivatives of aryl(or Ieteroaryl)azolylcarbinol of general formula (I)                           
     where 
     Ar is a phenyl or thienyl radical, unsubstituted or optionally substituted by 1, 2 or 3 identical or different substituents, selected from the group composed of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy; 
     R1 is a hydrogen atom, a cyclohexyl group, an N-methylpiperidyl group, a phenyl group, a vinyl group or a C 1 -C 4  alkyl group; 
     R2 is a hydrogen atom or di(C 1 -C 4  alkyl)amino (C 2 -C 3  alkyl), (C 1 -C 2  alkyl)azaheterocyclyl (C 2 -C 3  alkyl), or azaheterocyclyl (C 2 -C 3  alkyl); and 
     Het is a heterocyclic azotic five-membered ring that contains from one to three nitrogen atoms, unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group composed of fluorine, chlorine, bromine, a C 1 -C 12  alkyl group, a benzyl radical, a cyano C 2 -C 3 alkyl) radical, a carboxyalkyl (C 2 -C 3  alkyl) radical, a methoxycarbonyl (C 2 -C 3  alkyl) radical, a hydroxy (C 2 -C 3  alkyl) radical, an amino (C 2 -C 3  alkyl) radical, a di(C 1 -C 4  alkyl)amino (C 2 -C 3  alkyl) radical and an azaheterocyclyl (C 2 -C 3  alkyl) radical; or one of its physiologically acceptable salts, in the manufacture of a medicament for the treatment of disorders that are produced by an excess of substance P, and specially disorders of the central nervous system involving substance P receptors such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug dependency, cognitive disorders, locomotive disorders, etc., in mammals, including man. 
     The term “C 1 -C 4  alkyl group” represents a straight or branched radical that is derived from a saturated hydrocarbon of from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and terc-butyl for example. 
     The term “di(C 1 -C 4  alkyl)amino (C 2 -C 3  alkyl), (C 1 -C 2  alkyl)azaheterocyclyl (C 2 -C 3  alkyl), or azaheterocyclyl (C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to a diC 1 -C 4  alkyl)amine or to a (C 1 -C 2  alkyl)azaheterocycle or to an azaheterocycle, respectively, such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidylethyl, N-ethylpiperidylethyl, N-methylpyrrolidinylethyl, morpholinylpropyl, pyrrolidinylalkyl, etc. 
     The term “cyano (C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to a cyano functional group. 
     The term “carboxy(C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to a carboxyl functional group. 
     The term “methoxycarbonyl(C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to a methoxycarbonyl functional group. 
     The term “hydroxy(C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to a hydroxyl functional group. 
     The term “amino(C 2 -C 3  alkyl)” represents an alkyl radical of two or three carbon atoms joined to an amino functional group. 
     The compounds of general formula (I) can be synthesised according to the procedures described in patents EP 289380 or ES 9800793. The compounds of general formula (I) have a stereogenic centre and the invention relates both to the use of a pure enantiomer and to a mixture of enantiomers. The enantiomers can be prepared by some of the procedures described in our patents PCT/EP 96/05596, ES 9701538, ES 9701728 or ES 9800793. 
     Examples of pharmaceutical compositions that contain compounds of general formula (I) are described in our patents EP 289380 or ES 9800793. 
     Illustrative examples of the compounds provided in the present invention include the compounds that are characterised by the data presented in tables 1 to 7. 
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Example No. 
                 R 5   
                 R 1   
                 R 3   
                 Z 1   
                 Z 2   
                 R 4   
                 R 2   
               
               
                   
               
               
                  1 
                 H 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  2 
                 4-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  3 
                 4-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  4 
                 3-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  5 
                 2-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  6 
                 4-F 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  7 
                 3-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  8 
                 3-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                  9 
                 3-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 10 
                 4-Cl 
                 Me 
                 n-But 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 11 
                 4-OMe 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 12 
                 3-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 Pyr 
               
               
                 13 
                 3,4,5-tri-OMe 
                 n-But 
                 C 12 H 25 — 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 14 
                 4-CF 3   
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 15 
                 3-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 Pip 
               
               
                   
               
               
                 16 
                 3,4-di-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 17 
                 3,4-di-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 18 
                 3,4-di-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                 19 
                 3,4-di-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 20 
                 4-Cl 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 21 
                 4-Cl 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 22 
                 4-Cl 
                 H 
                 N≡C—(CH 2 ) 3 — 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 23 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 DMA 
               
               
                   
               
               
                 24 
                 4-Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 MBA 
               
               
                   
               
             
          
           
               
                 25 
                 4-Cl 
                 Me 
                 —(CH 2 ) 3 —N(CH 3 )—CH 2 — 
                 N 
                 H 
                 DMA 
               
               
                 26 
                 4-Cl 
                 H 
                 —(CH 2 ) 3 —N(CH 3 )—CH 2 — 
                 N 
                 H 
                 DMA 
               
             
          
           
               
                 27 
                 H 
                 H 
                 n-But 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                   
               
               
                 28 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                   
               
               
                 29 
                 3,4,5-tri-OMe 
                 H 
                 n-But 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 30 
                 4-Cl 
                 Me 
                 n-But 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 31 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 32 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 33 
                 3,4,5-tri-OMe 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 34 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 Pyr 
               
               
                 35 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 Mor 
               
               
                 36 
                 3,4,5-tri-OMe 
                 Me 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 37 
                 H 
                 H 
                 Me 
                 N 
                 CBr 
                 H 
                 DMA 
               
               
                 38 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 CH 3   
                 DMA 
               
               
                 39 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 CH 3   
                 DMA 
               
               
                 40 
                 2-Me 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 41 
                 4-Cl 
                 H 
                 Me 
                 N 
                 CCl 
                 H 
                 DMA 
               
               
                 42 
                 4-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 43 
                 3-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 44 
                 4-Me 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 45 
                 2-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMA 
               
               
                 46 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 Pip 
               
               
                   
               
               
                 47 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DIPA 
               
               
                   
               
               
                 51 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 4-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 53 
                 3-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 54 
                 4-Cl 
                 Et 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 55 
                 3-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 56 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 57 
                 4-F 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 58 
                 3-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 59 
                 2-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 60 
                 3-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 61 
                 3,4,5-tri-OMe 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 62 
                 4-OMe 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 63 
                 4-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 64 
                 3,4,5-tri-OMe 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 65 
                 4-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 66 
                 3-CF 3   
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 67 
                 4-CF 3   
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 68 
                 4-OMe 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 69 
                 3-CF 3   
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 70 
                 4-Cl 
                 Me 
                 n-But 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 71 
                 3,4,5-tri-OMe 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 72 
                 2-Cl 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 73 
                 2,4-di-Cl 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 74 
                 4-CF 3   
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 75 
                 4-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 PipP 
               
               
                 76 
                 4-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 PipP 
               
               
                 77 
                 2-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 78 
                 3,4-di-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 79 
                 3,4-di-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                 80 
                 3,4-di-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 81 
                 3,4-di-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 82 
                 4-Cl 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 83 
                 4-Cl 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 84 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 DMAP 
               
               
                   
               
               
                 85 
                 H 
                 H 
                 n-But 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 56 
                 4-Cl 
                 Me 
                 n-But 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 87 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 88 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 89 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 Me 
                 DMAP 
               
               
                 90 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 Me 
                 DMAP 
               
               
                 91 
                 2-Me 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 92 
                 4 Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 DMAP 
               
               
                 93 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 PipP 
               
               
                 94 
                 H 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 PirP 
               
               
                   
               
               
