Triazole compounds with dopamine-D3-receptor affinity

The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D

3

receptor ligands.

Compounds of the type which is under discussion here and which possess physiological activity are already known. Thus, WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med. Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D

3

receptor ligands. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in

Pharmazie

46 (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.

A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.

By 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D

1

and D

2

receptors.

More recently, a third subtype has been found, namely the D

3

receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J. C. Schwartz et al., The Dopamine D

3

Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).

Since D

3

receptors are chiefly expressed in the limbic system, it is assumed that while a selective D

3

ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D

3

receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D

3

Dopamine Receptor,

Arzneim. Forsch./Drug Res

. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D

3

) as a Target for Neuroleptics,

Nature

, 347, 146 (1990)).

Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D

3

receptor and a low affinity for the D

2

receptor. These compounds are consequently selective D

3

ligands.

The present invention relates, therefore, to the compounds of the formula I:

where

R

1

is H, C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, halogen or phenyl, C

3

-C

6

-cycloalkyl or phenyl;

R

2

is H, C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, halogen or phenyl, C

1

-C

6

-alkoxy, C

1

-C

6

-alkylthio, C

2

-C

6

-alkenyl, C

2

-C

6

-alkynyl, C

3

-C

6

-cycloalkyl, halogen, CN, COOR

3

, CONR

3

R

4

, NR

3

R

4

, SO

2

R

3

, SO

2

NR

3

R

4

, or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered-heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, halogen or phenyl, C

1

-C

6

-alkoxy, C

2

-C

6

-alkenyl, C

2

-C

6

-alkynyl, C

3

-C

6

-cycloalkyl, halogen, CN, COR

3

, NR

3

R

4

, NO

2

, SO

2

R

3

, SO

2

NR

3

R

4

and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C

1

-C

6

-alkyl, C

1

-C

6

-alkoxy, NR

3

R

4

, CN, CF

3

, CHF

2

or halogen;

R

3

and R

4

are, independently of each other, H, C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, halogen or phenyl, or phenyl;

A is C

4

-C

10

-alkylene or C

3

-C

10

-alkylene which comprises at least one group Z which is selected from O, S, CONR

3

, COO, CO, C

3

-C

6

-cycloalkyl and a double or triple bond;

B is a radical of the following formula:

X is CH

2

or CH

2

CH

2

;

R

5

is H, C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, halogen or phenyl, C

3

-C

6

-cycloalkyl, C

2

-C

6

-alkenyl, which may be substituted by halogen (1 or 2 halogen atoms), or C

2

-C

6

-alkynyl;

R

6

, R

7

and R

8

are, independently of each other, selected from H, C

1

-C

6

-alkyl, which may be substituted by OH, OC

1

-C

6

-alkyl, C

1

-C

6

-alkylthio, halogen or phenyl, OH, C

1

-C

6

-alkoxy, SH, C

1

-C

6

-alkylthio, C

2

-C

6

-alkenyl, C

2

-C

6

-alkynyl, halogen, CN, NO

2

, SO

2

R

3

, SO

2

NR

3

R

4

, CONR

3

R

4

, NHSO

2

R

3

and NR

3

R

4

;

and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D

3

receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D

2

receptor, have fewer side-effects than do the classic neuroleptic agents, which are D

2

receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D

3

ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D

3

receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses, parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover, they are useful in the treatment of stroke.

Addictive disorders include the pysychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impluse control disorders not elsewhere classified). Addictive substances are, for exampel: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride canal complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

The compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.

Within the context of the present invention, the following expressions have the meanings given in conjunction with them:

Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC

1

-C

6

-alkyl, halogen or phenyl. In the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the α or ω position. CF

3

, CHF

2

, CF

2

Cl or CH

2

F are particularly preferred.

Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.

Cycloalkyl is, in particular, C

3

-C

6

-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.

If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR

2

and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is —Z—C

3

-C

6

-alkylene, in particular —Z—CH

2

CH

2

CH

2

—, —Z—CH

2

CH

2

CH

2

CH

2

—, —Z—CH

2

CH═CHCH

2

—, —Z—CH

2

C(CH

3

)═CHCH

2

—,

—Z—CH

2

CH(CH

3

)CH

2

— or a linear —Z—C

7

-C

10

-alkylene radical, with Z being bonded to the triazole ring. Z is preferably CH

2

, O and, in particular, S. Preference is additionally given to A being —(CH

2

)

4

—, —(CH

2

)

5

—, —CH

2

CH

2

CH═CHCH

2

—,

—CH

2

CH

2

C(CH

3

)═CHCH

2

— or —CH

2

CH

2

CH(CH

3

)CH

2

—.

Halogen is F, Cl, Br or I, preferably F or Cl.

R

1

is preferably H, C

1

-C

6

-alkyl or C

3

-C

6

-cycloalkyl.

If R

2

is an aromatic radical, this radical is then preferably one of the following radicals:

where

R

9

to R

11

are H or the abovementioned substituents of the aromatic radical,

R

12

is H, C

1

-C

6

-alkyl or phenyl, and

T is N or CH.

If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.

The aromatic radical is particularly preferably a group of the formula:

where R

9

, R

10

and R

12

have the abovementioned meanings. The indicated phenyl, pyridyl, thiazolyl and pyrrole radicals are particularly preferred.

The radicals R

9

to R

11

are preferably H, C

1

-C

6

-alkyl, OR

3

, CN, phenyl, which may be substituted by C

1

-C

6

-alkyl, C

1

-C

6

-alkoxy or halogen, CF

3

and halogen, and are, in particular, H, C

1

-C

6

-alkyl, OR

3

and halogen. In this context, R

3

has the abovementioned meanings.

Particularly preferably, R

2

is H, C

1

-C

6

-alkyl, NR

3

R

4

(R

3

and R

4

are, independently of each other, H or C

1

-C

6

-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and O. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.

In the radical B, X is preferably CH

2

CH

2

.

Preferably, at least one of the radicals R

6

, R

7

and R

8

is H.

The radicals R

6

, R

7

and R

8

are preferably, and independently of each other, selected from H, C

1

-C

6

-alkyl, halogen-substituted C

1

-C

6

-alkyl, OH, C

1

-C

6

-alkoxy, C

1

-C

6

-alkylthio-C

1

-C

6

-alkyl, halogen, NO

2

, CN, SO

2

R

3

, SO

2

NR

3

R

4

and CONR

3

R

4

. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R

6

, R

7

and R

8

is/are C

1

-C

6

-alkyl, halogen, CN, SO

2

NR

3

R

4

, NO

2

or CF

3

.

Particular preference is given to the compounds of formula I where

R

1

is H, C

1

-C

6

-alkyl or phenyl,

R

2

is H, C

1

-C

6

-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl,

A is —SC

3

-C

10

-alkylene which can comprise a double bond or C

3

-C

6

-cycloalkyl, and

R

6

, R

7

and R

8

are selected from H, C

1

-C

6

-alkyl, C

1

-C

6

-alkoxy, halogen, SO

2

NR

3

R

4

, CN, NO

2

or CF

3

.

The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basle and Stuttgart, 1966.

The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention.

The process for preparing the compounds of the formula I consist in

a) reacting a compound of the formula (II)

where Y

1

is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)

HB (III);

or

b) reacting a compound of the formula (IV)

where Z

1

is O or S, and A

1

is C

1

-C

10

-alkylene or a bond, with a compound of the formula (V)

Y

1

—A

2

—B (V)

where Y

1

has the abovementioned meaning and A

2

is C

2

-C

10

-alkylene, with A

1

and A

2

together having from 3 to 10 C atoms and A

1

and/or A

2

where appropriate comprising at least one group Z; or

c) reacting a compound of the formula (VI)

where Y

1

and A

1

have the abovementioned meanings, with a compound of the formula (VII)

H—Z

1

—A—B (VII)

where Z

1

has the abovementioned meanings; or

d) reversing the polarity of a compound of the formula (VIII)

using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in

Albright

Tetrahedron

, 1983, 39, 3207 or

D. Seebach

Synthesis

1969, 17 und 1979, 19 or

H. Stetter

Angew. Chem. Int. Ed

. 1976, 15, 639 or

van Niel et al.

Tetrahedron

1989, 45, 7643

Martin et al.

Synthesis

1979, 633,

to give the products (VIIIa) (using 1,3-propanedithiol by way of example)

and then chain-elongating with compounds of the formula (IX)

Y

1

—A

3

—B (IX)

where Y

1

has the abovementioned meaning and A

3

is C

3

-C

9

-alkylene which can contain a group Z, with compounds of the formula (Ia)

where Z

2

is CO or a methylene group, and Z

2

and A

2

have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or

e) reacting a compound of the formula (VIII) with a compound of the formula (X)

Y

2

—A—B (X)

where Y

2

is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl “

Handbuch der Organischen Chemie

” [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/1b p. 383 ff, or Vol. V/1c p. 575 ff, or

f) reacting a compound of the formula (XI)

where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in

J. Org. Chem

. 1986, 50, 1927; or WO 92/20655, or

g) in order to prepare a compound of the formula (Ib)

where B

1

is a radical of the formula (XII)

reacting compounds of the formula (XIII) or (XIV),

with a compound of the formula (XV)

under reductive conditions.

The process for preparing a compound of the formula I where A comprises the groups COO or CONR

3

consists in reacting a compound of the formula (XVI)

where Y

3

is OH, OC

1

-C

4

-alkyl, Cl or, together with CO, an activated carboxyl group, and A

4

is C

0

-C

9

-alkylene, with a compound of the formula (XVII)

B—A—Z

3

(XVII)

where Z

3

is OH or NHR

3

.

