Utilization of derivatives of tetrahydropyridines (or 4-hydroxypiperidines)-butylazols in the preparation of a medicament for the treatment of pain

Abstract

Derivatives of tetrahydropyridines (or 4-hydroxypiperidines)-butylazols of formula (I), wherein R1, R2 and R3, which are similar or different, represent each of them hydrogen, halogen, alkyl C1-C4, trifluoromethyl, hydroxyl, alkoxyl, or two adjacent radicals can form a ring; A is a C atom and the dotted line represents an additional bond, or A is a C atom joined to a hydroxyl group and the dotted line represents absence of additional bond; Z1 is N or CR4; Z2 is N or CR5; Z4 is N or CR7; and R4, R5, R6 and R7, which different, represent hydrogen, halogen, alkyl C1-C4, aryl or substituted aryl, or two adjacent radicals can form part of another ring. These derivatives are useful for the treatment of acute pain, neuropathic pain or nociceptive pain in mammals, including human beings.

Description

FIELD OF THE INVENTION

The present invention relates to the use of derivatives of tetrahydropyridines (or 4-hydroxypyperidines)butylazoles of general formula (I), as well as their physiologically acceptable salts, in the preparation of medicaments useful in human and/or veterinary therapy for the treatment of acute pain, neuropathic pain and nociceptive pain, either alone or in combination with other analgesics, producing in this case a synergy.

BACKGROUND OF THE INVENTION

In our patent application WO 96/04287 compounds of general formula (I) are disclosed

that have an affinity for the cy and 5HT 1A receptors, and which are claimed as medicaments useful for the treatment of anxiety, psychosis, epilepsy, convulsion, amnesia, cerebro-vascular diseases and senile dementia.

We have now discovered that the compounds of general formula (I), as well as their pharmaceutically acceptable salts, are especially useful for the preparation of medicaments, useful in human and/or veterinary therapy for the prophylaxis, alleviation or curing of acute pain, neuropathic pain and nociceptive pain, either alone or in combination with other analgesics, giving rise in this case to a synergy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of derivatives of tetrahydropyridines (or 4-hydroxypyperidine)butylazoles of general formula:

where

R 1 , R 2 and R 3 are either identical or different and represent a hydrogen atom, a C 1 -C 4 alkyl group, a trifluoromethyl radical, a hydroxyl or alkoxyl radical, and furthermore, two adjacent radicals can form part of an six-member aromatic ring; A represents a carbon atom and the dotted line represents an additional bond, or A represents a carbon atom bound to a hydroxyl group (C—OH) and the dotted line represents the lack of an additional bond;

Z 1 represents a nitrogen atom or a substituted carbon atom that can be represented by C—R 4 ;

Z 2 represents a nitrogen atom or a substituted carbon atom that can be represented by C—R 5 ;

Z4 represents a nitrogen atom or a substituted carbon atom that can be represented by C—R 7 ;

with the condition that Z 1 , Z 2 and Z 4 taken together can represent, at most, two nitrogen atoms; and

R 4 , R 5 , R 6 and R 7 , are identical or different and represent a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, an aryl or substituted aryl group, or two adjacent radicals can form part of a six-member aromatic ring;

or one of their physiologically acceptable salts, in the elaboration of a medicament for the treatment of acute pain, neuropatic pain or nocipeptive pain in mammals, including man.

The term “a halogen atom” represents a fluorine, chlorine or bromine atom.

The term “aryl or substituted aryl” represents a phenyl radical or a phenyl radical substituted by halogen.

The term “alkoxyl” represents a methoxyl or ethoxyl radical.

The term “G 1 -G 4 alkyl” represents a straight chain or branched radical that is based on a saturated hydrocarbon of 1 to 4 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl y tercbutyl for example.

Physiologically acceptable salts of the compounds of general formula (I) refer both to salts formed with inorganic acids and organic acids, in particular, to salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinamic acid, salicylic acid and alkyl, cycloalkyl or arylsulphonic acids.

The use of derivatives of general formula (I) for the treatment of pain refers to the use of analgesics in clinical practice. The term acute pain includes, but is not limited to, headache, arthritis, muscular tension or dysmenorrhea. The term neuropathic pain includes, but is not limited to, chronic back pains, pain associated with arthritis, herpes, pain associated with cancer, pain of a phantom limb, pain during childbirth or neuropathic pain resistant to opoids. The term nociceptive pain includes, but is not limited to, post-operation pain, dental pain, pain arising from surgery, pain caused by serious burns, post-natal pain or pain related with the genitourinary tract.

The derivatives of general formula (I) can be prepared according to the procedures disclosed in our patent application WO 96/04287.

In human therapy, the dosage administered of the compounds of the present invention varies as a function of the seriousness of the affliction to be treated. Normally the dosage will lie between 1 and 100 mg/day. The compounds of the invention can be administered as the only active ingredient or in conjunction with another analgesic in 2 proportion of one part of compound of general formula (I) with around one to ten parts of the other analgesic, with the aim of provoking a synergy. Other analgesics include, but are not limited to, non-steroid anti-inflammatory compounds such as aspirin or indomethacine, other analgesics such as paracetamol, narcotic analgesics or related compounds such as morphine, meperidine or pentazocine. The compounds of the invention, with a suitable pharmaceutical formulation, are administered by different routes, such as orally, transdermically, parenterally, subcutaneously, intranasally, intramuscularly or intravenously. Pharmaceutical compositions that contain compounds of general formula (I) are disclosed in our patent application WO 96/04287.

Illustrative examples of compounds included in the scope of the present invention include compounds that are characterised by the data indicated in tables 1 and 2.

TABLE 1

Ex.

R 1

R 2

R 3

R 4

R 5

Z 1

Z 2

R 6

Z 4

m.p.

IR cm −1

1 H-RMN (300 MHz), δ (solvent)

1

H

H

H

H

H

N

CH

Cl

CH

102-103° C.

3364 (b.a., OH),

1.56(quin, J=7.1Hz, 2H), 1.65(b.a., 1H); 1.76

2950, 2810, 1375,

(d, J=12.4Hz, 2H); 1.90(quin, J=7.6Hz, 2H); 2.20(m,

1130, 991, 969,

2H); 2.40-2.55(a.c., 4H); 2.83(d, J=9.5Hz, 2H); 4.11

760, 696, 605

(t, JH=8Hz, 2H); 7.21-7.42(a.c., 5H); 7.52(d, J=8.5Hz,

KBr

2H) (CDCl 3 )

2

H

H

H

H

H

C—CH 3

N

Cl

CCl

86-89° C.

3196 (b.a., OH),

1.59(m, J=5.3 J′=6.6, 2H); 1.70-1.32(a.c., 4H); 2.16

2951, 2924, 2824,

(d, t, J=13.0Hz J′=4.4Hz, 2H); 2.37(s, 3H); 2.41-2.55

1406, 1247, 1146

(a.c., 5H); 2.79(d, J=11.3Hz, 2H); 3.88(t, J=7.5Hz,

762, 703 KBr

2H); 7.27(t, J=7.2Hz, 1H); 7.36(t, J=7.6Hz, 2H); 7.51

(d, J=7.3Hz, 2H) (CDCl 3 )

3

H

H

H

H

H

CH

N

CH═CH—CH═CH—C

122-123° C.

3180 (b.a., OH),

1.51 (quin, J=7.4Hz, 2H); 1.73(d, J=12.7Hz, 2H); 1.87

2929, 2818, 1496,

(quin, J=7.6Hz, 2H); 2.10(dt, J=12.9Hz J′=4.1Hz, 2H);

1467, 1459, 1445,

2.36-2.50(a.c., 4H); 2.70(d, J=11.2Hz, 2H); 3.25(b.a.,

1286, 1219, 1143,

1H); 4.12(t, J=7.1Hz, 2H); 7.21-7.40(a.c., 6H); 7.51

769, 743, 707

(d, J=8.3Hz, 2H); 7.70-7.75(a.c., 2H) (CDCl 3 )

KBr

4

H

H

H

H

H

CH

N

H

N

123° C.

3180 (b.a., OH),

1.45(quin, J=7.5Hz, 2H); 1.69(d, J=12.9Hz, 2H); 1.85

2949, 2919, 2838,

quin, J=7.5Hz, 2H); 2.07(dt, J=13.0Hz J′=4.1Hz, 2H);

1276, 1145, 1135,

2.33-2.45(a.c., 4H); 2.69(d, J=11.2Hz, 2H); 2.93(b.a.,

1006, 770, 707,

1H); 4.10(t, J=6.9Hz, 2H); 7.18(t, J=7Hz, 1H); 7.27

676

(t, J=7.8Hz, 2H); 7.46(d, J=8.3Hz, 2H); 7.80(s, 1H);

KBr

7.91(s, 1H) (CDCl 3 )

5

H

H

Cl

H

H

N

CH

Cl

CH

106° C.