                 DMA = dimethylaminoethyl  
               
               
                 Pyr = pyrrolidinylethyl  
               
               
                 Pip = piperidylethyl  
               
               
                 MBA = (methyl-benzylamino)ethyl  
               
               
                 Mor = morpholinylethyl  
               
               
                 DIPA = diisopropylaminoethyl  
               
               
                 DMAP = dimethylaminopropyl  
               
               
                 PipP = piperidylpropyl  
               
               
                 PirP = pyrrolidinylpropyl  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Example No. 
                 R 5   
                 R 1   
                 R 3   
                 R 2   
               
               
                   
               
               
                  95 
                 4-Cl 
                 H 
                 Me 
                 DMA 
               
               
                  96 
                 4-Cl 
                 Me 
                 Me 
                 DMA 
               
               
                   
               
               
                  97 
                 4-Cl 
                 H 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                  98 
                 4-Cl 
                 H 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                  99 
                 4-Cl 
                 H 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 4-Cl 
                 H 
                 Me 
                 DIPA 
               
               
                   
               
               
                 101 
                 4-Cl 
                 H 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 H 
                 H 
                 Me 
                 DMAP 
               
               
                 103 
                 4-Cl 
                 H 
                 Me 
                 MorP 
               
               
                 104 
                 4-Cl 
                 H 
                 Me 
                 PirP 
               
               
                   
               
               
                 DMA = dimethylaminoethyl  
               
               
                 DIPA = diisopropylaminoethyl  
               
               
                 DMAP = dimethylaminopropyl  
               
               
                 MorP = morpholinypropyl  
               
               
                 PirP = pyrrolidinylpropyl  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Example No. 
                 R 5   
                 R 1   
                 R 3   
                 Z 1   
                 Z 2   
                 R 4   
                 M.p. 
               
               
                   
               
               
                 105 
                 H 
                 H 
                 H 
                 CH 
                 N 
                 H 
                 202-3° C. 
               
               
                 106 
                 4-Cl 
                 H 
                 H 
                 CH 
                 N 
                 H 
                 196-7° C. 
               
               
                 107 
                 4-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 137-9° C. 
               
               
                 108 
                 3-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 126-8° C. 
               
               
                 109 
                 4-F 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 112-5° C. 
               
               
                 110 
                 3-CF 3   
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 125-6° C. 
               
               
                 111 
                 4-CF 3   
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 124-5° C. 
               
               
                 112 
                 3,4,5-tri-OMe 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 160-1° C. 
               
               
                 113 
                 3,4-di-Cl 
                 H 
                 Me 
                 CH 
                 N 
                 H 
                 157-9° C. 
               
               
                 114 
                 4-CF 3   
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                 111-2° C. 
               
               
                 115 
                 2,4-di-Cl 
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                  94-7° C. 
               
               
                 116 
                 4-Cl 
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                 108-110° C. 
               
               
                 117 
                 3,4,5-tri-OMe 
                 H 
                 n-But 
                 CH 
                 N 
                 H 
                 122-5° C. 
               
               
                 118 
                 3,4,5-tri-OMe 
                 H 
                 n-dodecyl 
                 CH 
                 N 
                 H 
                 Oil 
               
               
                 119 
                 3-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 125-6° C. 
               
               
                 120 
                 3-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 180-1° C. 
               
               
                 121 
                 4-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 191-2° C. 
               
               
                   
               
               
                 122 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 183-4° C. 
               
               
                   
               
               
                 123 
                 4-Cl 
                 Et 
                 Me 
                 CH 
                 N 
                 H 
                 166-8° C. 
               
               
                 124 
                 4-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 120-2° C. 
               
               
                   
               
               
                 125 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 161-2° C. 
               
               
                   
               
               
                 126 
                 2-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 181-2° C. 
               
               
                 127 
                 2-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 138-41° C. 
               
               
                 128 
                 3-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 193-4° C. 
               
               
                 129 
                 3-CF 3   
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 140-1° C. 
               
               
                   
               
               
                 130 
                 3-CF 3   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 156-7° C. 
               
               
                   
               
               
                 131 
                 4-CF 3   
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 167-8° C. 
               
               
                 132 
                 4-F 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 176-7° C. 
               
               
                 133 
                 4-OMe 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 181-2° C. 
               
               
                 134 
                 3,4-di-Cl 
                 Me 
                 Me 
                 CH 
                 N 
                 H 
                 207-8° C. 
               
               
                 135 
                 3,4-di-Cl 
                 n-But 
                 Me 
                 CH 
                 N 
                 H 
                 142-4° C. 
               
               
                   
               
               
                 136 
                 3,4-di-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 CH 
                 N 
                 H 
                 158-60° C. 
               
               
                   
               
               
                 137 
                 3,4,5-tri-OMe 
                 CH 3   
                 Me 
                 CH 
                 N 
                 H 
                 181-2° C. 
               
               
                 138 
                 4-Cl 
                 Me 
                 n-But 
                 CH 
                 N 
                 H 
                 174-5° C. 
               
               
                 139 
                 4-Cl 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 134-5° C. 
               
               
                   
               
               
                 140 
                 4-Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n-But 
                 CH 
                 N 
                 H 
                 184-5° C. 
               
               
                   
               
               
                 141 
                 3,4,5-tri-OMe 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 125-6° C. 
               
               
                 142 
                 2-Cl 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 132-3° C. 
               
               
                 143 
                 3-CF 3   
                 Et 
                 n-But 
                 CH 
                 N 
                 H 
                 164-5° C. 
               
               
                 144 
                 2,4-di-Cl 
                 n-But 
                 n-But 
                 CH 
                 N 
                 H 
                 142-3° C. 
               
               
                   
               
               
                 145 
                 4-Cl 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 N 
                 H 
                 136-7° C. 
               
               
                   
               
               
                 146 
                 4-Cl 
                 Me 
                 Me 2 N—(CH 2 ) 3 — 
                 CH 
                 N 
                 H 
                 147-8° C. 
               
               
                 147 
                 3,4,5-tri-OMe 
                 n-But 
                 n-Dodecyl 
                 CH 
                 N 
                 H 
                  75-7° C. 
               
               
                 148 
                 3-CF 3   
                 n-But 
                 Ph-CH 2 — 
                 CH 
                 N 
                 H 
                 Oil 
               
               
                 149 
                 4-Cl 
                 Me 
                 Ph-CH 2 — 
                 CH 
                 N 
                 H 
                 154-5° C. 
               
               
                 150 
                 4-Cl 
                 H 
                 —(CH 2 ) 2 —CN 
                 CH 
                 N 
                 H 
                 134-5° C. 
               
               
                 151 
                 4-Cl 
                 H 
                 —(CH 2 ) 2 —NH 2   
                 CH 
                 N 
                 H 
                 187-8° C. 
               
               
                 152 
                 3-Cl 
                 H 
                 —(CH 2 ) 2 —CO 2 H 
                 CH 
                 N 
                 H 
                 212-3° C. 
               
               
                 153 
                 4-Cl 
                 H 
                 —(CH 2 ) 2 —CH 2 OH 
                 CH 
                 N 
                 H 
                 121-2° C. 
               
               
                 154 
                 4-Cl 
                 H 
                 —(CH 2 ) 2 —CO 2 Me 
                 CH 
                 N 
                 H 
                  96-7° C. 
               
               
                 155 
                 H 
                 H 
                 —(CH 2 ) 2 —CH 2 OH 
                 CH 
                 N 
                 H 
                 110-1° C. 
               
               
                 156 
                 4-Me 
                 H 
                 —(CH 2 ) 2 —CH 2 OH 
                 CH 
                 N 
                 H 
                 104-5° C. 
               
               
                 157 
                 4-OMe 
                 H 
                 —(CH 2 ) 2 —CH 2 OH 
                 CH 
                 N 
                 H 
                 Oil 
               
               
                 158 
                 3,4-di-Cl 
                 H 
                 —(CH 2 ) 2 —CH 2 OH 
                 CH 
                 N 
                 H 
                 138-9° C. 
               