Compounds of the type (XV) can be synthesized by alkylating compounds of the formula (IV) with compounds of the formula (XVIII),

to give compounds of the formula (XIX),

subsequently carrying out hydrazinolysis to give compounds of the type (XX)

and then introducing the radical R

5

, by, for example, effecting a reductive amination (as described, for example, in

J. Org. Chem

. 1986, 50, 1927) using the corresponding aldehyde or by means of alkylation in the presence of a base.

Compounds of the formula XX can also be obtained by reacting compounds of the formula II with azides, such as sodium azide, and then reducing, as described, for example, in

H. Staudinger,

Helv. Chim. Acta

1919, 2, 635 or

R. Carrie,

Bull. Chem. Soc. Fr

. 1985, 815.

Compounds of the formula XIII and XIV are known from the literature or can be prepared using known methods, as described, for example, in

A. van Vliet et al.

J. Med. Chem

. 1996, 39, 4233

M. Langlois

Bioorg. Med. Chem. Lett

. 1993, 3, 203

U. Hacksell

J. Med. Chem

. 1993, 36, 4221 or in WO 93/08799 or WO 95/04713.

The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, in A. R. Katritzky, C. W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds” J. Wiley & Sons Inc. NY and the literature which is cited therein, or in S. Kubota et al.

Chem. Pharm. Bull

. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23, 955.

In the above formulae, R

1

, R

2

, R

5

, R

6

, R

7

, R

8

, A, B and X have the meanings given in connection with formula I.

The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset.

The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.

If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent.

Processes (f) and (g) are effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation.

The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound.

The acid addition salts are prepared in a customary manner by mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays.

The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 500 mg per patient and day when administered parenterally.

The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLES

Example 1

3-[3-(N-(Indan-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Fumarate

1A Preparation of the Starting Compounds

1A1 2-N-Propylaminoindan 18.8 g (300 mmol) of sodium cyanoborohydride were added to a mixture of 20 g (150 mmol) of 2-aminoindan, 40.9 g (300 mmol) of zinc dichloride and 10.4 g (180 mmol) of propionaldehyde in 550 ml of methanol, and the whole was heated to boiling for 3.5 hours. For the working up, 460 ml of 1M sodium hydroxide solution was added to the mixture and this new mixture was extracted several times with ethyl acetate. The combined organic phases were washed with a saturated solution of sodium chloride and dried, and the solvent was removed under reduced pressure. Chromatographic purification of the crude product (silica gel, methylene chloride/methanol=9/1) yielded 7.8 g of a pale brown 45 oil.

Yield: 7.8 g (30% of theory);

1

H-NMR (DMSO-D

6

): 0.9 (t, 3H); 1.4 (m, 2H); 2.5-2.7 (m, 4H); 3.0-3.1 (m, 2H); 3.3 (sbr, NH); 3.5 (m, 1H).

1A2 2-(N-(3-Chloropropyl)propylamino)indan

7.6 g (44 mmol) of 2-N-propylaminoindan were heated to boiling in 100 ml of acetonitrile, for 4 hours under reflux, together with 17.1 g (109 mmol) of 1-bromo-3-chloropropane, 9.0 g (138 mmol) of potassium carbonate and 3.3 g (150 mmol) of sodium iodide. The mixture was then filtered with suction through Celite, after which the solvent was evaporated under reduced pressure; the crude product was then used for the subsequent reaction.

1B Preparation of the End Product

6.1 g (26 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole (prepared by the method of Kubota et al., Chem. Pharm. Bull 1975, 23, 955) and 9.6 g (38 mmol) of the crude product obtained in 1A2 were heated, together with 2.8 g (19 mmol) of lithium hydroxide, at 80° C. for 2.5 hours, and with stirring, in 100 ml of DMF (dimethylformamide). The solvent was subsequently distilled off under reduced pressure and 500 ml of a saturated solution of sodium hydrogen carbonate were added to the residue; this mixture was then extracted several times with methyl tert-butyl ether and ethyl acetate. After drying and evaporating, 9.5 g of an oil remained, with this oil being purified by column chromatography (methylene chloride containing 0-3% methanol).

C

24

H

30

ON

4

S (406) MS (m/z): 407 [M+H]

+

; 0.71 g of substance was isolated as the fumarate after precipitating in isopropanol/methyl tert-butyl ether.

1

H-NMR (CDCl

3

): 0.9 (t, 3H); 1.5 (m, 2H); 1.9 (q, 2H); 2.6-3.2 (m, 10H); 3.5 (s, 3H); 3.6 (m, 1H); 6.6 (s, 2H); 7.2 (m, 4H); 7.5(m, 3H); 7.7. (m, 2H).

Example 2

3-[3-(N-(6-Methoxyindan-1-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

6-Methoxy-1-propylaminoindan was obtained by the reductive amination of 6-methoxyindan-1-one with n-propylamine in the presence of zinc dichloride and sodium cyanoborohydride in methanol, as described in 1A1. After conversion into the chloropropyl compound, as described in 1A2, this latter was reacted with 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole, in analogy with 1B, with the compound of Example 2 being obtained.

C

25

H

32

N

4

OS (436) MS (m/z): 436 [M+H]

+

;

1

H-NMR (CDCl

3

): 0.8 (t, 3H); 1.5 (m, 2H); 1.9 (m, 3H); 2.0 (m, 1H); 2.45-2.9 (m, 6H); 3.2 (m, 1H), 3.3 (m, 1H); 3.6 (s, 3H); 3.7 (s, 3H); 4.6 (t, 1H); 6.8 (dd, 1H); 6.9 (d, 1H); 7.1 (d, 1H); 7.6 (m, 3H); 7.75 (m, 2H).

Example 3

3-[3-(6-Methylmercaptomethyl-1,2,3,4-tetrahydronaphth-2-ylamino)-propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

3A Preparation of the Starting Compound

3-(3-Aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole 3-Mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole (11.8 g, 50 mmol) was heated, together with 13.8 g (50 mmol) of N-(3-bromopropyl)phthalimide and 1.2 g (50 mmol) of lithium hydroxide, at 100° C. for 3.5 hours, in 150 ml of DMF. After the mixture had cooled down, 1 l of water was added and this new mixture was extracted several times with methylene chloride; the organic phase was then dried and evaporated. 14.5 g (75% of theory) of 3-[4-methyl-5-phenyl-3-phthalimidopropylmercapto]-1,2,4(4H)-triazole were obtained. 14.5 g (38 mmol) of the above-described compound were reacted with 2.3 ml (46 mmol) of hydrazine hydrate in ethanol, and 9.7 g (39 mmol) of 3-(3-aminopropylmercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole were isolated.

Yield: 9.7 (quantitative);

1

H-NMR (CDCl

3

): 1.6 (sbr, 2H); 2.0 (q, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 7.5 (m, 3H); 7.7 (m, 2H).

3B Preparation of the End Product

1.0 g (4 mmol) of the compound described in 3A was initially introduced in 15 ml of methanol; 6-methyl-mercaptomethyltetral-2-one (prepared in accordance with EP 96/01238) (1.0 g, 4.7 mmol), dissolved in 10 ml of methanol, was added, and 0.5 g of sodium cyanoborohydride was introduced in portions. The mixture was heated to boiling for 6 hours. After it had cooled down, 25 ml of 1M sodium hydroxide solution were added and the whole was extracted several times with ethyl acetate. After washing with water, drying and evaporating, the residue was purified by column chromatography on silica gel (eluent: methylene chlorie/methanol=9/1).

Yield: 0.56 g (32% of theory); C

24

H

30

N

4

S

2

(438) MS (m/z): 439 [M+H]

+

.

The compounds below were prepared in an analogous manner using the following cyclic ketones:

Example 4

3-[3-(6-Methyl-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 6-methyltetral-2-one with 3-(3-aminopropylmercapto)4-methyl-5-phenyl-1,2,4(4H)-triazole.

1

H-NMR (CDCl

3

): 1.5-1.6 (mbr, 3H); 2.0 (m, 3H); 2.3 (m, 1H); 2.7-3.0 (m, 7H); 3.4 (t, 3H); 3.6 (s, 3H); 6.8-7.0 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C

23

H

28

N

4

S (392); m.p.: 69-73° C.

Example 5

3-[3-(6-Bromo-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 6-bromotetral-2-one with 3-(3-aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole.

1

H-NMR (CDCl

3

): 2.1 (m, 1H); 2.5-2.9 (m, 5H); 3.2 (m, 1H); 3.3-3.7 (m, 9H); 6.8 (m, 1H); 7.2 (m, 2H); 7.5 (m, 3H); 7.6 (m, 2H). C

22

H

25

BrN

4

S (457) MS (m/z): 458 [M+H]

+

.

Example 6

3-[3-(1,2,3,4-Tetrahydronaphth-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

C

22

H

26

N

4

S (378.5) MS (m/z): 379 [M+H]

+

.

In order to precipitate the hydrochloride, the compound was dissolved in ether/isopropanol, and ethereal hydrochloride acid was then added to the solution while cooling in ice.

C

22

H

26

N

4

S×HCl; m.p.: 125° C. (decomp.).

Example 7

3-[3-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 7-methoxytetral-2-one with 3-(3-Aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole.