3145 (b.a., OH),

1.47(quin, J=7.5Hz, 2H); 1.69(d, J=11.9Hz, 2H); 1.84

2947, 2918, 2834,

(quin, J=7.6Hz, 2H); 2.05(dt, J=13Hz, J′=4.4Hz, 2H);

1318, 1147, 1083,

2.34-2.50(a.c., 5H); 2.72(d, J=11.2Hz, 2H); 4.05

1112, 990, 817,

(t, J=7.0Hz, 2H); 7.29(AB system, J=8.6Hz, 2H); 7.36

612

(s, 2H); 7.42(AB system, J=8.6Hz, 2H) (CDCl 3 )

KBr

6

H

H

Cl

H

H

C—CH 3

N

Cl

CCl

oil

3340 (b.a., OH),

1.54(m, 2H); 1.67-1.78(a.c., 4H); 2.06(dt, J=13Hz,

2946, 2820, 1537,

J′=4.2Hz, 2H); 2.32(s, 3H); 2.38-2.45(a.c., 5H); 2.73

1492, 1471, 1406,

(d, J=11.2Hz, 2H); 3.86(t, J=7.3Hz, 2H); 7.28(AB

1376, 1247, 1135,

system, J=8.6Hz, 2H); 7.43(AB system, J=8.6Hz, 2H)

1094, 1013, 828,

(CDCl 3 )

755

film

7

H

CF 3

H

H

H

N

CH

Cl

CH

oil

3360 (b.a., OH),

1.48(quin, J=7.6Hz, 2H); 1.71(d, J=12.5Hz, 2H); 1.85

2948, 2823, 1438,

(quin, J=7.6Hz, 2H); 2.06-2.21(a.c., 3H); 2.36-2.43

1378, 1330, 1212,

(a.c., 4H); 2.76(d, J=11.5Hz, 2H); 4.06(t, J=7.1Hz,

1165, 1124, 1047,

2H); 7.35(s, 2H); 7.43-7.51(a.c., 2H); 7.66

972, 804, 704

(d, J=7.5Hz, 1H); 7.79(s, 1H) (CDCl 3 )

film

8

H

CF 3

H

H

H

C—CH 3

N

Cl

CCl

oil

3340 (b.a., OH),

1.57(quin, J=7.5Hz, 2H); 1.70-1.80(a.c., 4H); 2.15

2948, 2823, 1408,

(dt, J=12.9Hz J′=3.6Hz, 2H); 2.35(s, 3H); 2.40-2.52

1330, 1165, 1126,

(a.c., 4H); 2.80(d, J=11.7Hz, 2H); 3.88(t, J=7.0Hz,

1075, 789, 763,

2H); 7.42-7.57(a.c., 2H); 7.69(d, J=7.5Hz, 1H); 7.82

704

(s, 1H) (CDCl 3 )

film

9

H

H

F

H

H

C—CH 3

N

Cl

CCl

oil

3330 (b.a., OH),

1.58(m, 2H); 1.64-1.81(a.c., 4H); 2.14(dt, J=12.9Hz

2946, 2818, 1509,

J′=3.6Hz 2H); 2.32(s, 3H); 2.43-2.60(a.c., 4H); 2.84

1406, 1247, 1222,

(d, J=11Hz, 2H); 3.87(t, J=7.1Hz, 2H); 4.18(b.a., 1H),

1160, 835

7.01(t, J=8.8Hz, 2H); 7.46(dd, J=8.8Hz J′=5.2Hz, 2H)

film

(CDCl 3 )

10

H

H

H

H

H

CH

CH

CH═CH—CH═CH—C

109-111° C.

3190 (b.a., OH),

1.57(m, 2H); 1.73(d, J=14Hz, 2H); 1.80(b.a., 1H);

2956, 2823, 1461,

1.90(m, 2H); 2.13(dt, J=13Hz J′=4Hz, 2H); 2.32-2.46

1446, 1319, 1303,

(a.c., 4H); 2.76(d, J=11.3Hz, 2H); 4.16(t, J=7.1Hz,

1218, 1142, 738,

2H); 6.50(d, J=3.1Hz, 1H); 7.05-7.14(a.c., 2H); 7.18-

703

7.40(a.c., 5H); 7.50(d, J=7.8Hz, 2H); 7.00

KBr

(d, J=7.3Hz, 1H) (CDCl 3 )

11

H

H

CH 3

H

H

C—CH 3

N

Cl

CCl

oil

3360, (b.A., OH),

1.53(m, 2H); 1.66-1.84(a.c., 4H); 2.09(dt, J=12.9Hz,

2946, 2818, 1535,

J′=3.6Hz, 2H); 2.33(s, 3H); 2.36(s, 3H); 2.39-2.50

1471, 1406, 1376,

(a.c., 4H); 2.77(d, J=11.2Hz, 2H); 3.87(t, J=7.0Hz,

1247, 1134, 817,

2H); 7.15(AB system, J=7.8Hz, 2H); 7.33(AB

755

system, J=7.8Hz, 2H) (CDCl 3 )

12

H

H

H

H

H

N

CH

H

CH

89-91° C.

3137 (b.A., OH)

1.51(quin, J=7.6Hz, 2H); 1.73(d, J=12.3Hz, 2H); 1.89

2947, 2532, 1396,

(quin, J=7.6Hz, 2H); 2.00-2.20(a.c., 3H); 2.35-2.45

1378, 1119, 1046,

(a.c., 4H); 2.76(d, J=10.2Hz, 2H); 4.13(t, J=7.1Hz,

756, 697

2H); 6.21(s, 1H); 7.21(m, 1H); 7.30-7.37(a.c., 3H);

KBr

7.44-7.52(a.c., 3H) (CDCl 3 )

13

H

H

H

H

H

N

CH

CH═CH—CH═CH—C

107-109° C.

3311 (b.a., OH),

1.53(m, 2H); 1.71(d, J=12.2Hz, 2H); 1.95(m, 2H);

2953, 2803, 1465,

2.10(m, 2H); 2.29(b.a., 1H); 2.35-2.47(a.c., 4H);

1375, 1133, 1117,

2.71(d, 2H); 4.39(t, J=7.1Hz, 2H); 7.13(t, 1H); 7.22-

1043, 1017, 761,

7.44(a.c., 5H); 7.50(d, J=8Hz, 2H); 7.71(d, J=8.3Hz,

744, 704

1H); 7.95(s, 1H) (CDCl 3 )

KBr

14

H

H

H

H

H

N

C—CH═CH—CH═CH

CH

120-122° C.

3295 (b.a., OH)

1.58(m, 2H); 1.73(d, J=13.5Hz, 2H); 1.90-2.20(a.c.,

2946, 2817, 1377,

4H); 2.38-2.47(a.c., 4H); 2.75(d, J=10.5Hz, 2H); 4.42

1126, 786, 735,

(t, J=6.Hz, 2H); 7.06(t, J=7.5Hz, 1H); 7.22-7.37(a.c.,

700

4H); 7.49(d, J=7.8Hz, 2H); 7.61-7.71(a.c., 2H); 7.90

KBr

(s, 1H) (CDCl 3 )

15

H

H

CH 3

H

H

N

CH

Cl

CH

81-82° C.

3122 (b.a., OH)

1.51(quin, J=7.6Hz, 2H); 1.73(d, J=11.7Hz, 2H); 1.87

2936, 1475,

(quin, J=7.6Hz, 2H); 2.12(dt, J=12.8Hz J′=4.4Hz, 2H),

1434, 1378, 1319,

2.33(s, 3H); 2.35-2.48(a.c., 5H); 2.74(d, J=11.2Hz,

989, 973, 814

2H); 4.07(t, J=7.1Hz, 2H); 7.15(d, J=8Hz, 2H); 7.25-

KBr

7.40(a.c., 4H) (CDCl 3 )

16

H

H

CH 3 O

H

H

N

CH

Cl

CH

122-123° C.

3190 (b.a., OH)

1.49(quin, J=7.6Hz, 2H); 1.72(d, J=11.8Hz, 2H); 1.84

2954, 2923, 2827,

(quin J=7.4Hz, 2H); 2.00-2.14(a.c.(dt+b.a.), 3H);

1509, 1314, 1243,

2.34-2.47(a.c., 4H); 2.72(d, J=11Hz, 2H); 3.77(s,

1178, 971

3H); 4.05(t, J=7.1Hz, 2H); 6.85(d, J=9Hz, 2H); 7.24-

KBr

7.42(a.c., 4H) (CDCl 3 )

17

H

H

H

H

H

CPh

N

H

CH

108-110° C.

3220 (b.a., OH)

1.45(quin, J=7.6Hz, 2H); 1.68-1.82(a.c., 4H); 2.08

2944, 2817, 1473,

(dt, J=13.0Hz J′=4.1Hz, 2H); 2.29-2.42(a.c., 4H); 2.5

1446, 1421, 1136,

(b.a., 1H); 2.67d, J=11.2Hz, 2H); 4.01 m(t, J=7.3Hz,

1046, 787, 773,

2H); 7.01(s, 1H); 7.08(s, 1H); 7.20-7.56(a.c., 10H)

761, 700

(CDCl 3 )

KBr

18

H

H

CH 3

H

H

CH

N

CH═CH—CH═CH—C

oil

3260 (b.a., OH)

1.58(quin, J=7.6Hz, 2H); 1.74(d, J=12Hz, 2H); 1.82

2944, 2817, 1497,

(b.a., 1H); 1.95(quin, J=7.6Hz, 2H); 2.11(dt, 2H);

1459, 1381, 1287,

2.33(s, 3H); 2.40-2.50(a.c., 4H); 2.74(d, J=11.5Hz,

1135, 1046, 817,

2H); 4.20(t, J=7.1Hz, 2H); 7.15(d, J=8.3Hz, 2H);

745

7.22-7.35(a.c., 3H); 7.37-7.43(a.c., 2H); 7.79(m,

film

1H); 7.87(s, 1H) (CDCl 3 )

19

H

H

H

H

H

CH

N

Ph

CPh

138-139° C.

3194(b.a., OH)

1.38(m, 2H); 1.56(m, 2H); 1.72(d, J=12.4Hz, 2H);

2939, 2806, 1509,

2.09(dt, 2H); 2.25(t, J=7.4Hz, 2H); 2.39(m, 2H); 2.66

1446, 773, 766,

(m, 2H); 3.10(b.a., 1H); 3.78(t, J=7.2Hz, 2H); 7.10-

758, 696

7.52(a.c., 16H);

KBr

20

CH═CH—CH═CH

H

H

H

N

CH

Cl

CH

oil

3357 (b.a., OH),

1.44(quin, J=7.3Hz, 2H); 1.77(quin, J=7.5Hz, 2H);

2946, 2833, 1434,

2.15-2.30(a.c., 5H); 2.34(t, J=7.5Hz, 2H); 2.57(m, 2H);

1379, 1315, 1140,

2.73(d, J=11.3Hz, 2H); 3.99(t, J=7.1Hz, 2H); 7.26-7.46

1123, 972, 781,

(a.c., 6H); 7.73(d, J=8.1Hz, 1H); 7.82(m, 1H); 8.91

613

(m, 1H) (CDCl 3 )

KBr

21

H

CH═CH—CH═CH

H

H

N

CH

Cl

CH

142-143° C.

3131 (b.a., OH),

1.55(quin, J=7.5Hz, 2H); 1.70-1.97(a.c., 5H); 2.29

2950, 2820, 1377,

(dt, J=12.7Hz, J′=4.1Hz, 2H); 2.41-2.55(a.c., 4H); 2.83

1311, 971, 829,

(d, J=11.7Hz, 2H); 4.11(t, J=7.0Hz, 2H); 7.39-7.50

761, 613

(a.c., 4H); 7.64(dd, J=9.1Hz, J′=1.5Hz, 1H); 7.81-7.85

KBr

(a.c., 3H); 7.95(s, 1H) (CDCl 3 )

22

H

H

H

H

H

N

CH

C 6 HCl

CH

137-140° C.