               
                 159 
                 H 
                 H 
                 —(CH 2 ) 2 —CO 2 Me 
                 CH 
                 N 
                 H 
                  93-6° C. 
               
               
                 160 
                 4-Cl 
                 H 
                 —(CH 2 ) 4 —OH 
                 CH 
                 N 
                 H 
                 131-2° C. 
               
               
                 161 
                 4-Cl 
                 H 
                 —(CH 2 ) 3 —CN 
                 CH 
                 N 
                 H 
                 Oil 
               
               
                 162 
                 4-Cl 
                 H 
                 —(CH 2 ) 3 —CO 2 H 
                 CH 
                 N 
                 H 
                 &gt;300° C. 
               
               
                 163 
                 4-Cl 
                 H 
                 —(CH 2 ) 3 —CO 2 Me 
                 CH 
                 N 
                 H 
                  85-7° C. 
               
               
                 164 
                 H 
                 H 
                 n-But 
                 N 
                 CH 
                 H 
                  47-8° C. 
               
               
                 165 
                 4-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                  94-7° C. 
               
               
                 166 
                 3,4,5-tri-OMe 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 Oil 
               
               
                 167 
                 3,4,5-tri-OMe 
                 H 
                 n-But 
                 N 
                 CH 
                 H 
                 Oil 
               
               
                 168 
                 H 
                 H 
                 Me 
                 N 
                 CBr 
                 H 
                 110-11° C. 
               
               
                 169 
                 4-Cl 
                 Ph 
                 Me 
                 N 
                 CH 
                 H 
                 167-8° C. 
               
               
                 170 
                 4-Cl 
                 Me 
                 n-But 
                 N 
                 CH 
                 H 
                 Oil 
               
               
                 171 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 H 
                  99-100° C. 
               
               
                 172 
                 3,4,5-tri-OMe 
                 Me 
                 Me 
                 N 
                 CH 
                 H 
                 144-5° C. 
               
               
                 173 
                 H 
                 Me 
                 Me 
                 N 
                 CH 
                 Me 
                 137-8° C. 
               
               
                 174 
                 H 
                 CH 2 ═CH— 
                 Me 
                 N 
                 CH 
                 H 
                  95-6° C. 
               
               
                 175 
                 4-Cl 
                 CH 2 ═CH— 
                 n-But 
                 N 
                 CH 
                 H 
                  84-5° C. 
               
               
                 176 
                 H 
                 H 
                 Me 
                 N 
                 CCl 
                 H 
                 Oil 
               
               
                 177 
                 2-Me 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 113-4° C. 
               
               
                 178 
                 3-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 128-9° C. 
               
               
                 179 
                 4-Me 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 123-6° C. 
               
               
                 180 
                 2-Cl 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                  96-8° C. 
               
               
                 181 
                 4-OMe 
                 H 
                 Me 
                 N 
                 CH 
                 H 
                 129-30° C. 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
             
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Exam- 
                   
               
               
                 ple No. 
                   1 H RMN, δ (CDCl 3 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 7.2(s, 5H); 6.8(d, 2H); 5.7(s, 1H); 3.5(m, 2H); 3.35(s, 3H); 2.6(t, 2H); 2.3(s, 6H) 
               
               
                 2 
                 7.2(s, 4H); 6.85(d, 2H); 3.7(m, 1H); 3.2(s, 3H); 3.1(m, 1H); 2.5(t, 2H); 2.2(s, 6H); 1.85(s, 
               
               
                   
                 3H) 
               
               
                 3 
                 7.25(s, 4H); 6.85(d, 2H); 6.65(s, 1H); 3.6(m, 2H); 3.45(s, 3H); 2.6(t, 2H); 2.25(s, 6H) 
               
               
                 4 
                 7.3(m, 4H); 6.9(d, 2H); 5.7(s, 1H); 3.6(m, 2H); 3.5(s, 3H); 2.65(t, 2H); 2.35(s, 6H) 
               
               
                 5 
                 7.9(m, 1H); 7.1(m, 3H); 6.8(d, 2H); 3.55(m, 1H); 3.05(s, 3H); 2.8(m, 1H); 2.4(t, 2H); 2.15(s, 
               
               
                   
                 6H); 2.0(s, 3H) 
               
               
                 6 
                 7.0(m, 6H); 3.5(m, 2H); 3.3(s, 3H); 2.5(t, 2H); 2.3(s, 6H); 1.8(s, 3H) 
               
               
                 7 
                 7.3(m, 3H); 6.8(d, 2H); 3.6(m, 2H); 3.2(s, 3H); 2.5(m, 2H); 2.2(s, 6H); 1.8(s, 3H) 
               
               
                 8 
                 7.0(m, 3H); 6.8(d, 2H); 3.55(m, 2H); 3.2(s, 3H); 2.5(m, 2H); 2.2(s, 6H); 1.8(s, 3H) 
               
               
                 9 
                 7.5-6.6(m, 6H); 3.55(m, 1H); 3.2(s, 3H); 3.0(m, 1H); 2.6(m, 2H); 2.2(s, 6H); 1.5-0.5(m, 7H) 
               
               
                 10 
                 7.2(s, 4H); 6.9(d, 2H); 3.7(m, 3H); 3.0(m, 1H); 2.5(t, 2H); 2.25(s, 6H); 1.9(s, 3H); 1.4-0.6 
               
               
                   
                 (m, 7H) 
               
               
                 11 
                 7.0(q, 4H); 6.75(d, 2H); 3.7(s, 3H); 3.6(m, 1H); 3.25(s, 3H); 3.0(m, 1H); 2.55(t, 2H); 2.2(s, 
               
               
                   
                 6H); 1.9(s, 3H) 
               
               
                 12 
                 7.1(m, 6H); 3.7(m, 1H); 3.2(s, 3H); 3.05(m, 1H); 2.7(m, 2H); 2.4(m, 4H); 1.9(s, 3H); 2.75 
               
               
                   
                 (m, 4H) 
               
               
                 13 
                 6.9(d, 2H); 6.5(s, 2H); 3.8(s, 3H); 3.7(s, 6H); 3.55(m, 1H); 3.0(m, 1H); 2.55(t, 2H); 2.2(s, 
               
               
                   
                 6H); 1.3-0.7(m, 34H) 
               
               
                 14 
                 7.4(s, 4H); 6.8(d, 2H); 5.8(s, 1H); 3.6(m, 4H); 2.45(t, 2H); 2.1(s, 6H); 1.6-0.5(m, 7H) 
               
               
                 15 
                 7.7(s, 1H); 7.35(m, 3H); 6.9(d, 2H); 3.7(m, 3H); 3.2(s, 3H); 3.1(m, 1H); 2.6(m, 2H); 2.4(m, 
               
               
                   
                 4H); 1.9(s, 3H); 1.45(4H) 
               
               
                 16 
                 7.5-6.7(m, 5H); 3.5(m, 1H); 3.1(s, 3H); 2.8(m, 2H); 2.4(m, 3H); 2.15(s, 6H); 2.0-0.3(m, 9H) 
               
               
                 17 
                 7.5-6.7(m, 5H); 3.55(m, 2H); 3.20(s, 3H); 1.0(m, 1H); 3.5(m, 3H); 2.2(s, 6H); 1.4-0.6(m, 
               
               
                   
                 7H) 
               
               
                 18 
                 7.4-6.7(m, 5H); 3.6(m, 2H); 3.20(s, 3H); 3.05(m, 2H); 2.5(m, 2H); 2.2(s, 6H); 1.8(s, 3H) 
               
               
                 19 
                 7.6-6.7(m, 5H); 5.6(s, 1H); 3.6(m, 2H); 3.45(s, 3H); 2.6(t, 2H); 2.2(s, 6H) 
               
               
                 20 
                 7.2(s, 4H); 6.95(d, 2H); 3.7(m, 3H); 3.0(m, 1H); 2.5(t, 2H); 2.2(s, 6H); 2.1(m, 6H); 1.8(s, 
               