1

H-NMR (CDCl

3

): 1.5 (m, 1H); 2.0 (m, 3H); 2.5 (m, 1H); 2.8-3.0 (m, 7H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 6.6 (d, 1H); 6.7 (dd, 1H); 7.0 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C

23

H

28

N

4

OS (408) MS (m/z)=408 [M]

+

.

Example 8

3-[3-(6-Methoxyindan-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained in analogy with Example 1, starting from 6-methoxyindan-1-one.

C

22

H

26

N

4

OS (394) MS (m/z): 395 [M+H]

+

;

1

H-NMR (DMSO-d

6

): 2.1 (m, 3H); 2.4 (m, 1H); 2.75 (m, 1H); 3.0 (m, 3H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 4.7 (t, 1H); 6.5 (s, 2H); 6.9 (dd, 1H); 7.2 (d, 1H); 7.25 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H).

Example 9

3-[3-(5,6-Dimethoxyindan-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole hydrochloride, obtained by the reaction of 5,6-dimethoxyindan-1-one with 3-(3-aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole in analogy With 3B, and Subsequent Precipitation of the Salt With Ethereal HCl.

C

23

H

28

N

4

O

2

S×HCl (461.1); m.p: 201-202° C.;

1

H-NMR (CDCl

3

): 2.2-2.5 (m, 4H); 2.8 (m, 1H); 3.2-3.3 (m, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 3.9 (s, 3H); 4.6 (m, 1H); 6.7 (s, 1H); 7.0 (br, 2H); 7.4 (s, 1H); 7.6 (m, 5H).

Example 10

5-Amino-3-[3-(1,2,3,4-tetrahydronaphth-1-ylamino)propylmercapto-4-methyl-1,2,4(4H)-triazole Hydrochloride

10A Preparation of the Starting Compound

N-(3-Chloropropyl)-1,2,3,4-tetrahydronaphthyl-1-amine 5.0 g (34 mmol) of 1,2,3,4-tetrahydronaphth-1-ylamine were dissolved, together with 6.4 g (40 mmol) of 1-bromo-3-chloropropane and 5.2 g (50 mmol) of triethylamine, in 50 ml of THF and the solution was heated to boiling for 16 h. The solvent was then distilled off and the residue was dissolved in methylene chloride; this solution was washed twice with water, dried and concentrated. The crude product was purified by chromatography on silica gel (eluent:methylene chloride/methanol=97/3), and 3.4 g of a yellowish oil were isolated.

Yield: 3.4 g (44% of theory);

1

H-NMR (CDCl

3

): 1.1 (sbr, NH); 1.7-2.0 (m, 6H); 2.6-3.0 (m, 4H); 3.6-3.8 (m, 3H); 7.0-7.4 (m, 4H). C

13

H

18

ClN (223.8).

10B Preparation of the End Product

670 mg (3 mmol) of the above-described chlorine compound were dissolved, together with 390 mg (3 mmol) of 5-amino-3-mercapto-4-methyl-1,2,4(4H)-triazole and 72 mg (3 mmol) of lithium hydroxide, in 9 ml of DMF and the solution was stirred at 100° C. for four hours. Water was added and the whole was extracted three times with methyl tert-butyl ether. After the combined organic phases had been dried over sodium sulfate and concentrated, the resulting crude product was purified by chromatography on silica gel (eluent:methylene chloride containing 3-5% methanol).

Yield: 460 mg (48% of theory); C

16

H

23

N

5

S (317.5).

Precipitation of the hydrochloride in ethereal hydrochloric acid yielded the title compound as a white solid.

C

16

H

23

N

5

S×HCl (352.9); m.p: 140° C. (decomp.).

Example 11

5-Amino-3-({2-[(1,2,3,4-tetrahydronaphth-1-ylamino)-2-methyl]-prop-2-enyl}mercapto)-4-methyl-1,2,4(4H)-triazole Hydrochloride

11A Preparation of the Starting Compound

1-(3-Chloro-2-methylenepropyl)-1,2,3,4-tetrahydronaphthyl-1-amine

5.0 g (34 mmol) of 1,2,3,4-tetrahydronaphth-1-ylamine were dissolved, together with 5.1 g (41 mmol) of 1,3-dichloro-2-methylenepropane and 5.2 g (51 mmol) of triethylamine, in 50 ml of THF and the solution was heated to boiling for 24 h. The solvent was then distilled off and the residue was dissolved in methylene chloride; this solution was washed twice with water, dried and concentrated. The crude product was purified by chromatography on silica gel (eluent:methylene chloride/methanol=97/3), and 2.6 g of a yellowish oil were isolated.

Yield: 2.6 g (33% of theory);

1

H-NMR (CDCl

3

): 1.3 (m, 1H); 1.7-2.0 (m, 4H); 2.6-2.9 (m, 2H); 3.4 (m, 2H); 3.7 (m, 1H); 4.2 (m, 2H); 5.2 (m, 2H); 7.2 (m, 3H); 7.4 (m, 1H).

11B Preparation of the End Product

0.6 g (2.6 mmol) of the above-described chlorine compound was dissolved, together with 0.6 g (2.6 mmol) of 5-amino-3-mercapto-4-methyl-1,2,4(4H)-triazole and 63 mg (2.6 mmol) of lithium hydroxide, in 8 ml of DMF, and the solution was stirred at 100° C. for two hours. Water was then added and the whole was extracted three times with methyl tert-butyl ether. After the combined organic phases had been dried over sodium sulfate and concentrated, the resulting crude product was purified by chromatography on silica gel (eluent:methylene chloride containing 3% methanol).

Yield: 0.55 g (53% of theory) of a colorless oil; C

17

H

23

N

5

S (329.5) MS (m/z)=331 [M+H]

+

.

The salt was precipitated with ethereal hydrochloric acid at 0° C.

C

17

H

23

N

5

S×HCl; m.p.: 125° C.

Example 12

3-({2-[(1,2,3,4-Tetrahydronaphth-1-ylamino)-2-methyl]prop-2-enyl}-mercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

The compound was obtained by reacting the precursor 11A from Example 11 with 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole.

Yield: 53% of theory. C

23

H

26

N

4

S×HCl; m.p.: 100° C. (decomp.).

Example 13

3-[3-(6-Bromo-1,2,3,4-tetrahydronaphth-2-ylmethylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

The above substance was obtained by methylating the substance from Example 5 with methyl iodide in a manner known per se.

C

23

H

27

BrN

4

S (471.5) MS (m/z): 470 [M−H]

+

; C

23

H

27

BrN

4

S×HCl; m.p.: 88° C. (decomp.).

Example 14

3-[3-(6-Methyl-1,2,3,4-tetrahydronaphth-2-ylmethylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

The above substance was obtained by methylating 3-[3-(6-methyl-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole (Example 4) with methyl iodide in a manner known per se.

1

H-NMR (CDCl

3

): 1.9 (m, 2H); 2.3 (s, 3H); 2.5 (mbr, 3H); 2.9 (m, 4H); 3.2 (m, 1H); 3.3-3.5 (m, 4H); 3.6-3.8 (m, 5H); 6.8-7.0 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C

24

H

30

N

4

S (406.6).

Example 15

3-[3-(N-(6-Fluoroindan-1-yl)propylamino)propylmercapto]-4-methyl-5-(2-pyrrolyl)-1,2,4(4H)-triazole Hydrochloride

15A Preparation of the Starting Compounds

15A1 6-Fluoro-1-propylaminoindan

3.27 g (55 mmol) of n-propylamine were initially introduced in 100 ml of methanol, and 15 g (110 mmol) of zinc dichloride were added. 10 g (66 mmol) of 6-fluoro-1-indanone, dissolved in 100 ml of methanol, were then added dropwise. After that, 6.94 g (110 mmol) of sodium cyanoborohydride were added in portions and the reaction mixture was heated to boiling for 3 hours while stirring. After the mixture had cooled down, 200 ml of 1M-NaOH were added and the precipitated salts were filtered off; the filtrate was then extracted with ethyl acetate. After drying and evaporating, the combined organic phases yielded 10.4 g of an oil which was purified by column chromatography on silica gel (eluent:methylene chloride containing 2-5% methanol).

Yield: 4.0 g (31% of theory);

1

H-NMR (CDCl

3

): 0.9 (t, 3H); 1.3 (sbr, NH); 1.5 (m, 2H); 1.8 (m, 1H); 2.6 (t, 2H); 2.8 (m, 1H); 3.0 (m, 1H); 4.2 (t, 1H); 6.9 (m, 2H); 7.3 (m, 1H). C

12

H

16

FN (193.3) MS (m/z): 193 [M

+

].

15A2 6-Fluoro-1-(3-chloropropyl)-1-propylaminoindan

The above-described product was subsequently reacted as described under 1A.

1

H-NMR (CDCl

3

): 0.9 (t, 3H); 1.5 (m, 2H); 1.8-2.1 (m, 4H); 2.3 (t, 2H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.6 (m, 2H); 4.4 (t, 1H); 6.9 (m, 2H); 7.3 (m, 1H). C

15

H

21

ClFN (269.8).

15A3 3-Mercapto-4-methyl-5-(pyrrol-2-yl)-1,2,4(4H)-triazole

The triazole was prepared by reacting pyrrole-2-carbonyl chloride with N-methylthiosemicarbazide in pyridine and then cyclizing in an aqueous solution of sodium hydrogen carbonate (in analogy with S. Kubota et al., Chem. Pharm. Bull. 1975,23,955).