3347, 2944, 2810,

1.56(m, 2H); 1.74(m, 2H); 1.80(b.a., 1H); 1.94(m,

1562, 1492, 1376,

2H); 2.40(dt, J=13.1Hz, J′=4.0Hz, 2H); 2.40-2.50(a.c.,

1127, 1094, 1002,

4H); 2.77(m, 2H); 4.15(t, J=7.0Hz, 2H); 7.25-7.40

952, 828, 760, 699

(a.c., 7H); 7.50(d, J=8.3Hz, 2H); 7.61(s, 1H); 7.72

KBr

(s, 1H) (CDCl 3 )

23

H

H

F

H

H

CH

N

CH═CH—CH═CH—C

120-122° C.

3230, 2947, 2915,

1.58(m, 2H); 1.70(m, 2H); 1.93(m, 2H); 2.12(m, 2H);

1504, 1219, 1135,

2.40-2.55(a.c., 4H); 2.76(m, 2H); 4.19(t, J=7.0Hz,

835, 746

2H); 7.02(m, 2H); 7.26(m, 2H); 7.30-7.50(a.c., 3H);

KBr

7.74(m, 1H); 7.83(s, 1H) (CDCl 3 )

24

H

CF 3

H

H

H

N

CH

Cl

CH

HCl

3259, 2465, 2420,

1.62-1.84(a.c., 6H); 2.53(m, 2H); 3.09-3.40(a.c., 6H);

147-148° C.

2365, 1328, 1108,

4.12(t, J=6.8Hz, 2H); 5.76(s, 1H); 7.51(s, 1H); 7.52-

1073

7.82(a.c., 4H); 8.02(s, 1H); 10.96(b.a., 1H)

KBr

(DMSO-d 6 )

25

H

H

F

H

H

N

CH

CH═CH—CH═CH—C

136-137° C.

3303, 2951, 2805,

1.54(m, 2H); 1.60-1.80(a.c., 3H); 1.97(m, 2H); 2.06

1506, 1464, 1376,

(dt, J=13.0Hz, J′=4.3Hz, 2H); 2.30-2.43(a.c. 4H, 2.72

1218, 1162, 1118,

(m, 2H); 4.40(t, J=7.0Hz, 2H); 6.99(t, J=8.8Hz, 2H),

832, 741

7.12(m, 1H); 7.32-7.47(a.c., 4H); 7.71(d, J=8.1Hz,

KBr

1H); 7.96(s, 1H) (CDCl 3 -CD 3 OD [1:1])

26

H

H

F

H

H

N

C—CH═CH—CH═CH

CH

148-150° C.

3325, 2950, 2923,

1.57(m, 2H); 1.70-1.77(a.c., 3H); 1.98-2.19(a.c., 4H);

2812, 1509, 1377,

2.35-2.49(a.c., 4H); 2.77(d, J=11.2Hz, 2H); 4.45

1218, 1131, 834,

(t, J=7.0Hz, 2H); 6.98-7.15(a.c., 3H); 7.25-7.49(a.c.,

758

3H); 7.63(d, J=8.3Hz, 1H); 7.69(d, J=7.8Hz, 1H); 7.91

KBr

(s, 1H) (CDCl 3 -CD 3 OD [1:1])

27

H

H

F

H

N

N

C—CH═CH—CH═CH

N

109-110° C.

3400, 2931, 2812,

1.47-1.80(a.c., 4H); 1.90-2.25(a.c., 5H); 2.25-2.55

1509, 1229, 1101,

(a.c., 4H); 2.70(m, 2H); 4.78(t, J=6.9Hz, 2H); 7.01

831, 745

(t, J=8.7Hz, 2H); 7.26-7.54(a.c., 4H); 7.85(dd, J=6.7Hz,

KBr

J′=3.0Hz, 2H) (CDCl 3 -CD 3 OD [1:1])

28

H

H

F

H

H

N

N

CH═CH—CH═CH—C

102-103° C.

3430, 2952, 2925,

1.45-1.80(a.c., 4H); 1.85-2.25(a.c., 5H); 2.25-2.55

1508, 1223, 1140,

(a.c., 4H); 2.77(m, 2H); 4.69(t, J=6.9Hz, 2H); 7.01

833, 744

(t, J=8.7Hz, 2H); 7.26-7.53(a.c., 5H); 8.06(d, J=7.3Hz,

KBr

1H) (CDCl 3 -CD 3 OD [1:1])

29

H

H

F

H

H

CH

N

H

N

oil

3350 (b.a., OH),

1.55(m, 2H); 1.74(d, J=12.6Hz, 2H); 1.94(m, 2H);

2947, 2818, 1509,

2.13(m, 2H); 2.40-2.55(a.c.; 4H); 2.79(m, 2H); 4.20

1222, 1138, 836,

(t, J=6.9Hz, 2H); 7.02(t, J=8.4Hz, 2H); 7.46(m, 2H);

681

7.91(s, 1H); 8.04(s, 1H) (CDCl 3 )

film

30

H

H

Cl

H

H

CH

N

H

N

89-91° C.

3119 (b.a., OH),

1.46(m, 2H); 1.71(m, 2H); 1.90(quin, J=7.4Hz, 2H);

2956, 2829, 1509,

2.05(m, 2H); 2.33-2.50(a.c., 4H); 2.54(b.a., 1H); 2.72

1379, 1277, 1145,

(m, 2H); 4.16(t, J=7.1Hz, 2H); 7.28(m, 2H); 7.42(m,

1007, 824, 685

2H); 7.86(s, 1H); 7.99(s, 1H) (CDCl 3 )

KBr

TABLE 2

Ex.

R 1

R 2

R 3

R 4

R 5

Z 1

Z 2

R 6

Z 4

Salt/m.p.

IR cm −1

1 H-RMN (300 MHz), δ (solvent)

1a

H

H

H

H

H

N

CH

Cl

CH

62-64° C.

3113, 2920, 2745,

1.56(quin, J=7.6Hz, 2H); 1.91(quin, J=7.6Hz,

1375, 1325, 1138,

2H); 2.47(t, J=7.4Hz, 2H); 2.58(m, 2H); 2.65

965, 837, 742,

(t, J=5.6Hz, 2H); 3.14(m, 2H); 4.11(t, J=7.1Hz,

688

2H); 6.06(m, 1H); 7.23-7.42(a.c., 7H) (CDCl 3 )

2a

H

H

H

H

H

CH

N

CH═CH—CH═CH—C

66-69° C.

2933, 1495, 745,

1.55(quin, J=7.6Hz, 2H); 1.92(quin, J=7.6Hz,

694, 665

2H); 2.43(t, J=7.3Hz, 2H); 2.52(m, 2H); 2.61

film

(t, J=5.6Hz, 2H); 3.07(m, 2H); 4.14(t, J=7.1Hz,

2H); 6.02(m, 1H); 7.20-7.40(a.c., 8H); 7.80(m,

1H); 7.86(s, 1H) (CDCl 3 )

3a

H

H

H

H

H

CH

N

H

N

63-64° C.

2942, 1438, 1381,

1.56(m, 2H); 1.95(m, 2H); 2.47(t, J=7.1Hz,

1271, 1142, 1006,

2H); 2.56(m, 2H); 2.66(t, J=5.3Hz, 2H); 3.11

753, 697, 681,

(m, 2H); 4.19(t, J=7.0Hz, 2H); 6.05(s, 1H); 7.21

KBr

(m, 1H); 7.30(t, J=7.6Hz, 2H); 7.36(d, J=7.8Hz,

2H); 7.94(s, 1H); 8.06(s. 1H) (CDCl 3 )

4a

H

H

Cl

H

H

N

CH

Cl

CH

103-104° C.

2939, 1493, 1436,

1.54(m, 2H); 1.90(m, 2H); 2.45(t, J=7.4Hz,

1381, 1306, 1122,

2H); 2.51(m, 2H); 2.65(t, J=5.6Hz, 2H); 3.10

1097, 973, 843,

(m, 2H); 4.10(t, J=7.0Hz, 2H); 6.03(m, 1H);

824, 730

7.26(AB system, J=8.6Hz, 2H); 7.29(AB

KBr

system, J=8.6Hz, 2H); 7.37(s, 1H); 7.41(s, 1H)

(CDCl 3 )

5a

H

H

Cl

H

H

C—CH 3

N

Cl

CCl

119-120° C.

2922, 1531, 1494,

1.59(m, 2H); 1.76(m, 2H); 2.36(s, 3H); 2.42-

1469, 1403, 1380,

2.53(a.c., 4H); 2.67(t, J=5.3Hz, 2H); 3.12(m,

1366, 1245, 1094,

2H); 3.88(t, J=7.4Hz, 2H); 6.04(m, 1H); 7.27

1010

(AB system, J=9.1Hz, 2H); 7.30(AB

KBr

system, J=9.1Hz, 2H) (CDCl 3 )

6a

H

CF 3

H

H

H

N

CH

Cl

CH

oil

2944, 1434, 1375,

1.53, (quin, J=7.5Hz, 2H); 1.89(quin, J=7.7Hz,

1331, 1247, 1165,

2H); 2.45(t, J=7.3Hz, 2H); 2.54(m, 2H); 2.66

1126, 1076, 972,

(t, J=5.5Hz, 2H); 3.10(m, 2H); 4.08(t, J=7.1Hz,

800, 698

2H); 6.10(m, 1H); 7.35-7.56(a.c., 5H); 7.59(s,

film

1H) (CDCl 3 )

7a

H

CF 3

H

H

H

C—CH 3

N

Cl

CCl

oil

2931, 2815, 1533,

1.62(quin, J=6.6Hz, 2H); 1.77(quin, J=7.6Hz,

1405, 1331, 1246,

2H); 2.37(s, 3H); 2.51(t, J=7.2Hz, 2H); 2.60(m,

1165, 1125, 1076,

2H); 2.71(t, J=5.6Hz, 2H); 3.17(m, 2H); 3.89

797, 699

(t, J=7.3Hz, 2H); 6.14(m, 1H); 7.40-7.50(a.c.,

film

2H); 7.55(d, J=7.5Hz, 1H); 7.62(s, 1H) (CDCl 3 )

8a

H

H

F

H

H

N

CH

Cl

CH

86-87° C.