               
                   
                 3H); 1.4(m, 6H) 
               
               
                 21 
                 7.25(s, 4H); 6.9(d, 2H); 3.7(m, 3H); 3.1(m, 1H); 2.6(t, 2H); 2.20(s, 6H); 2.15(m, 6H); 1.9 
               
               
                   
                 (m, 5H) 
               
               
                 22 
                 7.3(s, 4H); 6.95(d, 2H); 5.7(s, 1H); 3.95(m, 4H); 3.6(m, 2H); 2.6(t, 2H); 2.2(m, 8H); 1.9(m, 
               
               
                   
                 2H); 1.45(m, 6H) 
               
               
                 23 
                 7.3-6.7(m, 6H); 3.5(m, 1H); 3.1(s, 3H); 2.8(m, 4H); 2.4(t, 2H); 2.15-1.0(m, 15H) 
               
               
                 24 
                 7.2(s, 12H); 7.0-6.8(m, 3H); 5.7(s, 1H); 5.0(s, 2H); 3.6(m, 2H); 3.5(s, 2H); 2.6(t, 2H); 2.2 
               
               
                   
                 (s, 3H) 
               
               
                 25 
                 7.25(m, 4H); 6.9(s, 1H); 4.0-3.0(m, 9H); 2.75(m, 2H); 2.55(t, 2H); 2.3(s, 6H); 1.9(s, 3H); 
               
               
                   
                 1.6-1.1(m, 3H) 
               
               
                 26 
                 7.3(s, 4H); 6.8(s, 1H); 5.6(s, 1H); 4.5(m, 2H); 4.1-3.5(m, 8H); 2.8(m, 4H); 2.6(t, 2H); 2.2(d, 
               
               
                   
                 9H); 1.5(m, 3H) 
               
               
                 27 
                 7.35(m, 6H); 5.95(m, 1H); 5.50(s, 1H); 4.05(t, 2H); 3.56(t, 2H); 2.52(t, 2H); 2.20(s, 6H); 
               
               
                   
                 1.75-0.7(m, 7H) 
               
               
                 28 
                 7.5-7.1(m, 9H); 6.3(d, 1H); 3.45(s, 2H); 3.2(t, 2H); 2.55(t, 2H); 2.20(s, 6H) 
               
               
                 29 
                 7.35(m, 1H); 6.6(m, 2H); 5.9(t, 1H); 5.45(s, 1H); 4.05(t, 2H); 3.8(m, 9H); 3.55(t, 2H); 2.6(t, 
               
               
                   
                 2H); 2.25(d, 6H); 1.9-07(m, 7H) 
               
               
                 30 
                 7.45(m, 1H); 7.2(s, 4H), 6.3(m, 1H); 3.7(t, 2H); 3.15(t, 2H); 2.5(t, 2H); 2.25(s, 6H); 1.75(s, 
               
               
                   
                 3H); 1.65-0.6(m, 7H) 
               
               
                 31 
                 7.2(m, 6H); 5.85(d, 1H); 5.35(s, 1H); 3.65(s, 3H); 3.4(t, 2H); 2.4(t, 2H); 2.1(s, 6H) 
               
               
                 32 
                 7.45(d, 1H); 7.2(s, 5H); 6.4(d, 1H); 3.6(m, 1H); 3.4(s, 3H); 3.15(m, 1H); 2.55(t, 2H); 2.25 
               
               
                   
                 (s, 6H); 1.8(s, 3H) 
               
               
                 33 
                 7.35(d, 1H); 6.6(s, 2H); 6.0(d, 1H); 5.45(s, 1H); 3.85(m, 12H); 3.6(t, 2H); 2.6(t, 2H); 2.25 
               
               
                   
                 (s, 6H) 
               
               
                 34 
                 7.15-7.4(m, 6H); 5.9(s, 1H); 5.4(s, 1H); 3.65(s, 3H); 3.5(t, 2H); 2.65(t, 2H); 2.40(m, 4H); 
               
               
                   
                 1.65(m, 4H) 
               
               
                 35 
                 7.3(m, 6H); 5.85(d, 1H); 5.4(s, 1H); 3.75(s, 3H); 3.55(m, 6H); 2.5(t, 2H); 2.35(m, 4H) 
               
               
                 36 
                 7.45(d, 1H); 6.5(s, 2H); 6.35(d, 1H); 3.8(s, 3H); 3.75(s, 6H); 3.5(s, 3H); 2.5(t, 2H); 2.3(s, 
               
               
                   
                 6H); 1.8(s, 2H) 
               
               
                 37 
                 7.45(S, 1H); 7.25(s, 5H); 5.85(s, 1H); 3.6(m, 5H); 2.6(t, 2H); 2.25(s, 6H) 
               
               
                 38 
                 7.2(s, 5H); 6.15(s, 1H); 3.65(m, 1H); 3.35(s, 3H); 3.2(m, 1H); 2.5(t, 2H); 2.2(s, 9H); 1.75 
               
               
                   
                 (s, 3H) 
               
               
                 39 
                 7.25(s, 5H); 5.7(s, 1H); 5.45(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 2.6(b, 2H); 2.25(s, 6H); 2.1(s, 
               
               
                   
                 3H) 
               
               
                 40 
                 7.4-7.0(m, 5H); 5.7(s, 1H); 5.6(s, 1H); 3.85(s, 3H); 3.5(t, 2H); 2.55(t, 2H); 2.15(s, 9H) 
               
               
                 41 
                 7.5-7.0(m, 6H); 6.1(s, 1H); 3.6(m, 5H); 2.7(t, 2H); 2.2(s, 6H) 
               
               
                 42 
                 7.3(m, 5H); 5.9(s, 1H); 5.5(s, 1H); 3.8(s, 3H); 3.5(t, 2H); 2.5(t, 2H); 2.2(s, 6H) 
               
               
                 43 
                 7.4-7.1(m, 5H); 6.0(s, 1H); 5.5(s, 1H); 3.8(s, 3H); 3.6(t, 2H); 2.6(t, 2H); 2.2(s, 6H) 
               
               
                 44 
                 7.3(s, 1H); 7.2(d, 4H); 5.9(s, 1H); 5.4(s, 1H); 3.8(s, 3H); 3.5(t, 2H); 2.5(t, 2H); 2.3(s, 3H); 
               
               
                   
                 2.2(s, 6H) 
               
               
                 45 
                 7.7-7.1(m, 5H); 5.9(s, 1H); 5.8(s, 1H); 3.9(s, 3H); 3.6(t, 2H); 2.5(t, 2H); 2.2(s, 6H) 
               
               
                 46 
                 7.2(s, 6H); 5.8(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 2.5(t, 2H); 2.3(m, 6H); 1.4(m, 6H) 
               
               
                 47 
                 7.4(s, 6H); 6.0(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.6(t, 2H); 3.0-1(m, 5H); 0.9(t, 3H) 
               
               
                 48 
                 7.3(s, 6H); 6.0(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 2.8-1.1(m, 13H); 1.0(t, 3H) 
               
               
                 49 
                 7.3(s, 6H); 6.0(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 3.0(m, 1H); 2.2-1.0(m, 1 1H) 
               
               
                 50 
                 7.3(s, 6H); 6.0(s, 1H); 5.5(s, 1H); 3.7(s, 3H); 3.4(t, 2H); 2.9(m, 2H); 2.6(t, 2H); 0.95(d, 
               
               
                   
                 12H) 
               
               
                 51 
                 7.3(s, 6H); 6.0(s, 1H); 5.5(s, 1H); 3.8(s, 3H); 3.6(t, 2H); 2.8(m, 1H); 2.3(s, 3H); 2.2-1.1(m, 
               
               
                   
                 12H) 
               