1

H-NMR (DMSO-d

6

): 3.7 (s, 3H); 6.2 (m, 1H); 6.8 (m, 1H); 7.0 (m, 1H); 11.8 (s, 1H); 14.0 (s, 1H). C

7

H

8

N

4

S (180); m.p.: 200-201° C.

15B Preparation of the End Product

The substance 15 was obtained by reacting 3-mercapto-4-methyl-5-(pyrrol-2-yl)-1,2,4(4H)-triazole with the chlorine base prepared in 15A2, in analogy with Example 1B.

Yield: 73% of theory; C

22

H

2

8FN

5

S (413.6);

1

H-NMR (CDCl

3

): 0.9 (t, 3H); 1.5 (m, 2H); 1.8-2.0 (m, 3H); 2.1 (m, 1H); 2.3 (t, 2H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.15 (m, 1H); 3.3 (m, 1H); 3.7 (s, 3H); 4.4 (t, 1H); 6.3 (s, 1H); 6.5 (s, 1H); 6.8 (m, 2H); 7.1 (s, 1H); 7.2 (m, 1H); 12.0 (s, 1H).

Precipitation with isopropanolic hydrochloric acid yielded the title compound as a white solid.

C

22

H

28

FN

5

S×HCl (450.1); m.p.: 120° C. (decomp.).

Example 16

3-[3-(N-(6-Fluoroindan-1-yl)propylamino)propylmercapto]-4-methyl-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole Hydrochloride

16A Preparation of the Starting Compounds

4-Methyl-3-mercapto-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole

The triazole was prepared by reacting 4-methylthiazole-5-carbonyl chloride with N-methylthiosemicarbazide in pyridine and then cyclizing in an aqueous solution of sodium hydrogencarbonate.

1

H-NMR (DMSO-d

6

): 2.4 (s, 3H); 3.4 (s, 3H); 9.2 (s, 1H); 14.1 (s, 1H).

16B Preparation of the End Product

The preparation was effected, in analogy with Example 15, by reacting substance 15A with 3-mercapto-4-methyl-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole.

Yield: (70% of theory); C

22

H

28

FN

5

S

2

(445.6) MS (m/z): 447 [M+H]

+

;

1

H-NMR (CDCl

3

): 0.9 (t, 3H); 1.5 (m, 2H); 2.0 (m, 3H); 2.15 (m, 1H); 2.4 (t, 2H); 2.6 (m, 5H); 2.8 (m, 1H); 2.9 (m, 1H); 3.3 (m, 1H); 3.4-3.5 (m, 4H); 4.5 (t, 1H); 6.8 (m, 2H); 7.2 (t, 1H); 9.1 (s, 1H). C

22

H

28

FN

5

S

2

×HCl (482.1); m.p.: 123° C.

The compounds of Examples 17 to 28 were prepared in an analogous manner:

Example 17

5-Amino-3-[3-(N-(8-chloro-1,2,3,4-terahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-1,2,4(4H)-triazole

Example 18

3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

C

26

H

34

N

4

OS×HCl (487.1); m.p.: 92-95° C.

Example 19

3-[3-(Indan-2-yl-amino)propylmercapto]4-methyl-5-phenyl-1,2,4-(4H)-triazole

1

H-NMR (CDCl

3

): 2.0 (m, 2H); 2.2 (sbr, NH), 2.7-2.85 (m, 4H); 3.1 (dd, 2H); 3.3 (t, 2H); 3.5 (s, 3H); 3.7 (t, 1H); 7.1-7.2 (m, 4H); 7.5 (m, 3H); 7.7 (m, 2H). C

21

H

24

N

4

S (364.5) MS (m/z): 365 [M]

+

.

Example 20

3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

C

23

H

28

N

4

OS (409) MS (m/z): 409 [M]

+

.

Example 21

3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

1

H-NMR (CDCl

3

): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.6 (m, 1H); 1.9 (q, 2H); 2.0 (m, 1H); 2.5 (m, 3H); 2.6 (t, 2H); 2.7-3.0 (m, 4H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H), 6.6 (d, 1H); 6.7 (d, 1H); 7.0 (t, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C

26

H

34

N

4

OS (450.7).

Example 22

3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-5-tert-butyl-4-methyl-1,2,4(4H)-triazole

C

24

H

38

N

4

OS (430) MS (m/z): 431 [M+H]

+

.

Example 23

3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-5-methylamino-4-methyl-1,2,4(4H)-triazole

C

21

H

33

N

5

OS (403.6) MS (m/z): 404.3 [M+H]

+

.

Example 24

3-({2-[(1,2,3,4-Tetrahydronaphth-1-yl-amino)-2-methyl]prop-2-enyl}-mercapto)4-methyl-5-phenyl-1,2,4(4H)-triazole

C

23

H

26

N

4

OS (390.6).

Example 25

Ethyl-5-{[3-(indan-2-ylamino)propyl]mercapto}-4-methyl-1,2,4(4H)-triazole-3-carboxylate

C

18

H

24

N

4

O

2

S (360).

Treatment with ethereal hydrochloric acid results in the hydrochloride.

C

18

H

24

N

4

O

2

S×HCl (396.9); Melting point: 135-139° C.

Example 26

3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)propylmercapto]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-1,2,4(4H)-triazole

1

H-NMR (CDCl

3

): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.6 (m, 1H); 2.0 (m, 3H); 2.5 (t, 2H); 2.6 (s, 3H); 2.7-3.0 (m, 7H); 3.4 (t, 2H); 3.5 (s, 3H); 3.8 (s, 3H), 6.6 (s, 1H); 6.7 (d, 1H); 6.9 (d, 1H); 8.9 (s, 1H). C

24

H

33

N

5

OS

2

(472).

Example 27

3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole

1

H-NMR (CDCl

3

): δ=0.9 (t, 3H); 1.5 (m, 3H); 2.0 (m, 2H); 2.2 (m, 1H); 2.5 (m, 3H); 2.7 (t, 2H); 2.9 (m, 4H); 3.0 (m, 2H); 3.6 (s, 3H); 3.8 (s, 3H), 6.6 (d, 1H); 6.7 (d, 1H); 7.0 (t, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C

27

H

36

N

4

O (432.6).

Example 28

3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole

1

H-NMR (CDCl

3

): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.7 (m, 1H); 1.9 (q, 2H); 2.1 (m, 1H); 2.5 (t, 2H); 2.6 (t, 2H); 2.65-2.8 (m, 8H); 3.1 (s, 1H); 3.5 (s, 3H); 3.8 (s, 3H), 6.5 (s, 1H); 6.6 (dd, 1H); 6.9 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C

27

H

36

N

4

O (432.6).

The following compounds can be prepared in an analogous way in principle:

Example 29

3-[3-(N-(Indan-2-yl)propylamino)propylmercapto]-4-methyl-5-(pyridin-3-yl)-1,2,4(4H)-triazole

Example 30

3-[3-(N-(5-Mercaptomethyl-indan-2-yl)propylamino)propylmercapto]-4-methyl-5-thien-3-yl-1,2,4(4H)-triazole

Example 31

4-Cyclopropyl-3-[3-N-(7-methoxy-(1,2,3,4-tetrahydronaphthalin-2-yl)propylamino)propylmercapto]-5-(4-methyl-1,3-thiazol-5-yl)-1,2,4(4H)-triazole

Example 32

3-[3-(N-(7-cyano-1,2,3,4-tetrahydronaphth-2-yl)methylamino)propylmercapto]-4-isopropyl-5-(1,3-thiazol-4-yl)-1,2,4(4H)-triazole Hydrochloride

Example 33

3-[3-(N-(7-Bromo-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-ethyl-5-(1-methyl-1H-pyrrol-2-yl)-1,2,4(4H)-triazole

Example 34

N-{4-[(5-Methoxy-7-methyl)-1,2,3,4-tetrahydronaphthalin-2-yl]-(but-2-enyl)amino]propylmercapto}-4-methyl-5-(3-cyano-phenyl)-1,2,4(4H)-triazole

Example 35

3-[7-(N-(5-Fluorindan-2-yl)methylamino)heptylmercapto]-4-propyl-5-(1,3-thiazol-4-yl)-1,2,4(4H)-triazole

Example 36

3-[3-(N-(Indan-2-yl)propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole

Example 37

3-[3-(N-(5-Methoxyindan-2-yl)propylamino)propoxy]-4-methyl-5-phenyl-1,2,4(4H)-triazole

Example 38

N-{4-[(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalin-2-yl)(propyl)amino]butyl}-4-methyl-5-phenyl-1,2,4(4H)-triazole-3-carboxamide

TABLE 1

Ex.