2936, 1512, 1378,

1.60(quin, J=7.5Hz, 2H); 1.91(quin, J=7.5Hz,

1326, 1229, 988,

2H); 2.50-2.82(a.c., 4H); 2.76(t, J=5.6Hz, 2H);

967

3.19(m, 2H); 4.11(t, J=6.9Hz, 2H); 5.97(s, 1H);

KBr

6.99(t, J=8.8Hz, 2H); 7.32(dd, J=8.8Hz J′=5.4Hz,

2H); 7.38(s, 1H); 7.40(s, 1H) (CDCl 3 )

9a

H

H

F

H

H

C—CH 3

N

Cl

CCl

79-82° C.

2934, 1531, 1512,

1.74(m, 4H); 2.35(s, 3H); 2.60-2.72(a.c., 4H);

1408, 1247, 1225,

2.90(m. 2H); 3.33(m, 2H); 3.88(m, 2H); 5.95(s,

1167, 818

1H); 6.99(t, J=8.6Hz, 2H); 7.31(a.c., 2H)

KBr

(CDCl 3 )

10a

H

H

H

H

H

C—CH 3

N

Cl

CCl

oil

2929, 1533, 1405,

1.59(m, 2H); 1.76(m, 2H); 2.37(s, 3H); 2.49

1246, 748

(t, J=7.3Hz, 2H); 2.58(m, 2H); 2.69(t, J=5.4Hz,

film

2H); 3.14(m, 2H); 3.89(t, J=7.4Hz, 2H); 6.06

(m, 1H); 7.22-7.40(a.c., 5H) (CDCl 3 )

11a

H

H

H

H

H

C—CH 3

N

Cl

CCl

.HCl

2930, 2576, 1407,

1.69(m, 2H); 1.81(m, 2H); 2.35(s, 3H); 2.71

203-204° C.

1376, 1245, 750,

(d, J=7.2Hz, 1H); 2.91(m, 1H); 3.17(a.c., 3H);

KBr

3.56(m, 1H); 3.75(m, 1H); 3.90-3.97(a.c., 3H);

6.17(s, 1H); 7.25-7.40(a.c., 3H); 7.47

(d, J=7.6Hz, 2H); 11.30(b.a., 1H) (DMSO-d 6 )

12a

H

H

H

H

H

C—CH 3

N

Cl

CCl

.2HCl

3569, 2941, 2692,

1.67(m, 2H); 1.79(m, 2H); 2.36(s, 3H); 2.69

192-194° C.

2556, 1601, 1446,

(d, J=18.0Hz, 1H); 2.88(m, 1H); 3.15(a.c., 3H);

769, 753, 698

3.54(m, 1H); 3.72(m, 1H); 3.85-398(a.c., 3H);

KBr

6.15(s, 1H); 7.22-7.38(a.c., 3H); 7.45

(d, J=7.3Hz, 2H); 9.93(b.a., 1H); 11.36(b.a., 1H)

(DMSO-d 6 )

13a

H

H

F

H

H

CH

CH

CH═CH—CH═CH—C

oil

2937, 1510, 1464,

1.61(quin, J=7.7Hz, 2H); 1.93(quin, J=7.6Hz,

1230, 1161, 816,

2H); 2.42-2.58(a.c., 4H); 2.66(t, J=5.6Hz, 2H);

742

3.11(m, 2H); 4.17(t, J=7.0Hz, 2H); 5.98(m,

film

1H); 6.51(d, J=3.9Hz, 1H); 6.95-7.39(a.c., 8H);

7.65(d, J=7.8Hz, 1H) (CDCl 3 )

14a

H

H

H

H

H

CH

CH

CH═CH—CH═CH—C

oil

2938, 1510, 1485,

1.63(quin, J=7.4Hz, 2H); 1.94(quin, J=7.4Hz,

1463, 1446, 1376,

2H); 2.49(t, J=7.6Hz, 2H); 2.60(m, 2H); 2.69

1336, 1315, 763,

(t, J=5.3Hz, 2H); 3.14(m, 2H); 4.19(t, J=7.1Hz,

740, 695

2H); 6.08(m, 1H); 6.53(m, 1H); 7.08-7.44(a.c.,

film

9H); 7.67(d, J=8.1Hz, 1H) (CDCl 3 )

15a

H

H

CH 3

H

H

C—CH 3

N

Cl

CCl

87-88° C.

2939, 2916, 1529,

1.59(m, 2H); 1.75(m, 2H); 2.32(s, 3H); 2.36(s,

1404, 1378, 1243,

3H); 2.47(t, J=7.2Hz, 2H); 2.54(m, 2H); 2.67

1166, 1131, 1016

(t, J=5.2Hz, 2H); 3.11(m, 2H); 3.87(t, J=7.3Hz,

film

2H); 6.01(s, 1H); 7.11(AB system, J=8.1Hz,

2H); 7.27(AB system, J=8.1Hz, 2H) (CDCl 3 )

16a

H

H

H

H

H

N

CH

H

CH

36-38° C.

2941, 1396, 748,

1.54(quin, J=7.6Hz, 2H); 1.91(quin, J=7.6Hz,

695

2H); 2.45(t, J=7.6Hz, 2H); 2.55(m, 2H); 2.65

film

(t, J=5.6Hz, 2H); 3.11(m, 2H); 4.14(t, J=7.1Hz,

2H); 6.03(m, 1H); 6.21(m, 1H); 7.20-7.39(a.c.,

6H); 7.49(m, 1H) (CDCl 3 )

17a

H

H

H

H

H

N

CH

CH═CH—CH═CH—C

50-52° C.

2942, 1465, 1158,

1.61(quin, 2H); 2.00(quin, J=7.5Hz, 2H); 2.43-

832, 740, 691

2.58(a.c., 4H); 2.68(m, 2H); 3.14(s, 2H); 4.43

KBr

(t, J=6.6Hz, 2H); 6.02(s, 1H); 7.13(t, J=7.3Hz,

1H); 7.20-7.51(a.c., 7H); 7.73(d, J=7.9Hz, 1H);

7.99(s, 1H) (CDCl 3 )

18a

H

H

H

H

H

N

C—CH═CH—CH═CH

CH

73-75° C.

3049, 2940, 2778,

1.60(quin, J=7.6Hz, 2H); 2.09(quin, J=7.4Hz,

1467, 1371, 1158,

2H); 2.48(t, J=7.4Hz, 2H); 2.55(m, 2H); 2.66

1143, 1131, 757,

(t, J=5.6Hz, 2H); 3.11(d, J=2.9Hz, 2H); 4.45

742, 692

(t, J=7.1Hz, 2H); 6.03(s, 1H); 7.07(t, J=7.5Hz,

KBr

1H); 7.20-7.39(a.c., 6H); 7.63(d, J=4.3Hz, 1H);

7.70(d, J=8Hz, 1H); 7.91(s, 1H) (CDCl 3 )

19a

H

H

CH 3

H

H

N

CH

Cl

CH

72-73° C.

3115, 2938, 2740,

1.55(quin, 2H); 1.90(quin, J=7.5Hz, 2H); 2.33

1376, 1328, 1137,

(s, 3H); 2.46(t, J=7.5Hz, 2H); 2.55(m, 2H); 2.66

986, 966, 844,

(t, J=6.4Hz, 2H); 3.11(m, 2H); 4.10(t, J=7.0Hz,

824, 797

2H); 6.01(s, 1H); 7.12(AB system, J=8Hz, 2H);

KBr

7.27(AB system, J=8Hz, 2H); 7.37(s, 1H); 7.41

(s, 1H) (CDCl 3 )

20a

H

H

CH 3 O

H

H

N

CH

Cl

CH

104-105° C.

2923, 1533, 1405,

1.54(quin, 2H); 1.89(quin, J=7.6Hz, 2H); 2.44

1379, 1246, 749

(t, J=7.4Hz, 2H); 2.52(m, 2H); 2.65(t, J=5.3Hz,

KBr

2H); 3.10(m, 2H); 3.78(s, 3H); 4.09(t, J=7.0Hz,

2H); 5.95(s, 1H); 6.84(AB system, J=8.5Hz,

2H); 7.31(AB system, J=8.5Hz, 2H); 7.36(s,

1H); 7.40(s, 1H) (CDCl 3 )

21a

H

H

H

H

H

N

CH

Cl

CH

oil

2948, 223, 2811,

2.08(quin, J=7.0Hz, 2H); 2.42(t, J=7.0Hz, 2H);

2774, 1446, 1382,

2.58(m, 2H); 2.67(t, J=5.6Hz, 2H); 3.13(m,

1316, 971, 748,

2H); 4.17(t, J=6.9Hz, 2H); 6.07(m, 1H); 7.23-

695

7.45(a.c., 7H) (CDCl 3 )

film

22a

H

H

H

H

H

CCH 3

N

Cl

CCl

oil

2923, 1533, 1405,

1.95(quin, J=7.2Hz, 2H); 2.39(s, 3H); 2.46

1379, 1246, 749

(t, J=7.0Hz, 2H); 2.58(m, 2H); 2.69(t, J=4.9Hz,

film

2H); 3.13(m, 2H); 3.96(t, J=7.3Hz, 2H); 6.07

(m, 1H); 7.20-7.41(a.c., 5H) (CDCl 3 )

23a

H

H

H

H

H

CPh

N

H

CH

oil

2940, 1496, 1474,

1.51(m, 2H); 1.81(m, 2H); 2.40(t, J=7.4Hz,

1445, 1379, 1275,

2H); 2.56(m, 2H); 2.63(t, J=4.9Hz, 2H); 3.09

774, 698

(m, 2H); 4.04(t, J=7.2Hz, 2H); 6.03(m, 1H);

film

7.03(m, 1H); 7.13(m, 1H); 7.22-7.48(a.c., 8H);

7.58(m, 2H) (CDCl 3 )

24a

H

H

CH 3

H

H

CH

N

CH═CH—CH═CH—C

90-91° C.