               
                 52 
                 7.2(m, 4H); 6.85(d, 2H); 3.6(m, 1H); 3.2(s, 3H); 3.0(m, 1H); 2.4(m, 2H); 2.15(s, 6H); 1.8(s, 
               
               
                   
                 3H) 
               
               
                 53 
                 7.2(s, 1H); 7.15(s, 3H); 6.8(d, 2H); 5.6(s, 1H); 3.55(m, 2H); 3.45(s, 3H); 2.4(m, 2H); 2.25 
               
               
                   
                 (s, 6H); 1.8(m, 2H) 
               
               
                 54 
                 7.2(s, 4H); 6.8(d, 2H); 3.4(m, 3H); 3.1(s, 3H); 2.9(m, 1H); 2.3(m, 2H); 2.2(s, 6H); 1.8(m, 
               
               
                   
                 2H); 0.5(t, 3H) 
               
               
                 55 
                 7.2(s, 1H); 7.0(s, 3H); 3.4(m, 3H); 3.1(s, 3H); 2.9(m, 1H); 2.3(m, 2H); 2.25(s, 6H); 1.8(m, 
               
               
                   
                 2H); 0.5(t, 3H) 
               
               
                 56 
                 7.15(s, 4H); 6.8(d, 2H); 3.5(m, 1H); 2.7(m, 1H); 2.4(m, 4H); 2.5(s, 6H); 1.9-0.5(m, 14H) 
               
               
                 57 
                 7.3-6.7(m, 6H); 3.6(m, 1H); 3.3(s, 3H); 3.1(m, 1H); 2.4(m, 2H); 2.25(s, 6H); 1.9(s, 3H); 
               
               
                   
                 1.85(m, 2H) 
               
               
                 58 
                 7.5(m, 4H); 6.9(d, 2H); 3.5(m, 1H); 3.4(s, 3H); 3.2(m, 1H); 2.4(m, 2H); 2.2(s, 6H); 1.9(s, 
               
               
                   
                 3H); 1.8(m, 2H) 
               
               
                 59 
                 8.0(m, 1H); 7.2(m, 3H); 6.8(d, 2H); 3.6(m, 1H); 3.1(, 3H); 2.8(m, 1H); 2.3(m, 2H); 2.2(s, 
               
               
                   
                 6H); 2.0(s, 3H); 1.7(m, 2H) 
               
               
                 60 
                 7.3-6.6(m, 6H); 3.5(m, 1H); 3.3(s, 3H); 3.05(m, 1H); 2.3(m, 2H); 2.15(s, 6H); 1.9(s, 3H); 
               
               
                   
                 1.8(m, 2H) 
               
               
                 61 
                 6.85(d, 2H); 6.45(s, 2H); 3.8(s,.3H); 3.75(s,6H); 3.7(m, 1H); 3.3(s, 3H); 3.0(m, 1H); 2.4 
               
               
                   
                 (m, 2H); 2.25(s, 6H); 1.9(s, 3H); 1.8(m, 2H) 
               
               
                 62 
                 7.2-6.5(m, 6H); 3.65(s, 3H); 3.5(m, 1H); 3.15(s, 3H); 2.9(m, 1H); 2.3(m, 2H); 2.15(s, 6H); 
               
               
                   
                 1.85(s, 3H); 1.8(m, 2H) 
               
               
                 63 
                 7.25(s, 4H); 6.85(d, 2H); 5.65(s, 1H); 3.5(m, 2H); 3.40(s, 3H); 2.35(m, 2H); 2.2(s, 6H); 1.8 
               
               
                   
                 (m, 2H) 
               
               
                 64 
                 6.8(d, 2H); 6.55(s, 2H); 6.6(s, 1H); 3.75(s, 9H); 3.55(m, 2H); 3.45(s, 3H); 2.3(m, 2H); 2.2 
               
               
                   
                 (s, 6H); 1.8(m, 2H) 
               
               
                 65 
                 7.4(q, 4H); 6.85(d, 2H); 3.6(m, 1H); 3.25(s, 3H); 3.0(m, 1H); 2.4(m, 2H); 2.25(s, 6H); 1.9 
               
               
                   
                 (s, 3H); 1.8(m, 2H) 
               
               
                 66 
                 7.6(s, 1H); 7.4(s, 2H); 6.8(d, 2H); 6.7(s, 1H); 3.6(m, 2H); 3.4(s, 3H); 2.4(m, 2H); 2.15(s, 
               
               
                   
                 6H); 1.9(m, 2H) 
               
               
                 67 
                 7.5(q, 4H); 6.85(d, 2H); 5.65(s, 1H); 3.55(m, 2H); 3.45(s, 3H); 2.4(m, 2H); 2.25(s, 6H); 1.8 
               
               
                   
                 (m, 2H) 
               
               
                 68 
                 7.3-6.7(m, 6H); 5.7(s, 1H); 3.8(s, 3H); 3.65(m, 2H); 3.55(s, 3H); 2.4(m, 2H); 2.25(s, 6H); 
               
               
                   
                 1.9(m, 2H) 
               
               
                 69 
                 7.6(s, 1H); 7.4(m, 3H); 6.8(d, 2H); 3.5(m, 1H); 3.2(s, 3H); 2.9(m, 1H); 2.4(m, 2H); 2.25(s, 
               
               
                   
                 6H); 1.9(m, 2H); 1.5-0.5(m, 7H) 
               
               
                 70 
                 7.2(s, 4H); 6.9(d, 2H); 3.6(m, 3H); 3.0(m1H); 2.3(m, 2H); 2.2(s, 6H); 1.9(s, 3H); 1.7(m, 
               
               
                   
                 2H); 1.5-0.5(m, 7H) 
               
               
                 71 
                 6.8(d, 2H); 6.4(s, 2H); 3.75(s, 3H); 3.65(s, 6H); 3.6(m, 9H); 3.6-2.5(m, 6H); 2.2(s, 6H); 1.6- 
               
               
                   
                 0.4(m, 16H) 
               
               
                 72 
                 7.9(m, 1H); 7.15(m, 3H); 6.8(d, 2H); 3.45(m, 2H); 3.0-2.2(m, 4H); 2.2(s, 6H); 2-0.5(m, 
               
               
                   
                 18H) 
               
               
                 73 
                 7.9(m, 1H); 7.4(m, 2H); 6.8(dd, 2H); 3.4(m, 3H); 2.7(m, 2H); 2.3(m, 3H); 2.1(d, 6H); 1.9- 
               
               
                   
                 0.5(m, 16H) 
               
               
                 74 
                 7.4(q, 4H); 6.8(d, 2H); 5.6(s, 1H); 3.5(m, 4H); 2.2(m, 2H); 2.05(s, 6H); 1.8-0.5(m, 9H) 
               
               
                 75 
                 7.3(s, 4H); 6.9(d, 2H); 5.6(s, 1H); 3.4(m, 5H); 2.45(m, 6H); 2-1.2(m, 8H) 
               
               
                 76 
                 7.4(q, 4H); 7.85(d, 2H); 3.6(m, 1H); 3.2(s, 3H); 3.0(m, 1H); 2.3(m, 6H); 1.9(s, 3H); 1.4(m, 
               
               
                   
                 8H) 
               
               
                 77 
                 8.0(d, 1H); 7.2(m, 3H); 6.8(d, 2H); 3.4(m, 1H); 3.0(s, 3H); 2.8(m, 1H); 2.3(m, 4H); 2.15(s, 
               
               
                   
                 6H); 1.8-0.5(m, 9H) 
               
               
                 78 
                 7.4-6.6(m, 5H); 3.4(m, 1H); 3.2(s, 3H); 2.9(1H); 2.3(m, 4H); 2.15(s, 6H); 1.9-0.5(m, 2H) 
               