R

1

R

2

A

R

5

R

6

R

7

39

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

6-chloro

40

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

6-chloro

41

Ethyl

N-Methyl-2-Pyrrolyl—

CO—CH

2

—C(═CH

2

)—CH

2

n-propyl

7-methoxy

42

Me

Phenyl

S—(CH

2

)

3

—

but-2-en-yl

6-iod

43

Me

4-Methylthiazol-5-yl

S—(CH

2

)

7

—

n-propyl

6-methyl

7-cyano

44

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

H

45

Me

Amino

S—(CH

2

)

3

—

n-propyl

6-chloro

46

Me

4-Methylthiazol-5-yl

O—(CH

2

)

3

—

n-propyl

7-trifluoromethoxy

47

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

6-methyl

48

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

6-bromo

49

Me

4-Methoxyphenyl

(CH

2

)

4

—

n-propyl

5-cyano

50

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

51

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

5-cyano

52

Me

Phenyl

CONH—(CH

2

)

5

—

methyl

6-fluoro

53

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

6-methyl

54

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

5-cyano

55

Me

Amino

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

56

Me

3-Cyano-phenyl

CONH—(CH

2

)

5

—

n-propyl

5-fluoro

57

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

58

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

6-chloro

59

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-bromo

60

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

61

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

6-methyl

62

Me

3-Jod-phenyl

S—CH

2

—cycProp—CH

2

—

but-2-en-yl

5-cyano

63

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

6-bromo

64

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-chloro

7-chloro

65

Ethyl

Phenyl

CO—(CH

2

)

3

—

but-2-en-yl

5-cyano

66

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

6-bromo

67

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

6-methyl

68

Me

2-Pyrazinyl—

S—CH

2

—cycProp—CH

2

—

methyl

5-nitro

69

Ethyl

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

70

Me

4-Methoxyphenyl

O—(CH

2

)

3

—

n-propyl

5-cyano

71

Me

3-Cyano-phenyl

O—(CH

2

)

3

—

n-propyl

5-fluoro

72

Me

2-Thienyl

S—(CH

2

)

3

—

methyl

5-cyano

73

Me

3-Benzthienyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

74

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

6-bromo

75

Me

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

76

Propyl

Phenyl

S—CH

2

—CH═CH—CH

2

—

methyl

6-fluoro

77

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

6-methyl

78

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

5-cyano

79

cycProp

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

7-methoxy

80

Butyl

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

6-thiomethyl

81

Me

Carboxyethyl

S—(CH

2

)

3

—

methyl

5-cyano

82

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

H

83

Butyl

3-Cyano-phenyl

O—(CH

2

)

3

—

n-propyl

5-fluoro

84

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

85

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

7-methoxy

86

Me

4-Methylthiazol-5-yl

CONH—(CH

2

)

4

—

n-propyl

7-trifluoromethoxy

87

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

H

88

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

89

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

6-methyl

90

Me

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

91

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

6-thiomethyl

92

Me

Phenyl

O—(CH

2

)

3

—

methyl

6-fluoro

93

Me

Phenyl

S—CH

2

—cycHex—CH

2

—CH

2

—

methyl

6-fluoro

94

Me

Phenyl

(CH

2

)

4

—

n-propyl

6-methoxy

95

Ethyl

Phenyl

S—(CH

2

)

7

—

methyl

6-fluoro

96

Me

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

97

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

7-cyano

98

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

7-methoxy

99

Propyl

Pyridin-3-yl—

S—CH

2

—CH═CH—CH

2

—

n-propyl

6-bromo

7-bromo

100

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

101

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

102

Me

Phenyl

O—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

103

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

6-bromo

104

Me

Amino

S—(CH

2

)

3

—

n-propyl

6-methyl

105

Me

3-Thienyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

106

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

107

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

108

iProp

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

109

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

H

110

Ethyl

Phenyl

SCH

2

—C(CH

3

)═CH—CH

2

—

but-2-en-yl

5-cyano

111

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

H

112

Me

tert.Butyl

S—(CH

2

)

3

—

methyl

5-cyano

113

Me

4-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

114

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

5-cyano

115

Me

4-Methoxyphenyl

S—CH

2

—cycProp—(CH

2

)

2

—

prop-2en-yl

6-thiomethyl

116

Me

Phenyl

S—CH

2

—CH═CH—CH

2

—

n-propyl

7-methansulfonyloxy

117

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

5-cyano

118

cycProp

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

119

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

120

nHexyl

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

6-chloro

121

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

H

122

Me

Phenyl

COO—(CH

2

)

4

—

n-propyl

7-methansulfonyloxy

123

Me

cycPropyl

S—(CH

2

)

3

—

methyl

5-cyano

124

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

125

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

5-cyano

126

Butyl

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

127

iProp

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

128

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

129

Propyl

Methylamino

S—(CH

2

)

3

—

methyl

5-cyano

130

Me

Amino

S—(CH

2

)

3

—

n-propyl

6-bromo

131

Me

3-Jod-phenyl

S—(CH

2

)

3

—

methyl

5-cyano

132

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

6-chloro

133

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

6-bromo

134

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

5-cyano

135

Ethyl

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

136

Me

2-Pyrazinyl—

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

6-methyl

137

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

6-methyl

138

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

H

139

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

140

Me

2-Pyrazinyl—

O—(CH

2

)

3

—

n-propyl

6-methyl

141

Me

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

142

Ethyl

Phenyl

CO—(CH

2

)

3

—

prop-2en-yl

6-chloro

7-chloro

143

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

144

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

6-chloro

145

Me

3-Jod-phenyl

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

5-cyano

146

Me

3-Benzthienyl—

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

147

Phenyl

Phenyl

S—(CH

2

)

3

—

n-propyl

6-methoxy

148

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

6-methyl

149

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

150

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

151

Me

4-Methoxyphenyl

COO—(CH

2

)

3

—

n-propyl

5-cyano

152

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

153

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

154

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

155

Me

Trifluoromethyl

S—(CH

2

)

3

—

methyl

5-cyano

156

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

157

Me

Pyridin-3-yl—

CONH—(CH

2

)

4

—

n-propyl

6-bromo

158

Me

Pyridin-3-yl—

O—(CH

2

)

3

—

n-propyl

6-bromo

159

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

5-cyano

160

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

161

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

6-bromo

162

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

163

Me

Phenyl

S—CH

2

—cycHex—CH

2

—

n-propyl

7-trifluoromethoxy

164

Phenyl

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

6-ethyl

165

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

6-methyl

166

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

167

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

H

168

Me

4-Methoxyphenyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

5-cyano

169

Me

2-Thienyl

S—(CH

2

)

3

—

n-ethyl

6-methxoxy

7-methoxy

170

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

6-bromo

171

Me

2-Thienyl

O—(CH

2

)

3

—

n-propyl

6-chloro

172

Me

2-Pyrazinyl—

S—(CH

2

)3—

n-propyl

6-methyl

173

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

174

cycProp

2-Pyrazinyl—

S—(CH

2

)

3

—

prop-2en-yl

6-carboxamid

175

Me

Amino

S—(CH

2

)

3

—

n-propyl

7-methoxy

176

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

177

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

H

178

Me

2-Thienyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

6-chloro

179

Me

Phenyl

COO—(CH

2

)

4

—

n-propyl

6-methoxy

180

Butyl

Tetrazolyl—

S—(CH

2

)

3

—

methyl

5-cyano

181

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

6-chloro

182

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

H

183

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

5-cyano

184

Me

N-Methyl-2-Pyrrolyl—

O—(CH

2

)

3

—

n-propyl

7-methoxy

185

iProp

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

6-chloro

7-chloro

186

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

6-methyl

187

Me

Cyclohexyl—

S—(CH

2

)

7

—

n-propyl

6-chloro

7-chloro

188

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

189

Me

3-Jod-phenyl

COO—(CH

2

)

4

—

n-propyl

5-cyano

190

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

5-cyano

191

Me

2-Pyrazinyl—

S—CH

2

—CH═CH—CH

2

—

n-propyl

6-methyl

192

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

6-chloro

193

Me

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

194

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

H

195

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

5-cyano

196

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

197

Ethyl

3-Jod-phenyl

S—(CH

2

)

3

—

H

6-chloro

7-chloro

198

Me

3-Jod-phenyl

O—(CH

2

)3—

n-propyl

5-cyano

199

Butyl

Phenyl

O—(CH

2

)

3

—

methyl

6-fluoro

200

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

H

201

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

6-chloro

202

Me

Phenyl

S—CH

2

—cycHex—CH

2

—CH

2

—

n-propyl

5-fluoro

203

Me

3-Jod-phenyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

5-cyano

204

Me

3-Benzthienyl—

S—(CH

2

)3—

n-propyl

6-methyl

205

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

6-methyl

206

Me

Amino

S—(CH

2

)

3

—

n-propyl

5-cyano

207

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

208

Me

2-Thienyl

COO—(CH

2

)

4

—

n-propyl

6-chloro

209

Me

3-Benzthienyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

210

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

211

Me

Phenyl

S—CH

2

—cycProp—CH

2

—

H

6-bromo

212

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

213

Me

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

214

Me

3-Benzthienyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

215

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-methyl

216

Me

Methyl

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

217

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

218

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

methyl

5-cyano

219

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

methyl

5-cyano

220

Me

2-Thienyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

6-chloro

221

Me

3-Benzthienyl—

S—(CH

2

)

3

—

methyl

7-methoxy

222

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

5-cyano

223

Butyl

2-Thienyl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

224

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

225

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

226

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

H

227

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

6-methyl

228

Me

Phenyl

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

229

Ethyl

Phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

prop-2en-yl

6-chloro

7-chloro

230

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

231

Me

Dimethylamino

S—(CH

2

)

3

—

methyl

5-cyano

232

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

233

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

234

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

methyl

5-cyano

235

Me

4-Methoxyphenyl

S—CH

2

—cycProp—(CH

2

)

2

—

but-2-en-yl

5-methoxy

236

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

5-cyano

237

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

H

238

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

239

nHexyl

2-Pyrazinyl—

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

240

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

6-bromo

241

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

methyl

5-cyano

242

Me

N-Propyl-tetrazolyl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

243

Me

3-Br-Pyridin-5-yl—

S—(CH

2

)

3

—

n-propyl

7-methoxy

244

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

5-cyano

245

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

6-thiomethyl

246

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

247

Ethyl

Phenyl

S—(CH

2

)