2939, 2915, 1500,

1.59(m, 2H); 1.95(m, 2H); 2.32(s, 3H); 2.46

1461, 1377, 1365,

(t, J=7.3Hz, 2H); 2.53(m, 2H); 2.63(t, J=5.5Hz,

750

2H); 3.08(m, 2H); 4.20(t, J=6.95Hz, 2H); 6.00

KBr

(s, 1H); 7.11(d, J=7.8Hz, 2H); 7.27(a.c., 4H);

7.40(m, 1H); 7.80(m, 1H); 7.8(s, 1H) (CDCl 3 )

25a

H

H

H

H

H

CH

N

Ph

CPh

100-101° C.

3130, 2939, 2770,

1.46(quin, J=7.5Hz, 2H); 1.65(quin, J=7.6Hz,

1600, 1506, 1443,

2H); 2.33(t, J=7.3Hz, 2H); 2.53(m, 2H); 2.60

1259, 954, 780,

(m, 2H); 3.05(m, 2H); 3.84(t, J=7.2Hz, 2H);

774, 750, 696,

6.02(m, 1H); 7.05-7.50(a.c., 15H); 7.61(s, 1H)

649

(CDCl 3 )

KBr

26a

CH═CH—CH═CH

H

H

H

N

CH

Cl

CH

oil

3057, 3043, 2942,

1.61(quin, J=7.5Hz, 2H); 1.95(quin, J=7.6Hz, 2H);

2806, 2768, 1378,

2.51-2.57a.c., 4H); 2.76(t, J=5.6Hz, 2H); 3.20(m, 2H);

1365, 971, 801,

4.14(t, J=7.1Hz, 2H); 5.74(m, 1H); 7.26-7.50(a.c., 6H);

778

7.75(d, J=8Hz, 1H); 7.84(m, 1H); 8.02(m, 1H);

film

(CDCl 3 )

27a

H

CH═CH—CH═CH

H

H

N

CH

Cl

CH

95-96° C.

3111, 2920, 2806,

1.57(m, 2H); 1.92(m, 2H); 2.48(m, 2H); 2.71

1374, 1326, 966,

(a.c, 4H); 3.18(m, 2H); 4.11(m, 2H); 6.22(m, 1H);

826, 749, 612,

7.38-7.50(a.c., 4H); 7.61(m, 1H); 7.75-7.84(a.c., 4H)

KBr

(CDCl 3 )

28a

H

H

F

H

H

CH

N

CH═CH—CH═CH—C

135-136° C.

3050, 2920,

2.54(m, 2H); 2.74t, J=5.6Hz, 2H); 2.92(t, J=6.7Hz,

2780,

2H); 3.24(m, 2H); 4.35(t, J=6.7Hz, 2H); 5.98(m, 1H);

2760, 1510,

7.00(t, J=8.7Hz); 7.26-7.40(a.c., 4H); 7.42(m, 1H);

1492,

7.81(m, 1H); 8.01(s, 1H) (CDCl 3 )

1459, 1224,

1202,

1161, 771, 751

KBr

29a

H

H

H

H

H

CH

N

CH═CH—CH═CH—C

HCl

2940, 2488,

1.70-1.90(a.c., 4H); 2.78(m, 2H); 3.17(m, 2H);

177-178° C.

1500,

3.20-3.50(b.a., 2H); 3.79(m, 2H); 4.30(t, J=6.6Hz, 2H);

1420, 1390, 742

6.15(s, 1H); 7.17-7.40(a.c., 5H); 7.45(d, J=7.3Hz, 2H);

KBr

7.65(m, 2H); 8.35(s, 1H) (DMSO-d 6 )

30a

H

H

F

H

H

CH

N

CH═CH—CH═CH—C

106-108° C.

2942, 1512,

1.59(quin, J=7.5Hz, 2H); 1.96(quin, J=7.5Hz, 2H); 2.40-

1498,

2.50(a.c., 4H); 2.63(t, J=5.5Hz, 2H); 3.09(m, 2H); 4.21

1460, 1376,

(t, J=7.1Hz, 2H); 5.97(m, 1H); 6.98(t, J=8.1Hz, 2H);

1221,

7.20-7.35(a.c., 4H); 7.40(m, 1H); 7.80(m, 1H); 7.89(s,

756

1H) (CDCl 3 )

KBr

31a

H

H

F

H

H

CH

N

CH═CH—CH═CH—C

HCl

2930, 1600,

1.70-2.00(a.c., 4H); 2.78(m, 2H); 3.20(m, 2H); 3.20-

1510,

3.60(b.a., 2H); 3.81(m, 2H); 4.38(t, J=6.6Hz, 2H); 6.13

1275

(s, 1H); 7.19(t, J=8.7Hz, 2H); 7.33(m, 2H); 7.49(m,

KBr

2H); 7.71(d, J=7.8Hz, 1H); 7.77(d, J=7.6Hz, 1H); 8.79

(s, 1H); 11.20(b.a., 1H) (DMSO-d 6 )

32a

H

CF 3

H

H

H

CCH 3

N

Cl

CCl

HCl

2930, 2490,

1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.79(m, 1H);

205-206° C.

1330,

2.91(m, 1H); 3.10-3.20(a.c., 3H); 3.55(m, 1H); 3.77

1243, 1164,

(m, 1H); 3.91-4.00(a.c., 3H); 6.33(s, 1H); 7.58-7.80

1119,

(a.c., 4H); 11.32(b.a., 1H) (DMSO-d 6 )

33a

H

H

F

H

H

N

CH

Cl

CH

HCl

2543, 1512,

1.71-1.85(a.c., 4H); 2.68(m, 1H); 2.86(m, 1H); 3.10-

191-192° C.

1232,

3.20(a.c., 3H); 3.55(m, 1H); 3.72(m, 1H); 3.90(m,

967, 807

1H); 4.12(t, J=6.5Hz, 2H); 6.14(s, 1H); 7.20(t, J=8.7Hz,

KBr

2H); 7.40-7.55(a.c., 3H); 8.06(s, 1H); 11.20(b.a., 1H)

(DMSO-d 6 )

34a

H

H

H

H

H

N

CH

CH═CH—CH═CH—C

HCl

2931, 2566, 742

1.80(m, 2H); 1.91(m, 2H); 2.67(m, 1H); 2.88(m, 1H);

193-194° C.

KBr

3.10-3.20(a.c., 3H); 3.52(m, 1H); 3.71(m, 1H); 3.90

(m, 1H); 4.46(t, J=6.7Hz, 2H); 6.15(s, 1H); 7.14

(t, J=7.5Hz, 1H); 7.25-7.41(a.c., 4H); 7.46(d, J=8.6Hz,

2H); 7.71(d, J=8.6Hz, 1H); 7.75(d, J=8.3Hz, 1H); 8.08

(s, 1H); 11.18(b.a., 1H) (DMSO-d 6 )

35a

H

H

F

H

H

CCH 3

N

Cl

CCl

HCl

2930, 2590,

1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.67(m, 1H);

160-161° C.

1512,

2.90(m, 1H); 3.10-3.25(a.c., 3H); 3.54(m, 1H); 3.72

1409, 1241, 827

(m, 1H); 3.85-3.98(a.c., 3H); 6.13(s, 1H); 7.19(m,

KBr

2H); 7.50(m, 2H); 11.28(b.a., 1H) (DMSO-d 6 )

36a

H

H

H

H

H

N

CH

4-ClPh

CH

HCl

2472, 1560,

1.77(m, 2H); 1.87(m, 2H); 2.70(m, 1H); 2.86(m, 1H);

198-199° C.

1450,

3.16(a.c., 3H); 3.55(m, 1H); 3.73(m, 1H); 3.90(m,

1095, 955, 810,

1H); 4.17(t, J=6.6Hz, 2H); 6.15(m, 1H); 7.25-7.47(a.c.,

745

7H); 7.59(m, 2H); 7.90(s, 1H); 8.27(s, 1H); 10.91

KBr

(b.a., 1H) (DMSO-d 6 )

37a

H

H

H

H

H

N

CH

4-ClPh

CH

126-127° C.

2935, 1570,

1.60(m, 2H); 1.97(m, 2H); 2.48(t, J=7.3Hz, 2h); 2.56

1493,

(m, 2H); 2.67(t, J=5.1Hz, 2H); 3.13(m, 2H); 4.18

1455, 1379,

(t, J=7.1Hz, 2H); 6.05(m, 1H); 7.23-7.40(a.c., 9H); 7.61

1091,

(s, 1H); 7.74(s, 1H) (CDCl 3 )

953, 815, 746

KBr

38a

H

H

F

H

H

CH

N

H

N

HCl

3450, 2429,

1.74(m, 2H); 1.86(m, 2H); 2.68(m, 1H); 2.84(m, 1H);

166-168° C.

2707,

3.16(a.c., 3H); 3.53(m, 1H); 3.70(m, 1H); 3.91(m,

2593, 1512,

1H); 4.27(t, J=6.7Hz, 2H); 6.12(s, 1H); 7.19(t, J=8.9Hz,

1437,

2H); 7.50(dd, J=8.9Hz, J′=5.5Hz, 2H); 8.23(s, 1H); 8.93

1230, 816, 626

(s, 1H); 11.02(b.a., 1H) (DMSO-d 6 )

KBr

39a

H

H

F

H

H

CH

N

H

N

oil

2944, 2808,

1.60(m, 2H); 1.97(m, 2H); 2.40-2.70(a.c., 6H); 3.12

2773,

(m, 2H); 4.22(t, J=6.9Hz, 2H); 5.99(m, 1H); 6.98(m,

1602, 1510,

2H); 7.35(m, 2H); 7.95(s, 1H); 8.07*s. 1H) (CDCl 3 )

1273,

1227, 1161,

1140,

846, 824, 681

film

40a

H

H

F

H

H

CCH 3

N

CH═CH—CH═CH—C

oil

2932, 1512,

1.63(m, 2H); 1.88(m, 2H); 2.42-2.55(a.c., 4H); 2.61

1456,

(s. 3H); 2.65(t, J=5.5Hz, 2H); 3.09(m, 2H); 4.14

1404, 1231, 744

(t, J=7.3Hz, 2H); 5.97(m, 1H); 6.99(m, 2H); 7.19-7.35

film

(a.c., 5H); 7.68(m, 1H) (CDCl 3 )

41a

H

H

F

H

H

N

CH

CH═CH—CH═CH—C

oil

2932, 2805,

1.57(m, 2H); 1.99(m, 2H); 2.42-2.50(a.c., 4H); 2.62

1511,

(t, J=5.6Hz, 2H); 3.06(m, 2H); 4.42(t, J=6.9Hz, 2H);

1465, 1230,

5.95(m, 1H); 6.97(t, J=8.8Hz, 2H); 7.12(m, 1H); 7.25-

1160,

7.41(a.c., 4H); 7.71(d, J=8Hz, 1h); 7.99(s, 1H)

825, 752, 741

(CDCl 3 )

film

42a

H

H

F

H

H

N

C—CH═CH—CH═CH

CH

102-103° C.

