Use of thiazole and thiadiazole compounds

Abstract

The present invention relates to the use of thiazole and thiadiazole compounds of the following formula: ##STR1## where R.sup.1, A, B and Ar have the meanings stated in the description. The compounds according to the invention have a high affinity for the dopamine D.sub.3 receptor and can therefore be used to treat disorders of the central nervous system.

Description

The invention relates to the use of thiazole and thiadiazole compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D.sub.3 receptor ligands.

Compounds which are of the type under discussion here and have physiological activities have been disclosed. Thus, U.S. Pat. No. 4,074,049 describes aminoalkylthiothiadiazoles which act as fungicides and blood platelet aggregation inhibitors. JP-A-2 153 276 describes similar compounds which are used to treat liver disorders.

GB-A-1 053 085 describes aminoalkylthiadiazoles which show antitussive, analgesic, antipyretic and hypoglycemic effects. U.S. Pat. No. 3,717,651 describes 5-mercapto-substituted thiazoles which have herbicidal properties.

WO 89/11 476 describes substituted 2-aminothiazoles as dopaminergic agents which can be used, inter alia, for treating psychoses and disorders of the CNS.

WO 92/22 540 describes aminoalkyl-substituted 5-mercaptothiazoles of the formula: ##STR2## where R.sup.1 is H, C.sub.1 -C.sub.5 -alkyl, unsubstituted or substituted phenyl or thienyl; n is 2-6; and A is ##STR3## where Ar is a phenyl ring which is unsubstituted or substituted once by C.sub.1 -C.sub.5 -alkyl, C.sub.1 -C.sub.5 -alkoxy, amino, halogen, nitro, hydroxyl, trifluoromethyl or cyano, or a pyridyl, pyrimidinyl or thienyl radical. These compounds can be used to treat disorders of the central nervous system, eg. Parkinsonism, schizophrenia and disorders associated with elevated blood pressure.

WO 92/22 542 describes the corresponding 2-amino-5-mercapto-1,3,4-thiadiazole derivatives which can likewise be used to treat disorders of the central nervous system and disorders associated with elevated blood pressure.

WO 92/22 541 describes corresponding 2-amino-1,3,4-thiadiazole derivatives where the alkylene chain is linked directly, not via a sulfur atom, to the thiadiazole residue. These compounds can also be used for treating disorders of the central nervous system and disorders associated with elevated blood pressure.

WO 93/21 179 describes 1-aryl-4-(.omega.-amido-1-alkyl and .omega.-imido-1-alkyl)piperazine compounds. These compounds are dopamine D.sub.2 receptor antagonists and 5-HT.sub.1A receptor agonists. They can be used as antipsychotic agents, for example for treating schizophrenia.

Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.

Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.

By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D.sub.1 and D.sub.2 receptors.

Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D.sub.3 receptors. They are expressed mainly in the limbic system. The D.sub.3 receptors differ structurally from the D.sub.1 and D.sub.2 receptors in about half the amino-acid residues.

The effect of neuroleptics has generally been ascribed to their affinity for D.sub.2 receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D.sub.2 receptors but only low affinity for D.sub.3 receptors.

The prior art compounds described above are such D.sub.2 receptor agonists or antagonists.

We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D.sub.3 receptor and only a low affinity for the D.sub.2 receptor. They are thus selective D.sub.3 ligands.

The present invention therefore relates to the use of thiazole and thiadiazole compounds of the formula I: ##STR4## where A is a straight-chain or branched C.sub.1 -C.sub.18 -alkylene group which may comprise at least one group selected from O, S, NR.sup.3, CONR.sup.3, NR.sup.3 CO, COO, OCO or a double or triple bond,

B is a radical of the formula: ##STR5## R.sup.1 is H, halogen, CN, CO.sub.2 R.sup.2, NR.sup.2 R.sup.3, OR.sup.3, CF.sub.3 or C.sub.1 -C.sub.8 -alkyl, which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen; R.sup.2 is H, C.sub.1 -C.sub.8 -alkyl, which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen or phenyl-C.sub.1 -C.sub.8 -alkyl; R.sup.3 has the meanings indicated for R.sup.2 or is COR.sup.2 or CO.sub.2 R.sup.2 ; X is N or CR.sup.4 where R.sup.4 is H, C.sub.1 -C.sub.8 -alkyl which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen, or is phenyl which is unsubstituted or substituted by halogen, CF.sub.3, C.sub.1 -C.sub.8 -alkyl or C.sub.1 -C.sub.8 -alkoxy; Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have from one to four substituents which are selected, independently of one another, from H, OR.sup.3, C.sub.1 -C.sub.8 -alkyl, C.sub.2 -C.sub.8 -alkenyl, C.sub.2 -C.sub.8 -alkynyl, halogen, CN, CO.sub.2 R.sup.2, NO.sub.2, SO.sub.2 R.sup.2, SO.sub.3 R.sup.2, NR.sup.2 R.sup.3, SO.sub.2 NR.sup.2 R.sup.3, SR.sup.2, CF.sub.3, CH.sub.2, a 5- or 6-membered carbocyclic aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring having 1 to 3 hetero atoms selected from O, S and N, where the carbocyclic or the heterocyclic ring is unsubstituted or substituted by C.sub.1 -C.sub.8 -alkyl, halogen, OC.sub.1 -C.sub.8 -alkyl, OH, NO.sub.2 or CF.sub.3 and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above, and the salts thereof with physiologically tolerated acids for producing a pharmaceutical composition for treating disorders which respond to dopamine D.sub.3 receptor antagonists or agonists.