6

—

n-propyl

6-methoxy

248

Me

Pyridin-4-yl—

S—(CH

2

)

3

—

n-propyl

6-bromo

249

cycProp

3-Pyrrolyl

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

250

Me

Benzyl

S—(CH

2

)

3

—

methyl

5-cyano

251

Propyl

4-Methylthiazol-5-yl

S—CH

2

—CH═CH—CH

2

—

n-propyl

7-trifluoromethoxy

252

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

5-cyano

253

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

6-bromo

254

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

5-cyano

255

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

6-chloro

256

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

257

Me

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

H

258

Me

Cyano

S—(CH

2

)

3

—

methyl

5-cyano

259

Me

4-Methoxyphenyl

S—(CH

2

)3—

n-propyl

6-bromo

260

Ethyl

Phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

prop-2en-yl

6-thiomethyl

261

Ethyl

Phenyl

S—(CH

2

)

6

—

but-2-en-yl

5-cyano

262

Me

2-Thienyl

S—(CH

2

)

3

—

prop-2en-yl

5-methansulfonyloxy

263

Me

3-Benzthienyl—

S—(CH

2

)

3

—

n-propyl

H

264

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

6-bromo

265

Me

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

H

266

cycProp

Cyclohexyl—

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

267

Ethyl

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

7-methoxy

268

Me

2-Pyrazinyl—

S—(CH

2

)

3

—

n-propyl

5-cyano

269

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

5-cyano

270

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)3—

n-propyl

7-methoxy

H

271

cycProp

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

7-methoxy

272

Me

Phenyl

S—(CH

2

)3—

n-propyl

6-chloro

273

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

6-methyl

274

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

5-methansulfonyloxy

275

Me

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

H

276

Me

N-Methyl-2-Pyrrolyl—

S—(CH

2

)3—

n-propyl

5-cyano

277

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

6-chloro

278

Me

6-Chloro-biphenyl-2—

S—(CH

2

)3—

n-propyl

7-methoxy

279

nHexyl

3-Cyano-phenyl

S—(CH

2

)

3

—

prop-2en-yl

6-chloro

280

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-chloro

281

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

282

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

H

283

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

H

7-methansulfonyloxy

284

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

6-trifluoromethoxy

285

Me

Cyclohexyl—

S—(CH

2

)

3

—

n-propyl

6-chloro

286

Me

2-Pyrazinyl—

S—(CH

2

)

7

—

but-2-en-yl

7-iod

8-chloro

287

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

H

288

Ethyl

Phenyl

S—(CH

2

)

7

—

prop-2en-yl

6-thiomethyl

289

Me

Cyclohexyl—

S—(CH

2

)3—

n-propyl

7-methoxy

290

Me

N-Methyl-2-Pyrrolyl—

CONH—(CH

2

)4—

n-propyl

7-methoxy

291

Ethyl

Phenyl

(CH

2

)

4

—

but-2-en-yl

5-cyano

292

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

6-bromo

293

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

6-chloro

294

Ethyl

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

methyl

5-cyano

295

Me

Cyclohexyl—

S—(CH

2

)

3

—

methyl

5-cyano

296

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

6-methyl

7-methyl

297

Me

4-Methoxyphenyl

S—(CH

2

)3—

n-propyl

H

298

Me

Tetrazolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

299

Me

Tetrazolyl—

S—(CH

2

)3—

n-propyl

6-chloro

300

Me

Phenyl

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

7-methansulfonyloxy

301

Me

Amino

S—(CH

2

)

3

—

n-propyl

H

302

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

6-bromo

303

Me

6-Chloro-biphenyl-2—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

304

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

H

305

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

6-methyl

306

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

H

307

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

prop-2en-yl

7-methansulfonyloxy

308

Me

5-Methyl imidazol-4-yl—

S—(CH

2

)

3

—

n-propyl

5-cyano

309

Me

2,5-Di-methyl-furanyl-3—

S—(CH

2

)

3

—

n-propyl

6-methyl

310

Propyl

3-Cyano-phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

n-propyl

5-fluoro

311

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

6-methyl

312

Ethyl

3-Cyano-phenyl

S—(CH

2

)

8

—

n-propyl

5-fluoro

313

Me

2-Pyrazinyl—

COO—(CH

2

)

4

—

n-propyl

6-methyl

314

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

5-cyano

315

Me

Pyridin-3-yl—

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

316

Me

4-Imidazolyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

317

iProp

2-Aminothiazol-4yl—

S—(CH

2

)

3

—

n-propyl

6-chloro

318

nHexyl

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

7-methansulfonyloxy

319

Me

2-Me-4-Oxazolyl—

S—(CH

2

)

3

—

n-propyl

6-bromo

320

cycProp

3-Br-Pyridin-5-yl—

S—(CH

2

)3—

prop-2en-yl

7-methansulfonyloxy

321

Me

6-Chloro-biphenyl-2—

S—(CH

2

)3—

n-propyl

H

322

Me

Oxadiazol-2-yl

S—(CH

2

)3—

methyl

5-cyano

TABLE 2

Ex.

R

1

R

2

A

R

5

R

6

R

7

323

Ethyl

2,5-Di-methyl-fura-

S—(CH

2

)

3

—

n-propyl

5-bromo

nyl-3-

324

Me

4-Methylthiazol-5-yl

S—(CH

2

)

7

—

n-propyl

5-methyl

7-chloro

325

Ethyl

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-Propenyl

5-bromo

326

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

327

Me

3-Benzthienyl-

S—(CH

2

)

3

—

methyl

6-methoxy

328

cycProp

Cyclohexyl-

S—(CH

2

)

6

—

prop-2en-yl

6-methansulfonyloxy

329

Ethyl

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

5-bromo

330

Ethyl

3-Benzthienyl-

S—(CH

2

)

3

—

n-propyl

5-bromo

331

Ethyl

2,5-Di-methyl-fura-

S—(CH

2

)

3

—

methyl

4-cyano

nyl-3-

332

Me

Phenyl

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

6-methansulfonyloxy

333

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

334

Me

Pyridin-4-yl

S—(CH

2

)

3

—

n-propyl

4-cyano

335

Me

2,5-Di-methyl-fura-

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

nyl-3-

336

Me

2-Pyrazinyl-

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

5-methyl

337

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

6-methoxy

338

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

4-cyano

339

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

methyl

6-methoxy

340

Me

3-Jod-phenyl

COO—(CH

2

)

4

—

n-propyl

4-cyano

341

Propyl

3-Cyano-phenyl

S—CH

2

—C(CH

3

)═CH—CH2—

n-propyl

4-fluoro

342

Me

2-Me-4-Oxazolyl-

S—(CH

2

)3—

n-propyl

6-methoxy

343

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-propyl

H

344

Me

4-Imidazolyl-

S—(CH

2

)

3

—

n-propyl

5-methyl

345

Ethyl

Phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

prop-2en-yl

5-thiomethyl

346

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

4-cyano

347

Me

2-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

5-chloro

348

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

5-methyl

349

Me

2-Pyrazinyl-

S—(CH

2

)

7

—

but-2-en-yl

6-iod

350

Me

2-Pyrazinyl-

COO—(CH

2

)

4

—

n-propyl

5-methyl

351

Me

5-Methyl imida-

S—(CH

2

)

3

—

n-propyl

5-chloro

zol-4-yl-

352

Me

Pyridin-4-yl-

S—(CH

2

)

3

—

n-propyl

H

353

Me

2-Pyridin-3-yl

S—(CH

2

)3—

n-propyl

5-chloro

354

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

355

Me

2-Thienyl

S—(CH

2

)

3

—

methyl

4-cyano

356

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

5-chloro

357

Me

Tetrazolyl-

S—(CH

2

)

3

—

n-propyl

4-cyano

358

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

5-chloro

359

Me

Pyridin-3-yl-

S—(CH

2

)

3

—

n-Propenyl

5-methyl

360

Me

3-Thienyl

S—(CH

2

)

3

—

n-propyl

6-methoxy

361

Me

Phenyl

S—CH

2

-cycHex-CH

2

—

n-propyl

6-trifluoromethoxy

362

Ethyl

Phenyl

CO—(CH

2

)

3

—

but-2-en-yl

4-cyano

363

Me

3-Br-Pyridin-5-yl-

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

364

Me

Tetrazolyl-

S—(CH

2

)

3

—

n-propyl

H

365

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

4-cyano

366

Me

4-Methoxyphenyl

(CH

2

)

4

—

n-propyl

4-cyano

367

Me

Phenyl

O—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

368

Ethyl

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

6-methoxy

6-chloro

369

Me

Phenyl

S—(CH

2

)

3

—

prop-2-en-yl

H

370

Butyl

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

371

Me

Pyridin-3-yl-

O—(CH

2

)

3

—

n-propyl

5-bromo

372

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

methyl

4-cyano

373

Me

2-Pyrazinyl-

S—CH

2

-cycProp-CH

2

—

methyl

4-nitro

374

Me

2-Pyrazinyl-

S—(CH

2

)3—

n-propyl

5-methyl

6-methyl

375

Me

Amino

S—(CH

2

)

3

—

n-propyl

H

376

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

H

377

Butyl

2-Thienyl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

378

Ethyl

Amino

S—(CH

2

)

3

—

n-propyl

5-bromo

379

Me

4-Methoxyphenyl

S—CH

2

cycProp-(CH

2

)