2941, 1510,

1.59(quin, J=7.0Hz, 2H); 2.09(quin., J=7.5Hz, 2H);

1374,

2.40-2.50(a.c., 4H); 2.64(t, J=6.2Hz, 2H); 3.10(m, 2H);

1226, 1162, 806,

4.45(t, J=7.1Hz, 2H); 5.96(m, 1H); 6.98(t, J=8.8Hz,

759, 741

2H); 7.07(t, J=7.6Hz, 1H); 7.20-7.35(a.c., 3H); 7.63

KBr

(d, J=8.5Hz, 1H); 7.71(d, J=8.6Hz, 1H); 7.90(s. 1H)

(CDCl 3 )

43a

H

H

F

H

H

N

C—CH═CH—CH═CH

N

HCl

2574, 2482,

1.80(m, 2H); 2.11(quin., J=7.2Hz, 2H); 2.69(m, 1H);

208-209° C.

1510,

2.83(m, 1H); 3.10-3.20(a.c., 3H); 3.52(m, 1H); 3.71

1231, 745

(m, 1H); 3.88(m, 1H); 4.80(t, J=6.3Hz, 2H); 6.11(s,

KBr

1H); 7.19(m, 2H); 7.41(m, 2H); 7.50(m, 2H); 7.91(m,

2H); 11.07(b.a., 1H) (DMSO-d 6 )

44a

H

H

F

H

H

N

C—CH═CH—CH═CH

N

76-77° C.

2913, 1511,

1.60(quin., J=7.5Hz, 2H); 2.19(quin., J=8.2Hz, 2H);

1470,

2.41-2.59(a.c., 4H); 2.64(t, J=5.7Hz, 2H); 3.08(m, 2H);

1380, 1327,

4.77(t, J=7.0Hz, 2H); 5.95(m, 1H); 6.97(t, J=8.8Hz,

1224,

2H); 7.25-7.40(a.c., 4H); 7.85(m, 2H) (CDCl 3 )

1172, 1132, 851,

826, 757

KBr

45a

H

H

F

H

H

N

N

CH═CH—CH═CH—C

HCl

2928, 2680,

1.81(m, 2H); 1.99(m, 2H); 2.67(m, 1H); 2.84(m, 1H);

204-205° C.

2573,

3.10-3.20(a.c., 3H); 3.53(m, 1H); 3.72(m, 1H); 3.90

2559, 1515,

(m, 1H); 4.76(t, J=6.9Hz, 2H); 6.12(s. 1H); 7.19

1454,

(t, J=8.8Hz, 2H); 7.39(t, J=7.6Hz, 1H); 7.45-7.60(a.c.,

1272, 1242,

3H); 7.94(d, J=8.3Hz, 2H); 8.03(d, J=8.3Hz, 2H); 11.04

1224,

(b.a., 1H) (DMSO-d 6 )

1166, 819, 745

KBr

46a

H

H

F

H

H

N

N

CH═CH—CH═CH—C

88-90° C.

2939, 1510,

1.58(quin., J=7.5Hz, 2H); 2.07(quin, J=7.5Hz, 2H);

1229,

2.40-2.50(a.c., 4H); 2.61(m, 2H); 3.05(m, 2H); 4.66

1209, 1164, 744

(t, J=7.0Hz, 2H); 5.95(m, 1H); 6.96(t, J=8.8Hz, 2H);

KBr

7.23-7.38(a.c., 3H); 7.44(m, 1H); 7.52(m, 1H); 8.04

(d, J=8.3Hz, 1H) (CDCl 3 )

47a

H

H

Cl

H

H

N

CH

Cl

CH

HCl

3068, 2948,

1.71(m, 2H); 1.80(m, 2H); 2.70(m, 1H); 2.83(m, 1H);

172-173° C.

1491,

3.15-3.30(a.c., 3H); 3.44(m, 1H); 3.72(m, 1H); 3.89

1445, 1320,

(m, 1H); 4.11(t, J=6.5Hz, 2H); 6.20(s, 1H); 7.41(sys.

1308,

AB, J AB =8.8Hz, 2H); 7.48(Syst. AB, J AB = 8.8Hz, 2H);

1096, 968, 809,

7.52(s, 1H); 8.04(s, 1H); 10.98(b.a., 1H) (DMSO-d 6 )

48a

H

H

H

H

H

N

CH

H

CH

HCl

2955, 2929,

1.70-1.90(a.c., 4H); 2.69(m, 1H); 2.89(m, 1H); 3.10-

180-181° C.

2530,

3.20(a.c., 3H); 3.53(m, 1H); 3.70(m, 1H); 3.91(m,

1445, 965, 761,

1H); 4.15(t, J=6.5Hz, 2H); 6.16(m, 1H); 6.23(m, 1H);

745

7.28-7.50(a.c., 6H); 7.78(m, 1H); 11.26(b.a., 1H)

KBr

(DMSO-d 6 )

49a

H

H

H

H

H

CH

N

H

N

HCl

2937, 2370,

1.74(m, 2H); 1.84(m, 2H); 2.72(m, 1H); 2.87(m, 1H);

122-123° C.

1503,

3.10-3.20(a.c., 3H); 3.54(m, 1H); 3.73(m, 1H); 3.88

1276, 1142, 774,

(m, 1H); 4.22(t, J=6.6Hz, 2H); 6.15(s, 1H); 7.27-7.70

755

(a.c., 3H); 7.47(m, 2H); 7.97(s, 1H); 8.59(s, 1H);

KBr

11.20(b.a., 1H) (DMSO-d 6 )

50a

H

H

H

H

H

CPh

N

H

CH

HCl

2930, 2554,

1.62-1.78(a.c., 4H); 2.75(m, 2H); 3.00(m, 2H); 3.25

170-171° C.

1469,

(m, 2H); 3.69(m, 2H); 4.08(t, J=6.7Hz, 2H); 6.13(s,

1459, 1444,

1H); 7.07(s, 1H); 7.24-7.40(a.c., 3H); 7.42-7.52(a.c.,

1278,

6H); 7.62(Syst. AB, J AB = 7.6Hz, 2H) (DMSO-d 6 )

1075, 774, 762,

749, 732, 711,

702,

690

KBr

51a

H

H

H

H

H

CH

CH

H

CH

HCl

2930, 2482,

1.60-1.80(a.c., 4H): 2.70m, 1H); 2.84(m, 1H); 3.08-

197-199° C.

1448, 1280,

3.22(a.c., 3H); 3.50(m, 1H); 3.71(m, 1H); 3.86-3.96

1090, 732

(a.c., 3H): 5.97(t, J=2.1Hz, 2H); 6.16(m, 1H); 6.76

KBr

(t, J=2.1Hz, 2H); 7.25-7.50(a.c., 5H); 10.74(b.a., 1H)

(DMSO-d 6 )

52a

H

H

H

H

H

CH

CH

H

CH

58-60° C.

2928, 1498,

1.58(m, 2H); 1.84(m, 2H); 2.47(t, J=7.5Hz, 2H); 2.58

1280,

(m, 2H); 2.68(m, 2H); 3.13(m, 2H); 3.92(t, J=7.1Hz,

1262, 1137,

2H); 6.06(m, 1H); 6.15(t, J=2.2Hz, 2H); 6.67

1087,

(t, J=2.2Hz, 2H); 7.24-7.42(a.c., 5H) (CDCl 3 )

1060, 747, 723,

691

KBr

53a

H

H

H

H

H

N

CCl

CH═CH—CH═CH—C

oil

2939, 1495,

1.58(quin, J=7.6Hz, 2H); 1.99(quin, J=7.6Hz, 2H);

1467,

2.47(m, 2H); 2.55(m, 2H); 2.65(m, 2H); 3.10(m, 2H);

1338, 745

4.36(t, J=7.1Hz, 2H); 6.04(m, 1H); 7.18-7.42(a.c., 8H);

film

7.67(d, J=7.6Hz, 1H) (CDCl 3 )

54a

H

H

H

H

H

N

CCl

CH═CH—CH═CH—C

HCl

3460, 2940,

1.80(m, 2H); 1.90(m, 2H); 2.70(m, 1H); 2.87(m, 1H);

164-165° C.

2550,

3.07-3.22(a.c., 3H); 3.52(m, 1H); 3.71(m, 1H); 3.87

1338, 743

(m, 1H); 4.43(t, J=6.6Hz, 2H); 6.14(s, 1H); 7.20-7.52

KBr

(a.c., 7H); 7.65(m, 1H); 7.7(m, 1H); 11.16(b.a., 1H)

(DMSO-d 6 )

55a

H

H

OH

H

H

CCH 3

N

Cl

CCl

HCl

3062, 2561,

1.69(m, 2H); 1.75(m, 2H); 2.33(s, 3H); 2.68(m, 1H);

216-217° C.

1516, 1248

2.79(m, 1H); 3.14(a.c., 3H); 3.55(m, 1H); 3.68(m,

KBr

1H); 3.87-4.00(a.c., 3H), 5.97(s, 1H); 6.77(Syst.

AB, J=8.8Hz, 2H); 7.28(Syst. AB, J=8.8Hz, 2H); 9.62

(s, 1H); 10.82(b.a., 1H) (DMSO-d 6 )

56a

H

H

H

H

H

CH

N

Cl

CCl

HCl

2336, 1254

1.75(a.c., 4H); 2.70(m, 1H); 2.87(m, 1H); 3.17(a.c.,

166-167° C.

KBr

3H); 3.56(m, 1H); 3.74(m, 1H); 3.87-4.15(a.c., 3H),

6.17(s, 1H); 7.27-7.40(a.c., 3H); 7.47(m, 2H); 7.91(s,

1H); 11.02(b.a., 1H) (DMSO-d 6 )

57a

H

H

F

H

H

CH

N

H

N

Citrate

1720, 1709,

1.90(m, 2H); 2.08(quint., J=7.5Hz, 2H); 2.86(AB,

132-133° C.