               
                 79 
                 7.3(m, 2H); 6.8(m3H); 3.6(m, 1H); 3.2(s, 3H); 2.9(m, 1H); 2.3(m, 4H); 2.2(s, 3H); 1.8(s, 
               
               
                   
                 3H) 
               
               
                 80 
                 7.5-6.9(m, 3H); 6.8(d, 2H); 5.6(s, 1H); 3.5(m, 2H); 3.4(s, 3H); 2.3(m, 2H); 2.1(s, 6H); 1.8 
               
               
                   
                 (m, 2H) 
               
               
                 81 
                 7.6-6.7(m, 5H); 3.4(m, 1H); 2.7(m, 1H); 2.4(m, 4H); 2.15(s, 6H); 1.9-0.3(m, 14H) 
               
               
                 82 
                 7.1(s, 4H); 6.95(s, 1H); 6.85(s, 1H); 3.6(m, 4H); 2.3(m, 4H); 2.1(s, 6H); 2.05(m, 4H); 1.8 
               
               
                   
                 (m, 6H); 1.3(m, 8H) 
               
               
                 83 
                 7.2(s, 4H); 6.9(s, 1H); 6.85(s, 1H); 3.6(m, 4H); 2.3(m, 4H); 2.1(s, 6H); 2.05(m, 4H); 1.0(m, 
               
               
                   
                 6H); 1.4(m, 10H) 
               
               
                 84 
                 7.2-6.6(m, 6H); 3.4(m, 1H); 3.1-2.5(m, 8H); 2.15-1.5(m, 14H); 1.0(m, 4H) 
               
               
                 85 
                 7.25(m, 6H); 5.9(m, 1H); 5.4(s, 1H); 3.95(t, 2H); 3.40(t, 2H); 2.25(t, 2H); 2.1(s, 6H); 1.85- 
               
               
                   
                 0.5(m, 9H) 
               
               
                 86 
                 7.45(d, 1H); 1.2(s, 4H); 6.3(d, 1H); 3.8(m, 3H); 3.1(m, 1H); 2.35(t, 2H); 2.15(s, 6H); 1.8(s, 
               
               
                   
                 3H); 1.9-0.6(m, 9H) 
               
               
                 87 
                 7.3(s, 6H); 5.95(d, 1H); 5.45(s, 1H); 3.75(s, 3H); 3.5(t, 2H); 2.35(t, 2H); 2.15(s, 6H); 1.8 
               
               
                   
                 (m, 2H) 
               
               
                 88 
                 7.4(d, 1H); 7.2(s, 5H); 6.35(d, 1H); 3.55(m, 2H); 3.4(s, 3H); 2.35(t, 2H); 2.2(s, 6H); 1.95- 
               
               
                   
                 1.6(m, 5H) 
               
               
                 89 
                 7.15(s, 5H); 6.0(s, 1H); 3.4(m, 1H); 3.25(s, 3H); 3.0(m, 1H); 2.2(m, 11H); 1.6(m, 5H) 
               
               
                 90 
                 7.3(s, 5H); 5.75(s, 1H); 5.35(s, 1H); 3.7(s, 3H); 3.45(t, 2H); 2.35(t, 2H); 2.15(s, 9H); 1.75 
               
               
                   
                 (m, 2H) 
               
               
                 91 
                 7.4-7.1(m, 5H); 5.7(s, 1H); 5.5(s, 1H); 3.8(s, 3H); 3.5(t, 2H); 2.3(m, 2H); 2.2(s, 9H); 1.8(m, 
               
               
                   
                 2H) 
               
               
                 92 
                 7.4-7.2(m, 5H); 5.9(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 2.3(m, 2H); 2.15(s, 6H); 1.8 
               
               
                   
                 (m,2H) 
               
               
                 93 
                 7.3(s, 6H); 6.0(s, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.5(t, 2H); 2.3(m, 6H); 1.9(m, 2H), 1.5(m, 
               
               
                   
                 6H) 
               
               
                 94 
                 7.3(b, 6H); 6.0(b, 1H); 5.4(s, 1H); 3.7(s, 3H); 3.6(m, 2H); 2.5(m, 6H); 1.8(m, 6H) 
               
               
                 95 
                 7.2(s, 5H); 7.0(s, 1H); 3.75(s, 3H); 3.35(t, 2H); 2.4(t, 2H); 2.1(s, 6H) 
               
               
                 96 
                 7.2(m, 6H); 3.7(s, 3H); 3.25(t, 2H); 2.4(t, 2H); 2.15(s, 6H); 1.7(s, 3H) 
               
               
                 97 
                 7.3(s, 5H); 7.1(s, 1H); 5.2(s, 1H); 3.7(s, 3H); 3.45(m, 2H); 2.9-1.0(m, 17H); 0.8(t, 3H) 
               
               
                 98 
                 7.3(s, 5H); 7.1(s, 1H); 5.2(s, 1H); 3.8(s, 3H); 3.5(t, 2H); 2.7(m, 1H); 2.2(m, 3H); 2.1-1.0(m, 
               
               
                   
                 9H) 
               
               
                 99 
                 7.3(s, 5H); 7.1(s, 1H); 5.3(s, 3H); 3.5(t, 2H); 2.8-1.1(m, 13H); 1.0(t, 3H) 
               
               
                 100 
                 7.3(s, 5H); 7.1(s, 1H); 5.3(s, 1H); 3.8(s, 3H); 3.4(t, 2H); 3.0(m, 2H); 2.7(t, 2H); 1.0(d, 12H) 
               
               
                 101 
                 7.3(s, 5H); 7.1(s, 1H); 5.3(s, 1H); 3.8(s, 3H); 3.5(m, 2H); 3.0(m, 1H); 2.3(s, 3H); 2.2-1.2 
               
               
                   
                 (m, 8H) 
               
               
                 102 
                 7.3(b, 6H); 7.1(s, 1H); 5.3(s, 1H); 3.7(b, 3H); 3.7-3.3(m, 2H); 2.3(m, 2H); 2.2(b, 6H); 1.8 
               
               
                   
                 (m, 2H) 
               
               
                 103 
                 7.3(b, 5H); 7.1(s, 1H); 5.2(s, 1H); 3.8(s, 3H); 3.6(m, 6H); 2.4(m, 6H); 1.9(m, 2H) 
               
               
                 104 
                 7.3(b, 5H); 7.1(s, 1H); 5.3(s, 1H); 3.8(s, 3H); 3.5(m, 2H); 2.5(m, 6H); 1.8(m, 6H) 
               
               
                 118 
                 6.8(d, 2H); 6.5(s, 2H); 4.6(b, 1H); 3.7(m, 11H); 2.4(m, 2H); 1.5-0.6(m, 22H) 
               
               
                 148 
                 7.9-6.1(m, 10H); 4.9(m, 1H); 2.5(t, 2H); 1.5-0.5(m, 9H) 
               
               
                 161 
                 8.0(b, 1H); 7.2(s, 4H); 6.8(s, 1H); 5.9(s, 1H); 5.2(s, 1H); 4.8(t, 2H); 2.3-1.6(m, 4H) 
               
               
                 166 
                 7.3(d, 1H); 6.5(s, 2H), 5.9(s, 1H); 5.7(s, 1H), 3.6(m, 12H) 
               
               
                 167 
                 7.2(d, 1H); 6.5(s, 2H); 5.9(s, 1H), 5.7(s, 1H), 3.7(m, 11H), 1.7-0.4(m, 7H) 
               
               
                 176 
                 7.3(s, 6H); 5.8(s, 1H); 3.6(m, 5H); 2.6(t, 2H); 2.3(s, 6H) 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex- 
                   
                   
                   
                   
                   
                 Base 
                   
                   
                   
               
               
                 am- 
                   
                   
                   
                   
                   
                 or 
                 M.p. 
               