2

—

but-2-en-yl

4-methoxy

380

iProp

Cyclohexyl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

381

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

4-cyano

382

Me

N-Propyl-tetrazolyl-

S—(CH

2

)

3

—

n-propyl

H

383

Me

2-Thienyl

COO—(CH

2

)

4

—

n-propyl

5-chloro

384

Me

2-Thienyl

S—(CH

2

)

3

—

n-ethyl

5-methxoxy

385

Ethyl

2-Thienyl

S—(CH

2

)

3

—

n-propyl

5-bromo

386

cycProp

3-Br-Pyridin-5-yl-

S—(CH

2

)

6

—

prop-2en-yl

6-methansulfonyloxy

387

Propyl

Methylamino

S—(CH

2

)

3

—

methyl

4-cyano

388

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

389

Ethyl

3-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

390

Me

Pyridin-3-yl

S—(CH

2

)

3

—

n-propyl

6-methoxy

391

Ethyl

4-Imidazolyl-

S—(CH

2

)

3

—

n-propyl

5-bromo

392

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

4-cyano

393

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

H

394

Me

3-Jod-phenyl

S—(CH

2

)

3

—

H

4-cyano

395

nHexyl

3-Pyrrolyl

S—(CH

2

)3—

n-propyl

6-methansulfonyloxy

396

Me

Phenyl

CONH—(CH

2

)

5

—

methyl

5-fluoro

397

Ethyl

Phenyl

(CH

2

)

4

—

but-2-en-yl

4-cyano

398

Me

Amino

S—(CH

2

)

3

—

n-propyl

5-chloro

399

cycProp

3-Pyrrolyl

S—(CH

2

)

6

—

prop-2en-yl

6-methansulfonyloxy

6-chloro

400

Ethyl

Phenyl

S—CH

2

)

7

—

methyl

5-fluoro

401

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

5-methyl

402

Me

4-Methoxyphenyl

S—CH

2

-cycProp-(CH

2

)

2

—

prop-2en-yl

5-thiomethyl

403

Ethyl

3-Jod-phenyl

S—(CH

2

)

3

—

H

5-chloro

6-chloro

404

Ethyl

N-Methyl-2-Pyrrolyl-

CO—CH

2

—C(═CH

2

)—CH

2

n-propyl

6-methoxy

405

Me

4-Methoxyphenyl

O—(CH

2

)

3

—

n-propyl

4-cyano

406

Ethyl

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-Propenyl

5-bromo

407

Me

3-Jod-phenyl

(CH

2

)

2

—CH(CH

3

)—CH

2

—CH

2

—

n-propyl

4-cyano

408

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

5-thiomethyl

409

Me

2-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

4-cyano

410

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

H

411

Me

N-Methyl-2-Pyrrolyl-

CONH—(CH

2

)

4

—

n-propyl

6-methoxy

412

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-Propenyl

5-methyl

413

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-propyl

4-cyano

414

Me

Phenyl

S—(CH

2

)

3

—

n-propyl

4-cyano

415

Ethyl

Phenyl

S—(CH

2

)

6

—

n-propyl

5-methoxy

6-chloro

416

Ethyl

Phenyl

S—(CH

2

)

6

—

but-2-en-yl

4-cyano

417

Me

Cyclohexyl-

S—(CH

2

)

7

—

n-propyl

5-chloro

6-chloro

418

Me

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

5-thiomethyl

419

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

H

420

Me

N-Propyl-tetrazolyl-

S—(CH

2

)

3

—

n-propyl

5-methyl

421

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

methyl

4-cyano

422

Me

Cyclohexyl-

S—(CH

2

)3—

n-propyl

4-cyano

423

Me

2-Me-4-Oxazolyl-

S—(CH

2

)

3

—

n-propyl

4-cyano

424

Me

Methylamino

S—(CH

2

)

3

—

n-propyl

5-chloro

425

Me

2-Pyrazinyl-

s—CH

2

—CH═CH—CH

2

—

n-propyl

5-methyl

426

cycProp

6-Chloro-biphenyl-2-

S—(CH

2

)

3

—

n-propyl

6-methoxy

427

Ethyl

3-Cyano-phenyl

S—(CH

2

)

8

—

n-propyl

4-fluoro

6-chloro

428

Ethyl

Phenyl

S—(CH

2

)

3

—

n-propyl

5-bromo

429

Butyl

Phenyl

O—(CH

2

)

3

—

methyl

5-fluoro

430

Me

4-Imidazolyl-

S—(CH

2

)

3

—

methyl

6-methoxy

431

Ethyl

Phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

but-2-en-yl

4-cyano

432

Me

Phenyl

COO—(CH

2

)

4

—

n-propyl

6-methanesulfonyloxy

433

Me

3-Jod-phenyl

S—(CH

2

)

3

—

methyl

4-cyano

434

Me

2,5-Di-methyl-fura-

S—(CH

2

)

3

—

n-propyl

4-cyano

nyl-3-

435

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

5-methyl

436

Me

Tetrzolyl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

437

Me

3-Br-Pyridin-5-yl

S—(CH

2

)

3

—

n-propyl

4-cyano

6-methyl

438

Me

Tetrazolyl-

S—(CH

2

)

3

—

n-Propenyl

5-methyl

439

Me

Pyridin-3-yl-

S—(CH

2

)3—

n-propyl

4-cyano

440

Me

3-Br-Pyridin-5-yl-

S—(CH

2

)

3

—

n-propyl

5-methyl

441

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

4-methansulfonyloxy

442

Me

3-Benzthienyl-

S—CH

2

)3—

n-propyl

5-methyl

443

Me

Pyridin-4-yl-

S—(CH

2

)

3

—

methyl

6-methoxy

444

Me

3-Jod-phenyl

S—CH

2

-cycProp-CH2-

but-2-en-yl

4-cyano

445

Me

2-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

H

446

Me

Phenyl

S—CH

2

-cycProp-CH2-

H

5-bromo

447

Me

Phenyl

O—(CH

2

)

3

—

methyl

5-fluoro

448

cycProp

2-Pyrazinyl-

S—(CH

2

)

3

—

prop-2en-yl

5-iod

449

Me

3-Cyano-phenyl

CONH—(CH

2

)

5

—

n-propyl

4-fluoro

450

nHexyl

2-Pyrazinyl-

S—(CH

2

)

3

—

prop-2en-yl

6-methansulfonyloxy

451

Me

Phenyl

S—CH

2

—CH═CH—CH

2

—

n-propyl

6-methansulfonyloxy

452

iProp

3-Br-Pyridin-5-yl-

S—(CH

2

)

3

—

n-propyl

5-chloro

453

Me

Phenyl

O—(CH

2

)

3

—

but-2-en-yl

4-cyano

454

Me

2-Thienyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

5-chloro

455

Me

Pyridin-3-yl-

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

456

Et

Phenyl

S—(CH

2

)

3

—

n-propyl

5-methoxy

6-methoxy

457

Propyl

Pyridin-3-yl

S—CH

2

—CH═CH—CH

2

—

n-propyl

5-bromo

458

Butyl

Tetrazolyl-

S—(CH

2

)

3

—

methyl

4-cyano

459

Me

3-Br-Pyridin-5-yl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

460

Me

2-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

5-methyl

461

Me

Pyridin-3-yl-

S—(CH

2

)

3

—

n-propyl

H

462

Me

3-Benzthienyl-

S—CH

2

)3—

n-propyl

5-chloro

463

Me

Phenyl

S—CH

2

-cycHex-CH

2

—CH

2

—

n-propyl

4-fluoro

464

Butyl

3-Cyano-phenyl

O—(CH

2

)

3

—

n-propyl

4-fluoro

465

Me

6-Chloro-biphenyl-2-

S—(CH

2

)

3

—

n-propyl

5-fluoro

466

Ethyl

3-Jod-phenyl

S—(CH

2

)

3

—

n-Propenyl

5-bromo

467

Ethyl

2-Me-4-Oxazolyl-

S—(CH

2

)

3

—

n-Propenyl

5-bromo

468

Me

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

5-chloro

469

Propyl

Phenyl

S—CH

2

—CH═CH—CH

2

—

methyl

5-fluoro

470

Me

3-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

471

Butyl

Phenyl

O—(CH

2

)

3

—

prop-2en-yl

5-thiomethyl

472

nHexyl

3-Cyano-phenyl

S—CH

2

—CH═CH—CH

2

—

prop-2en-yl

5-chloro

473

Me

5-Methyl imida-

S—(CH

2

)

3

—

n-propyl

4-cyano

zol-4-yl-

474

Me

2-Me-4-Oxazolyl-

S—(CH

2

)

3

—

n-propyl

5-chloro

475

Me

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

H

476

nHexyl

4-Methoxyphenyl

S—(CH

2

)

3

—

n-propyl

5-chloro

477

Me

2-Pyrazinyl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

478

Me

3-Jod-phenyl

S—CH

2

—C(CH═CH

2

)—CH

2

n-Propenyl

4-cyano

479

Me

4-Imidazolyl-

S—(CH

2

)

3

—

H

4-cyano

480

Ethyl

5-Methyl imida-

S—(CH

2

)

3

—

n-propyl

6-methoxy

zol-4-yl-

481

Me

Phenyl

COO—(CH

2

)

4

—

n-propyl

5-methoxy

482

Me

4-Methylthiazol-5-yl

CONH—(CH

2

)

4

—

n-propyl

6-trifluoromethoxy

483

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

6-methoxy

484

Me

4-Imidazolyl-

S—(CH

2

)

3

—

n-propyl

H

485

Me

2-Thienyl

O—(CH

2

)