1513, 1225,

J=15.5Hz, 4H); 2.93(b.a., 2H); 3.29(m, 2H); 3.54(t,

1193, 1166, 1133

J=5.9Hz, 2H) 3.93(b.a., 2H); 4.43(t, J=6.6Hz, 2H);

KBr

6.17(b.a., 1H); 7.19(m, 2H); 7.59(m, 2H); 8.10(s, 1H);

8.60(s, 1H) (MeOH-d 4 )

58a

H

H

Br

H

H

CH

N

H

N

113-115° C.

2939, 2773,

1.55(m, 2H); 1.95(m, 2H); 2.40-2.55(a.c., 4H); 2.64

2736, 1509,

(m, 2H); 3.08(m, 2H); 4.20(t, J=7.1Hz, 2H); 6.03(m,

1490, 1380,

1H); 7.22(AB, J=8.5Hz, 2H); 7.40(AB, J=8.5Hz, 2H);

1271, 1140, 1071,

7.93(s, 1H); 8.05(s, 1H) (CDCl 3 )

1006, 961, 844,

827, 800, 680

KBr

59a

H

H

Br

H

H

CH

N

H

N

HCl

3066, 2937,

1.76(m, 2H); 1.84(m, 2H); 2.71(m, 1H); 2.85(m, 1H);

162-164° C.

2479 (b.a.) 1514,

3.17(a.c., 3H); 3.55(m, 1H); 3.74(m, 1H); 3.80(m,

1146, 1012, 802

1H), 4.23(t, J=6.6Hz, 2H); 6.22(s, 1H); 7.42(Syst.

KBr

AB, J=8.1Hz, 2H); 7.56(Syst. AB, J=8.1Hz, 2H); 7.98

(s, 1H); 8.60(s, 1H) (DMSO-d 6 )

60a

H

H

Cl

H

H

CH

N

H

N

101-103° C.

2930, 2775,

1.56(quint, J=7.5Hz, 2H); 1.97(quint, J=7.5Hz, 2H);

2737, 1509,

2.40-2.70(a.c., 4H); 2.66(t, J=5.7Hz, 2H); 3.10(d, J=3

1493, 1381,

Hz, 2H), 4.21(t, J=7.0Hz, 2H); 6.04(s, 1H); 7.20-7.35

1271, 1141, 1091,

(m, 4H); 7.94(s, 1H); 8.06(s, 1H) (CDCl 3 )

1010, 961, 847,

828, 680

KBr

61a

H

H

Cl

H

H

CH

N

H

N

HCl

2951, 2505 (b.a.)

1.73(m, 2H); 1.83(m, 2H); 2.70(m, 1H); 2.85(m, 1H);

165-166° C.

1502, 1494,

3.10-3.20(a.c., 3H); 3.54(m, 1H); 3.73(m, 1H); 3.88

1275, 1136,

(m, 1H); 4.22(t, J=6.6Hz, 2H); 6.20(s, 1H); 7.42(syst.

1098, 1013, 810,

AB, J=8.6Hz, 2H); 7.49(Syst. AB, J=8.6Hz, 2H); 7.97

686

(s, 1H): 8.59(s, 1H); 11.17(b.a., 1H) (DMSO-d 6 )

KBr

62a

H

H

Cl

H

H

CPh

N

H

CH

oil

1445, 1379,

1.48(m, 2H); 1.80(m, 2H); 2.36(t, J=7.4Hz, 2H); 2.47

1271,

(m, 2H); 2.59(m, 2H); 3.04(d, J=3Hz, 2H), 4.03(t,

774, 681

J=7.4Hz, 2H); 6.01(s, 1H); 7.01(d, J=1.2Hz, 1H);

film

7.11(d, J=1.2Hz, 1H); 7.27(m, 4H); 7.35-7.60(a.c.,

5H) (CDCl 3 )

63a

H

H

Cl

H

H

CPh

N

H

CH

HCl

2935, 2695,

1.65(m, 2H); 1.80(m, 2H); 2.67(m, 1H): 2.82(m, 1H);

70° C.

2591, 1493,

3.05-3.21(a.c., 3H); 3.55(m, 1H); 3.69(m, 1H); 3.88

(hygrosc.)

1094, 777, 702

(m, 1H), 4.20(t, J=6.6Hz, 2H); 6.18(s, 1H); 7.40(Syst.

KBr

AB, J=8.7Hz, 2H); 7.47(Syst. AB, J=8.7Hz, 2H); 7.60-

7.880(a.c., 5H); 7.83(s, 1H); 7.96(s, 1H) (DMSO-d 6 +

TFA)

64a

H

H

H

H

H

CCH 3

CH

H

CCH 3

oil

2929, 1408, 1299,

1.65(a.c., 4H); 2.23 (s, 6H); 2.48(m, 2H); 2.58(m, 2H);

746, 693

2.69(m, 2H); 3.15(m, 2H); 3.76(t, J=7.2Hz, 2H); 5.76

film

(s, 2H): 6.06(s, 1H); 7.20-7.40(a.c., 5H) (CDCl 3 )

65a

H

H

H

H

H

CCH 3

CH

H

CCH 3

HCl

3434 (b.a.), 2935,

1.56(m, 2H); 1.77(m, 2H); 2.15(s, 6H); 2.70(m, 1H);

178-180° C.

2560, 1443,

2.84(m, 1H); 3.08-3.22(a.c., 3H); 3.59(m, 1H); 3.70-

1405, 1298, 748,

3.80(a.c., 3H); 3.93(m, 1H); ); 5.59(s, 2H); 6.17(s,

692

1H); 7.25-7.50(a.c., 5H); 10.72(b.a., 1H) (DMSO-d 6 )

66a

H

H

Cl

H

H

CCH 3

CH

H

CCH 3

86-88° C.

2933, 1493,

1.65(a.c., 4H); 2.24(s, 6H); 2.48(m, 2H); 2.54(m, 2H);

1413, 1376,

2.69(m, 2H); 3.15(m, 2H); 3.77(t, J=7.1Hz, 2H); 5.77

1300, 750

(s, 3H); 6.06(s, 1H); 7.30(m, 4H) (CDCl 3 )

film

67a

H

H

Cl

H

H

CCH 3

CH

H

CCH 3

HCl

3432 (b.a.), 2936,

1.56(m, 2H); 1.76(m, 2H); 2.14(s, 6H); 2.70(m, 1H);

182-184° C.

258-, 1495,

2.84(m, 1H); 3.00-3.28(a.c., 3H); 3.58(m, 1H); 3.69-

1410, 1298,

3.77(a.c., 3H); 3.92(m, 1H); ); 5.58(s, 2H); 6.22(s,

1097, 804, 752

1H); 7.42(AB, J=8.6, 2H); 7.50(AB, J=8.6, 2H); 10.65

KBr

(b.a., 1H) (DMSO-d 6 )

68a

H

H

Cl

H

H

CH

CH

H

CH

102-104° C.

2931, 1492,

1.56(t, J=7.5Hz, 2H); 1.84(t, J=7.4Hz, 2H); 2.46

1280, 1090, 967,

(t, J=7.5Hz, 2H); 2.53(m, 2H); 2.66(t, J=5.6Hz, 2H);

828, 727

3.12(m, 2H); 3.92(t, J=7.1Hz, 2H); 6.05(m, 1H): 6.15

KBr

(d, J=1.8Hz, 2H); 6.66(d, J=1.8Hz, 2H); 7.26AB, J=8.4,

2H); 7.30(AB, J=8.4, 2H) (CDCl 3 )

69a

H

H

Cl

H

H

CH

CH

H

CH

HCl

2937, 2479,

1.72(m, 4H); 2.65(m, 1H); 2.87(m, 1H); 3.08-3.22

194-195° C.

1492, 1282,

(a.c., 3H); 3.52(m, 1H); 3.70(m, 1H); 3.80-4.00(a.c.,

1096, 810, 737

3H); 5.96(t, J=2.1Hz, 2H); 6.19(s, 1H); 6.76(t, J=2.1Hz,

KBr

2H); 7.42(AB, J=8.6Hz, 2H); 7.48(AB, J=8.6Hz, 2H);

11.12(b.a., 1H) (DMSO-d 6 )

70a

H

H

Cl

H

H

CH

N

H

N

Citrate

3384 (b.a.), 3200-

1.54(m, 2H); 1.83(m, 2H); 2.54(Syst. AB, J=15Hz,

133° C.

2200 (b.a.) 1726,

2H); 2.63(Syst. AB, J=15Hz, 2H); 2.82(m, 2H); 3.03

1702, 1594,

(m, 2H); 3.20-3.50(a.c., 4H); 4.21(t, J=6.8Hz, 2H);

1432, 1221,

6.20(s, 1H); 7.40(Syst. AB, J=8.8Hz, 2H); 7.48(Syst.

1131, 802

AB, J=8.8Hz, 2H); 7.97(s, 1H); 8.52(s, 1H) (DMSO-

KBr

d 6 )

EBIOLOGICAL ASSAYS

The analgesic activity of the products object of the invention have been studied in several assays using the Swiss albino mice as the experimental animal. The assay of contortions induced by phenylbenzoquinone, the hot-plate assay and the hot-point assay are now described. The examples that are presented by way of illustration describe some of the pharmacological assays and should not limit the scope of the invention in any way.

The assay of contortions induced by phenylbenzoquinone was carried out following the method described by E. Siegmund et al. (Proc. Soc. Exp. Biol. Med. 95: 729-731,1957). In this assay the mice received |the product orally or sub-cutaneously (s.c.) and after 60 minutes (after oral administration) or after 30 minutes (after s.c. administration) they received an intraperitoneal (i.p.) injection of an 0.02% aqueous solution of phenylbenzoquinone, at a dosage of 10 ml/kg. The degree of analgesic was expressed as a percentage of the contortions with respect to the control group at each one of the dosages assayed. Using the results |obtained the effective dose-50 (ED-50) was calculated, that is to say the dose able to inhibit by 50% the contortions induced by phenylbenzoquinone.