               
                 ple 
                 Haz 
                 Ara 
                 R1 
                 R3 
                 R4 
                 Salt 
                 (° C.) 
                   1 H RMN(Mhz)(Solvent)δ 
                 IR, cm −1   
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.24(s, 6H), 2.54(t, J=6 Hz, 2H), 3.58(m, 2H), 3.79(s, 3H), 5.76(s, 1H), 6.17(d, J=1.8Hz, 1H), 6.83(m, 1H) 6.93(m, 1H), 7.28(m, 1H), 7.38(d, J=1.8 Hz, 1H). 
                 (film)2944, 2863, 2821, 2771, 1457, 1100, 1092, 1066, 1056, 1042, 705, 651. 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 ci- trate 
                 115- 116 
                 (300Mhz)(DMSO-d 6 )2.51(AB system, J= 15Hz, 2H), 2.71(AB system, J=15Hz, 2H), 2.66(s, 6H), 3.18(m, 2H), 3.70-3.80(a.c., 5H, (δ=3.74, s)), 6.07(s, 1H), 6.16(s, 1H), 7.01(m, 1H), 7.10(m, 1H), 7.34(s, 1H), 7.57(m, 1H). 
                 (KBr)3300-2300 (broad), 1732, 1589, 1475,  
               
               
                 # 1398, 1380, 1356, 1220, 1203, 1183. 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.24(s, 6H), 2.54(t, J=6 Hz, 2H), 3.56(m, 2H), 3.77(s, 3H), 5.59(s, 1H), 6.08(d, J=1.8Hz, 1H), 6.99(dd, J=5 Hz, J′=1.2Hz, 1H), 7.19(m, 1H), 7.30(dd, J=5Hz, J′=3Hz, 1H), 7.37(d, J=1.8Hz, 1H). 
                 (film)2942, 2819, 2769, 1456, 1103, 783, 753. 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.24(s, 6H), 2.56(m, 2H), 3.54(m, 1H), 3.56(s, 3H), 3.67(m, 1H), 5.90(s, 1H), 6.77(m, 1H), 6.85(d, J=1.2 Hz, 1H), 6.93(m, 1H), 6.98(d, J=1.2Hz, 1H), 7.27(m, 1H). 
                 (film)2943, 2864, 2820, 2770, 1496, 1456, 1278, 1103, 1056, 772, 702. 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.14(s, 3H), 2.23(s, 6H), 2.54(t, J=6Hz, 2H), 3.59(m, 2H), 3.84(s, 3H), 5.74(s, 1H), 6.04(s, 1H), 6.80(d, J= 5.0Hz, 1H), 7.18(d, J=5.0Hz 1H), 7.33(s, 1H). 
                 (film)2944, 2865, 2821, 2772, 1455, 1100, 1092, 1067, 1055, 1042, 782, 715. 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.24(s, 6H), 2.43(s, 3H) 2.53(t, J=6Hz, 2H), 3.56(m, 2H), 3.80(s, 3H), 5.65(s, 1H), 6.17(d, J=1.5Hz, 1H), 6.57(d, J=2.4Hz, 1H), 6.62(d, J=2.4Hz, 1H), 7.37(d, J=1.5Hz, 1H). 
                 (film)2944, 2863, 2820, 2772, 1456, 1286, 1101, 1092, 1067, 1055, 1042, 798, 783, 762, 652. 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.25(s, 6H), 2.55(t, J=6 Hz, 2H), 3.57(m, 2H), 3.80(s, 3H), 5.68(s, 1H), 6.20(d, J=2.1Hz, 1H), 6.56(d,J=4 Hz, 1H), 6.90(d, J=4Hz, 1H), 7.40(d, J= 2.1Hz, 1H). 
                 (film)2943, 2864, 2821, 2772, 1441, 1101, 1093, 1066, 1055, 1042, 968, 793, 761, 651. 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )2.23(s, 6H), 2.53(t, J= 5.7Hz, 2H), 3.57(m, 2H), 3.78(s, 3H), 5.72 (s, 1H), 6.18(d, J=2.1Hz, 1H), 6.74(d, J= 1.5Hz, 1H), 7.19(d, J=1.5Hz, 1H), 7.39(d, J=2.1Hz, 1H). 
                 (film)2944, 2864, 2821, 2772, 1456, 1344, 1101, 1093, 1056, 1042, 780. 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 3   
                 H 
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )1.91(s, 3H)2.26(s, 6H), 2.52(m, 2H), 3.17(m, 1H), 3.59(m, 1H), 3.63(s, 3H), 6.31(d, J=1.5Hz, 1H), 6.58 (m, 1H), 6.88(m, 1H), 7.21(m, 1H), 7.41(d, J=1.5Hz, 1H). 
                 (film)2940, 2819, 2770, 1456, 1369, 1235, 1108, 1041, 930, 699. 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 CH 3   
                 ci- trate 
                 138- 142 
                 (300Mhz)(DMSO-d 6 )2.51(d, J=15.1Hz, 2H), 2.59(d, J=15.1Hz, 2H), 2.66(s, 6H), 3.17(t, 2H), 3.59(quint, 1H), 3.71(quint, 1H), 3.76(s, 3H), 5.76(s, 1H), 5.95(d, 1H), 7.32(d, 1H), 7.39(m, 5H). 
                 (KBr)3300-2300 (broad), 1732, 1587, 1475, 1399, 1382, 1256, 1220, 1202, 1183. 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 CH 3   
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )1.15(d, J=6.1Hz, 3H), 2.18(s, 6H), 2.20(m, 1H), 2.57(dd, J=12.7 Hz, J′=7.3Hz, 1H), 3.65(m, 1H), 3.85(s, 3H), 5.92(m, 2H), 7.26-7.37(a.c., 6H) 
                 (film)2970, 2941, 2821, 2768, 1451, 1095, 1073, 1049, 724, 702 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 CH 3   
                 CH 3   
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )1.19(d, J=6.3Hz, 3H), 2.20(s, 6H), 2.30(dd, J=12.7Hz, J′=5.4 Hz, 1H), 2.53(dd, J=12.7Hz, J′=6.3Hz, 1H), 3.68(m, 1H), 3.75(s, 3H), 5.84(s, 1H), 6.07(d, J=2Hz, 1H), 7.28-7.36(a.c., 5H), 7.38(d, J=2Hz, 1H) 
                 (film)2972, 2941, 2821, 2768, 1454, 1096, 1074, 1043, 724, 703 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 Enantiomeric 
                   
                   
               
               
                   
                   
                   
                   
                   
                 Optic 
                 purity 
                 Specific rotation 
                 M.p. 
               
               
                 Example 
                 Az 
                 Ar 
                 R1 
                 Base or Salt 
                 isomer. 
                 % 
                 [α] D   
                 (° C.) 
               
               
                   
               
             
          
           
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 (+) 
                 99 
                 +31.8 (c = 2.0 CH 2 Cl 2 ) 
                 oil 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 (−) 
                 98.5 
                 −31.8 (c = 2.0 CH 2 Cl 2 ) 
                 oil 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 citrate 
                 (+) 
                 99 
                 +2.8 (c = 2.0 MeOH) 
                 121-122 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 citrate 
                 (−) 
                 98.5 
                 −2.3 (c = 2.0 MeOH) 
                 121-122 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 (D)-ditoluoyl- tartrate 
                 (+) 
                 99 
                 +87.5 (c = 2.0 MeOH) 
                 130-131 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 (L)-ditoluoyl- tartrate 
                 (−) 
                 98.5 
                 −85.4 (c = 2.0 MeOH) 
                 130-131 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 citrate 
                 (+) 
                 99.1 
                 +12.3 (c = 1.0 MeOH) 
                 130-131 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 citrate 
                 (−) 
                 99.0 
                 −12.2 (c = 1.0 MeOH) 
                 129-131 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex- 
                   
                   
                   
                   
                   
                   
                   
               
               
                 am- 
                   
                   
                   
                 Base 
                 M.P. 
               