3

—

n-propyl

5-chloro

486

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

5-chloro

487

Ethyl

Phenyl

S—CH

2

—C(CH

3

)═CH—CH

2

—

prop-2en-yl

5-chloro

488

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

5-chloro

489

Me

Pyridin-4-yl-

S—(CH

2

)

3

—

n-propyl

5-fluoro

490

Me

N-Propyl-tetrazolyl-

S—(CH

2

)

3

—

methyl

6-methoxy

491

Ethyl

Phenyl

S—(CH

2

)

7

—

prop-2en-yl

5-thiomethyl

492

cycProp

Oxadiazol-2-yl

S—(CH

2

)

3

—

n-propyl

6-methoxy

493

Me

4-Imidazolyl-

S—(CH

2

)3—

n-propyl

5-chloro

494

Me

4-Methylthiazol-5-yl

S—(CH

2

)

3

—

n-propyl

H

495

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

prop-2en-yl

5-methyl

496

Me

Phenyl

S—CH

2

-cycHex-CH

2

—CH

2

—

methyl

5-fluoro

497

Me

Pyridin-3-yl-

CONH—(CH

2

)

4

—

n-propyl

5-bromo

498

iProp

2-Aminothiazol-4yl-

S—(CH

2

)

4

—

n-propyl

5-chloro

6-bromo

499

Me

4-Methylthiazol-5-yl

S—(CH

2

)3—

n-propyl

4-cyano

500

Me

2-Aminothiazol-4yl-

S—(CH

2

)

3

—

n-propyl

6-methoxy

501

Me

4-Methoxyphenyl

COO—(CH

2

)

3

—

n-propyl

4-cyano

502

Me

N-Methyl-2-Pyrrolyl-

S—(CH

2

)

3

—

n-propyl

5-chloro

503

iProp

5-Methyl imida-

S—(CH

2

)

3

—

n-propyl

6-methansulfonyloxy

zol-4-yl-

504

Me

Cyclohexyl-

S—(CH

2

)

3

—

n-propyl

5-chloro

505

Me

3-Pyrrolyl

S—(CH

2

)

3

—

n-propyl

5-chloro

506

Ethyl

6-Chloro-biphenyl-2-

S—(CH

2

)

3

—

prop-2en-yl

5-bromo

507

Me

2-Thienyl

S—(CH

2

)

3

—

n-propyl

H

508

Ethyl

Pyridin-3-yl-

S—(CH

2

)

3

—

prop-2en-yl

5-bromo

509

cycProp

5-Methyl imida-

S—(CH

2

)

3

—

prop-2en-yl

6-methansulfonyloxy

zol-4-yl-

510

Me

Pyridin-3-yl-

S—(CH

2

)

3

—

methyl

4-cyano

511

Propyl

4-Methylthiazol-5-yl

S—CH

2

—CH═CH—CH

2

—

n-propyl

6-trifluoromethoxy

512

Ethyl

Phenyl

CO—(CH

2

)

3

—

prop-2en-yl

5-chloro

513

Me

2,5-Di-methyl-fura-

S—(CH

2

)

3

—

n-propyl

6-methoxy

H

nyl-3-

514

Me

2-Thienyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

5-chloro

515

Me

5-Methyl imida-

S—(CH

2

)

3

—

prop-2en-yl

6-cyano

/-methyl

zol-4-yl-

516

Me

Phenyl

(CH

2

)

4

—

n-propyl

5-methoxy

517

Me

4-Methoxyphenyl

S—CH

2

—C(═CH

2

)—CH

2

n-propyl

4-cyano

518

Me

Pyridin-4-yl-

S—(CH

2

)

3

—

n-propyl

5-methyl

519

Me

4-Jod-phenyl

S—(CH

2

)

3

—

n-propyl

6-methoxy

520

Me

3-Cyano-phenyl

S—(CH

2

)

3

—

n-propyl

5-methyl

If no meaning is given, R

7

is hydrogen.

Examples of pharmaceutical administration forms

A) Tablets

Tablets of the following composition were pressed on a tabletting machine in the customary manner

40 mg of the substance from Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silicic acid in a submicroscopically fine dispersion)

6.75 mg of potato starch (as a 6% paste)

B) Sugar-coated Tablets

20 mg of the substance from Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone-vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets which have been prepared in this way are then provided with an enteric coating.

Biological investigations—receptor binding studies

1) D

3

Binding Test

Cloned human D

3

-receptor-expressing CCL 1,3 mouse fibroblasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D

3

-expressing cells were multiplied in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U of penicillin/ml and 0.2% streptomycin (GIBO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated for 5 min with 0.05% trypsin-containing PBS. After that, the mixture was neutralized with medium and the cells were collected by centrifuging at 300 g. In order to lyse the cells, the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and after that incubated, at 4° C. for 30 min, at a concentration of 10

7

cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding Tests

For the D

3

-receptor binding test, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl

2

, 2 mM MgCl

2

, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10

6

cells/250 μl of test mixture, and incubated at 30° C. for 0.1 nM

125

iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10

−6

M spiperone.

After 60 min, the free radioligand and the bound radioligand were separated by filtering through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway), and the filters were washed with ice-cold Tris-HCl buffer, pH-7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K

i

values were determined by means of nonlinear regression analysis using the LIGAND program.

D

2

binding Test

Cell Culture

HEK-293 cells possessing stably expressed human dopamine D2A receptors were cultured in RPMI 1640 containing Glutamix I™ and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of penicillin per mol and 100 μg/ml of streptomycin/ml. The cells were maintained at 37° C. in a moist atmosphere containing 5% CO

2

.

The cells were prepared for the binding studies by trypsinizing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4° C. for 30 minutes. After centrifuging at 250 g for 10 minutes, the residue was stored at −20° C. until used.

Receptor Binding Tests

Low affinity state dopamine D

2

receptor using

125

I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The test mixtures (1 ml) consisted of 1×10

5

cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl

2

and 2 mM CaCl

2

, pH 7.4 with HCl) and 0.1 mM

125

I-spiperone (total binding) or additionally 1 μM haloperidol (nonspecific binding) or test substance.

After the test mixtures had been incubated at 25° C. for 60 minutes, they were filtered through GM/B glass filters (Whatman, England) on a Skatron cell harvester (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The results were evaluated as described in a).

The K

i

values were determined by way of nonlinear regression analysis using the LIGAND program or by converting the IC

50

values using the Cheng and Prusoff formula.

In these tests, the compounds according to the invention exhibit very good affinities for the D

3

receptor (<1μ molar, in particular <200 nmolar) and bond selectively to the D

3

receptor.

In table 3 the pK

i

-D

3

values and selectivity (K

i

(D

2

)/K

i

(D

3

)) are given for the compounds of the examples 1, 14 and 26.

TABLE 3

Example

pK

i

(D

3

)*

Selectivity

1

9.05

71

14

7.82

46

26

8.06

157

*negative logarithm of K

i

(D

3

) [M]

Number	Name	Date	Kind
4338453	Gall	Jul 1982	A
4408049	Gall	Oct 1983	A
4577020	Gall	Mar 1986	A
5387591	Lavielle et al.	Feb 1995	A
5407946	Lavielle et al.	Apr 1995	A
5663191	Lavielle et al.	Sep 1997	A
5723484	Lavielle et al.	Mar 1998	A
5872119	Wermuth et al.	Feb 1999	A
5968954	Peglion et al.	Oct 1999	A
5985895	Wermuth et al.	Nov 1999	A

Number	Date	Country
2195243	Feb 1996	CA
2242015	Dec 1998	CA
44 25 144	Jan 1996	DE
WO 9220655	Nov 1992	WO
WO 9308799	May 1993	WO
WO 9425013	Nov 1994	WO
WO 9630333	Oct 1996	WO
WO 9631512	Oct 1996	WO
WO 9710210	Mar 1997	WO
WO 9717326	May 1997	WO
WO 9725324	Jul 1997	WO
WO 9740015	Oct 1997	WO
WO 9743262	Nov 1997	WO
WO 9747602	Dec 1997	WO
WO 9806699	Feb 1998	WO
WO 9824791	Jun 1998	WO
WO 9849145	Nov 1998	WO
WO 9850363	Nov 1998	WO
WO 9850364	Nov 1998	WO
WO 9851671	Nov 1998	WO
WO 9902503	Jan 1999	WO

Triazole compounds with dopamine-D3-receptor affinity

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

PCT Information

US Referenced Citations (10)

Foreign Referenced Citations (21)

Non-Patent Literature Citations (6)

Entry
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Sokoloff et al. “Localization and Function of the D3 Dopamine Receptor” Arzneim-Forsch/Drug Res. vol. 42 No. 1(1992) pp. 224-230.
Dooley et al. “Pramipexole-A Review of it Use in the Management of Early and Advanced Parkinson's Disease” Drug & Aging vol. 12 No. 6 (1998) pp. 496-514.
Schwartz et al. “The Dopamine D3 Receptor as a Targe for Anti Psychotics” Novel Antipsychotic Drugs (1992) pp. 135-144.
Czarnocka-Janowicz et al. “Synthesis and Pharmacological activity of 5-substituteds-s-triazole-thiols” Pharmazie No. 46 (1991) pp. 109-112.
Dubuffet et al. “Novel Benzopyrano[3,4-c]pyrrole Derivatives As Potent and selective dopamine D3 Receptor Antagonists” Biororganic Medicinal Chemistry Letters No. 9 (1999) pp 2059-2064.