The hot-plate assay was carried out following the method described by M. Ocaña et al. (Europ.J.Pharmacol. 186: 377-378, 1990). The product under study was administered s.c. or i.p. and 30 minutes later the analgesic effect was registered. For this the animals were placed on a metallic surface kept at 50° C. or 55° C. and the time registered (latency) until the licked their hind legs and a jump. The analgesic activity was calculated at each dose, comparing the potency of the treated group with the control group. Using the results obtained the ED-50 was calculated.

The assay of withdrawal of the tail from a hot spot (tail flick) was carried out following the method described by M. Ocaña et al. (Br. J. Pharmacol. 110: 1049-1054, 1993). The mice were introduced into an immobiliser and placed on the tail-flick apparatus (LI7100, Letica, S.A). A beam of light was focussed on the tail, at 4 cm from the tip, and the latency for withdrawal of the tail automatically registered. Ten minutes before administering the product of the study the basal latency was registered.

After the product had been administered s.c. the tail withdrawal latencies at 10, 20, 30, 40, 45, 60, 90 and 120 minutes were registered. For each animal the area below curve of the latency was calculated during the time period following the method described by R. J. Tallarida and R. B. Murray (Manual of pharmacologic calculations with computer programs, Springer-Verlag, Berlin, p. 297, 1987). The degree of analgesic of each dosage was calculated comparing the area under curve of latency of the group treated with the medicament with the control group. Using these data the ED-50 was calculated.

The products object of the invention have a notable analgesic activity in the assay of contortions induced by phenylbenzoquinone. Several products have activity of the same order as morphine and clearly better that the products that inhibit biosynthesis of prostaglandins, such as aspirin and dipirone (see table 3).

The analgesic activity has also been demonstrated in the hot-plate assay, considered as a demonstration of analgesic action at the central nervous system level (see table 4).

The analgesic activity has also been demonstrated in the hot-beam assay applied to the mouse's tail, finding a good correspondence between the results obtained in the assay of the hot-plate and the assay of the calorific beam (see table 5).

Furthermore, the capacity of the products object of the invention for exhibiting synergistic analgesic activity with other analgesics, for example, pentazocine, has also been demonstrated. This has been shown for the compound of example 47a (see table 6). Effectively, the latency time in responding licking of the paws when the mice were placed on the hot-plate at 55° C., is much greater after the combined treatment with the compound of example 47a and pentazocine than the sum of the latencies of each one of the treatments carried out separately.

In summary, the products object of the invention have shown a clear analgesic activity in different assays, such as phenylbenzoquinone, hot-plate and calorific beam applied to the tail of the mouse. The activity of these products has been clearly superior to that of the inhibitors of the biosynthesis of prostaglandins such as aspirin and dipirone, and the activity has been shown to of the order of that of morphine. Furthermore, 5 the capacity for forming synergistic combinations with other analgesics has been demonstrated, as can be seen for the case of the compound of example 47a administered along with pentazocine in the hot-plate assay for mice.

TABLE 3
Analgesic activity in the assay of contortions induced by
phenylbenzoquinone in mouses
	ED-50 (mg/kg)
	PRODUCT	Oral route	S.C. route
	Example 5	20	28
	Example 6	80	34
	Example 33a	30	2
	Example 35a	37	1
	Example 38a	5	1
	Example 41a	58	6
	Example 47a	19	26
	Example 48a	38	1
	Example 49a	2	1
	Example 50a	10	2
	Example 5la	9	3
	Example 59a	13	2
	Example 61a	22	2
	Example 63a	44	33
	Morfine	4	1
	Dipirone	223	24
	Aspirin	100	80

TABLE 4
Analgesic activity in the hot-plate assay (55° C.) in mouses
PRODUCT     ED-50 (mg/kg, sc)
Example 38a 7
Example 47a 89
Example 48a 5
Example 49a 4
Example 50a 58
Example 51a 2
Example 59a 43
Example 61a 48
Morfina     2

TABLE 4
Analgesic activity in the hot-plate assay (55° C.) in mouses
PRODUCT     ED-50 (mg/kg, sc)
Example 38a 7
Example 47a 89
Example 48a 5
Example 49a 4
Example 50a 58
Example 51a 2
Example 59a 43
Example 61a 48
Morfina     2

TABLE 4
Analgesic activity in the hot-plate assay (55° C.) in mouses
PRODUCT     ED-50 (mg/kg, sc)
Example 38a 7
Example 47a 89
Example 48a 5
Example 49a 4
Example 50a 58
Example 51a 2
Example 59a 43
Example 61a 48
Morfina     2

Claims

1. A method of treating acute pain, neuropathic pain or nociceptive pain in a mammal which comprises administering to a patient in need thereof an effective amount of a derivative of tetrahydropyridines of formula (I) whereR1, R2 and R3 are identical or different and are selected from hydrogen, C1-C4 alkyl group, trifluoroethyl radical, hydroxyl or alkoxyl radical; and two adjacent radicals can form part of a six-membered aromatic ring; A is selected from a carbon atom or a carbon atom bound to a hydroxyl group (C—OH); wherein when A is a carbon atom the dotted line (- - -) represents a bond, and when A is a carbon atom bound to a hydroxyl group (C—OH) the dotted line (- - -) represents no bond; Z1, is a nitrogen atom or a substituted carbon atom represented by the formula C—R4; Z2 is a nitrogen atom or a substituted carbon atom represented by the formula C—R5; Z4 is a nitrogen atom or a substituted carbon atom represented by the formula C—R7; with the condition that Z1; Z2 and Z4 taken together can represent at most, two nitrogen atoms; and R4, R5, R6 and R7, are identical or different and are selected from hydrogen, halogen, C1-C4 alkyl group, aryl or substituted aryl group, and two adjacent radicals can form part of a six-membered aromatic ring; or physiologically acceptable salts thereof.

2. The method as claimed in claim 1, wherein R1, R2 and R3 are selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, methoxyl, methyl, ethyl, propyl, isopropyl, sec-butyl and a tert-butyl radical.

3. The method as claimed in claim 1, wherein R1, R2 and R3 are selected so that two adjacent radicals can form part of a six-membered aromatic ring.

4. The method as claimed in claim 1, wherein R4, R5, R6 and R7 are selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, methoxyl, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, unsubstituted phenyl, or a substituted phenyl wherein the substituent is selected front halogen atoms.

5. The method as claimed in claim 1, wherein R4, R5, R6 and R7 are selected so wt two adjacent radicals form part of a six-membered aromatic ring.

6. The method as claimed in claim 1, further comprising an analgesic used for the treatment of pain.

7. The method as claimed in claim 1, wherein the compound of formula (I), is selected from the group consisting of4-chloro-1-[4-(4hydroxy-4-phenyl-1-piperidinyl)butyl]-1-pyrazole; 4,5chloro-1-[4(4-hydroxy-phenyl-1-piperidinyl)butyl]-2-ethyl-1H-imidazole; 1-[4-(4hydroxy~phenyl-1 -piperidinyl)butyl]-1H-benzimidazole; 1-[(4hydroxy-phenyl-1 -piperidinyl)butyl]-1H-1,2,4-thiazole; 4-chloro-1-{4-[4chlorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-pyrazole; 4,5-dichloro-1-{4-[4-hydroxy-4-(chlorophenyl)-1 -piperidinyl]butyl}-2-methyl-1-H-imidazole; 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]-butyl}-1H-pyrazole 4,5-dichloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]-butyl}-2H-imidazole; 4,5-dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]-butyl}-2H-methyl-1-H-imidazole; 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)-butyl]-1H-indole 4,5-dichloro-1-{[4-hydroxy-(fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2-methyl-1-H-imidazole; 1-[4(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-indole 4,5-dichloro-1-{4-[4hydroxy 4-(4-methylphenyl)1-piperyl]-butyl}-2-methyl-1H-imidazolo; 1-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole; 1-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-imidazole; 2-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2H-imidazole; 4-chloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-(piperidinyl)]-butyl}-1H-pyrazole; 4-chloro-1-{4-[4-hydroxy-4-(4-methyoxphenyl)-1-(piperidinyl)]-butyl}-1H-pyrazole; 1-[4(4hydroxy-4-phenyl-1-piperidinyl)butyl]-2-phenyl-1H-imidazole 1-{4-[4-hydroxy-4-(4-methylphenyl-1-piperidinyl]butyl}-1H-benzimidazole; 4,5-diphenyl-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H -imidazole 4-chloro-1-{4-[4-hydroxy-4-(1-naphthyl)-1-piperidinyl]butyl}-1H-pyrazole; 4-chloro-1-{4-[4-hydroxy4-(2-naphthyl-1-piperidinyl]-butyl}-1H-pyrazole; 4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-pyrazole; 1-{4-[4phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole; 1-{4-[4phenyl-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-1,2,4-triazole; 4chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydro-pyridinyl)]butyl}-1H-pyrazole; 4,5-dichloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl-}-2-metbyl-1H-imidazole; 4chloro-1-{4-[4-(3-trifuoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl-}-1H-pyrazole; 4,5-dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6tetahydro-pyridinyl)]-butyl}-1H-imidazole; 4-chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole; 4chloro-1-{4-[4-(2-naphtyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole; 1-{2-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]etil}-1H-benzimidazole; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-bencimidazole hydrochloride; 4,5-dichloro-2-methyl-1-{4-[4(3-trifluoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole-hydrochloride; 4-chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6)-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride; 1-{4-[1-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride; 4,5-dichloro-1-{4-[4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole hydrochloride; 4-(chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride; 4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl }-1H-pyrazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-benzimidazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-imidazole; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole hydrochloride; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole; 4chloro-1-{4-[4(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole hydrochloride; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride; 2-phenyl-1-{4-[-4-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole hydrochloride; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrrole hydrochloride; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole; 4-(4-chlorophenyl)-1-[4-(4hydroxy-4-phenyl-1-piperdinyl)butyl]1H-pyrazole; 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazole; 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole; 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-imidazole; 2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-imidazole; 2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-benzotriazole; 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzotrizole; 3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole; 3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride; 1-{4-[4-hydroxy-4-(4-fluorophenyl)-1-piperidinyl]butyl}-1H-triazole; 1-{4-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]butyl}-1H-triazole; 4,5-dichloro-1-{4-[4-(4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole citrate; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrocloride; 2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole; 2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride; 2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole; 2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride; 2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole; 2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-trizole hydrochloride.