               
                 ple 
                 Az 
                 Ar 
                 R1 
                 or Salt 
                 (° C.) 
                   1 H RMN(Mhz)(Solvent)δ 
                 IR, cm −1   
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 oil 
                 (300Mhz)(CDCl 3 )3.67(s, 3H), 5.00(d, J= 4.5Hz, 1H), 6.06(d, J=4.5Hz, 1H), 6.16(s, 1H), 6.84(m, 1H), 6.94(m, 1H), 7.23(s, 1H), 7.27(d, J=5.1Hz, 1H). 
                 (film)3210(broad), 1433, 1400, 1284, 1201, 1055, 1037, 1003, 781, 760, 706. 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 109- 111 
                 (300Mhz)(CDCl 3 )2.19(s, 3H), 2.63(d, J= 4.5Hz, 1H), 3.82(s, 3H), 6.13(d, J=4.5Hz, 1H), 6.16(d, J=1.5Hz, 1H), 6.83(d, J=5.1 Hz, 1H), 7.20(d, J=5.1Hz, 1H), 7.37(d, J= 1.5Hz, 1H). 
                 (KBr) 3199(oil), 1400, 1282, 1200, 1060, 998, 940, 796, 776, 732. 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 131- 132 
                 (300Mhz)(CDCl 3 )2.46(s, 3H), 2.79(d, J= 4.6Hz, 1H), 3.80(s, 3H), 6.04(d, J=4.6Hz, 1H), 6.25(d, J=1.8Hz, 1H), 6.62(d, J=3.3 Hz, 1H), 6.70(d, J=3.3Hz, 1H), 7.39(d, J= 1.8Hz, 1H). 
                 (KBr)3163(broad), 3100, 1282, 1206, 1025, 1010, 801, 788. 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 107- 109 
                 (300Mhz)(CDCl 3 )3.76(s, 3H), 3.86(b.a., 1H), 6.02(s, 1H), 6.20(d, J=1.8Hz, 1H), 6.61(d, J=4.0Hz, 1H), 6.91(d, J=4.0Hz, 1H), 7.32(d, J=1.8Hz, 1H). 
                 (KBr)3170(broad), 3104, 1440, 1395, 1205, 1181, 1025, 1011, 966, 800, 791. 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 base 
                 95-6 
                 (300Mhz)(CDCl 3 )3.60(b.a., 1H), 3.78(s, 3H), 6.08(s, 1H), 6.20(d, J=1.8Hz, 1H), 6.80(s, 1H), 7.21(s, 1H), 7.35(d, J=1.8Hz, 1H). 
                 (KBr)3112(broad), 1397, 1343, 1205, 1182, 1132, 1052, 823, 795, 768. 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 3   
                 base 
                 130- 131 
                 (300Mhz)(CDCl 3 )2.00(s, 3H), 3.27(b.a., 1H), 3.68(s, 3H), 6.26(d, J=2.0Hz, 1H), 6.68(m, 1H), 6.91(m, 1H), 7.23(m, 1H), 7.32(d, J=2.0Hz, 1H). 
                 (KBr)3264(broad), 1384, 1221, 1159, 1114, 802, 779, 707. 
               
               
                   
               
             
          
         
       
     
     In the present invention the activity of the compounds of general formula (I) has been demonstrated experimentally in the claimed applications, by means of a study of the in vivo effect on the release of substance P and also in two in vivo trials of anti-depressive activity. 
    
    
     In the following examples some properties object of the invention are indicated for the (±)-5-{α-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazol citrate (example 191). 
     The examples that are now described, presented by way of illustration, described some biological trials and should in no way be considered to limit the scope of the invention. 
     EXAMPLE 1 
     Effect on the Spinal Release of Substance P in Rats: 
     The study was carried out in vivo, in rats anaesthetised with halothane. The trial consisted of intrathecal perfusion with an artificial cerebrospinal fluid, with a view to collecting the peptides released from the superficial layers of the spinal cord while the product under study is administered locally or systematically. The method used was that described by Collin, E. and co-workers ( Naunyn-Schmiedeberg&#39;s Arch. Pharmacol ., 1994, 349, 387-393). 
     The activity of the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191) was studied, administered intrathecally in the perfusion liquid, at a concentration of 1 μM. As is summarised in table 8, the product inhibited the release of substance P. The systematic administration of 46 mg/kg of product also reduced the release of substance P. 
     It is of note that the effect of the systematic administration of product on the intrathecal release of substance P lasted 2 hours, the average inhibition being 50% of the effect during this period. 
     EXAMPLE 2 
     Study of the Anti-depressive Activity: 
     The anti-depressive activity of the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191) was studied and demonstrated in two different trials in mice. In one the inhibition of ptosis induced by reserpine was studied, and in the other the effect on mobility in adverse situation was investigated. 
     2.1 Inhibition of Ptosis Induced by Reserpine in Mice: 
     The method used was that described by S.Garattini and co-workers ( Med. Exp ., 1960, 3, 315-320). The trial consists of observing the possible inhibition of ptosis induced by reserpine (25 mg/kg, ip: intraperitoneal) in mice, after the products under study had been administered orally. 
     The activity of the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191) administered orally at different doses has been determined. As is summarised in table 9, the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191) has been shown to have clear anti-depressive activity inhibiting the effects of reserpine with a good dose-response. 
     2.2 Effect on Mobility in Adverse Situation: 
     The method used was described by R. D. Porsolt and co-workers ( Arch. Int. Pharmacodyn ., 1987, 288, 11-30). The trial consists of suspending the mice by their tales for six minutes in an ITEMATIC-TST apparatus, which measures the mobility and the strength of the animals&#39; movements. The animals exposed to this adverse situation, after a start with vigorous activity, become desperate and end up staying still. The products with anti-depressive activity significantly reduce the time of immobility. 
     As is summarised in table 10, the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191) has clearly been active in this trial, reducing the immobility period significantly and in a dose-dependent fashion. 
     The pharmacological trials carried out show that the (±)-5-{α-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazol citrate (example 191), as an example of the properties object of the invention, display clear activity as inhibitor of the release of substance P, which bestows on it an application in the treatment of central nervous system disorders in which release of substance P is implicated. Furthermore, and by way of example, the anti-depressive activity has been demonstrated it two different trials carried out on experimental animals. 
     
       
         
               
             
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
             
             
               
                 Effect of citrate (±)-5-{α-[2-(dimethylamino)ethoxy]benzyl}-1-methyl- 
               
               
                 1H-pyrazol (example 191) on the intrathecal release of substance P. 
               
             
          
           
               
                   
                 % Inhibition, with respect to control, 
               
               
                 Treatment with example 191 
                 of intrathecal release of substance P 
               
               
                   
               
               
                 1 μM, intrathecal 
                 −58% 
               
               
                 46 mg/kg, ip 
                 −50% 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Inhibition of ptosis induced by reserpine in mice. 
               
             
          
           
               
                 Product 
                 Dose* (mg/kg, oral) 
                 % Activity 
                 SD-50 
               
               
                   
               
             
          
           
               
                 Example 191 
                 92 
                 84 
                 38.5 mg/kg, oral 
               
               
                   
                 80 
                 75 
               
               
                   
                 23 
                 30 
               
               
                   
                 12 
                 8 
               
               
                   
               
               
                 *Dose expressed in mg/kg of the base of the compound of example 191  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Inhibition of immobility time in adverse situation in mice. 
               
             
          
           
               
                 Product 
                 Dose (mg/kg, oral) 
                 % Inhibition 
                 DE-50 
               
               
                   
               
               
                 Example 191 
                 92 
                 69 
                 50.5 mg/kg, oral 
               
               
                   
                 46 
                 41 
               
               
                   
                 23 
                 30 
               
               
                   
                 12 
                 20