The compounds used according to the invention are selective dopamine D.sub.3 receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D.sub.2 receptor, have fewer side effects than classical neuroleptics. The compounds can therefore be used to treat disorders which respond to dopamine D.sub.3 receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.

Within the scope of the present invention, the following terms have the meanings indicated below:

Alkyl (also in radicals such as alkoxy, alkylamino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from among OH and OC.sub.1 -C.sub.8 -alkyl.

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

Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 14 carbon atoms, particularly preferably 3 to 12 carbon atoms and, in particular, 7 to 12 carbon atoms.

The alkylene groups may comprise at least one of the abovementioned groups. This can--just like the double or triple bond mentioned--be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the thiazole or thiadiazole residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.

Halogen is F, Cl, Br, I and, in particular, F, Cl, Br.

R.sup.1 is preferably H, OR.sup.3 or NR.sup.2 R.sup.3, where R.sup.2 and R.sup.3 are, independently of one another, H or C.sub.1 -C.sub.8 -alkyl.

Ar can have one, two, three or four substituents.

They are preferably selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen, or phenyl, naphthyl, C.sub.3 -C.sub.8 -cycloalkyl, a 5- or 6-membered heterocyclic aromatic or nonaromatic radical with 1 to 3 hetero atoms selected from O, N and S, CHF.sub.2, CF.sub.3, halogen, NO.sub.2, CN, OR.sup.3 or SR.sup.2, where R.sup.2 and R.sup.3 have the abovementioned meanings.

If one of the substituents of Ar is C.sub.1 -C.sub.8 -alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.

Ar preferably has at least one substituent and is, in particular, ##STR6## where D.sup.1, D.sup.2 and D.sup.3 are, independently of one another, CR or N, and R, Y and Z are H or have the meanings indicated above or below.

Ar is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.

When one of the substituents of Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.

When one of the substituents of Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.

A preferred embodiment comprises the compounds of the formula I where A is C.sub.3 -C.sub.14 -alkylene, in particular C.sub.3 -C.sub.12 -alkylene, which may comprise at least one group selected from O, S, NR.sup.3 and a double or triple bond.

Another preferred embodiment comprises the use of compounds of the formula I where

R.sup.1 is H, OR.sup.3 or NR.sup.2 R.sup.3, where R.sup.2 and R.sup.3 are, independently of one another, H, C.sub.1 -C.sub.8 -alkyl or phenyl-C.sub.1 -C.sub.8 -alkyl, R.sup.4 is H or C.sub.1 -C.sub.8 -alkyl when X is CR.sup.4 ; A is C.sub.3 -C.sub.12 -alkylene which may comprise at least one group selected from O, S, NR.sup.3 and a double or triple bond; Ar is phenyl, pyrimidyl or pyridyl which may have one, two, three or four substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen or phenyl, naphthyl, C.sub.3 -C.sub.8 -cycloalkyl, a 5- or 6-membered heterocyclic aromatic or nonaromatic radical with 1 to 3 hetero atoms selected from O, N and S, CHF.sub.2, CF.sub.3, halogen, NO.sub.2, CN, OR.sup.3 or SR.sup.2, where R.sup.2 and R.sup.3 have the abovementioned meanings.

Particularly preferred compounds in this connection are those of the formula I where

B is ##STR7##

Another preferred embodiment is the use of the compounds of the formula I where

Ar is phenyl which has one, two, three or four substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl, phenyl, naphthyl, pyrrolyl, CHF.sub.2, CF.sub.3, halogen, NO.sub.2, CN, OH, OC.sub.1 -C.sub.8 -alkyl, SH and SC.sub.1 -C.sub.8 -alkyl. Ar is particularly preferably phenyl with one or two substituents in position 3 or position 3,5.

Another preferred embodiment is the use of compounds of the formula I where Ar is pyrimidinyl which has one to three substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl, naphthyl, pyrrolyl, OH, OC.sub.1 -C.sub.8 -alkyl, CHF.sub.2, CF.sub.3 and halogen, or where Ar is pyridinyl which has one to four substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl, C.sub.2 -C.sub.8 -alkenyl, C.sub.2 -C.sub.8 -alkynyl, phenyl, naphthyl, pyrrolyl, OR, OC.sub.1 -C.sub.8 -alkyl, CHF.sub.2, CF.sub.3, CN and halogen.

The invention also relates to the compounds of the formula I where A is a straight-chain or branched C.sub.7 -C.sub.18 -alkylene group which may comprise a group which is selected from among O, S, NR.sup.3, CONR.sup.3, NR.sup.3 CO, COO, OCO or double or triple bond, and R.sup.1, R.sup.3, B and Ar have the abovementioned meanings.

The invention also embraces 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, Volume 10, pages 224 et seq., Birkhauser Verlag, Basel and Stuttgart, 1966.

The compounds of the formulae �sic! I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the tautomeric forms in each case.

The compounds of the formulae �sic! I can be prepared by methods similar to conventional ones as described, for example, in Houben Weyl, "Handbuch der Organishen Chemie", Ernst Schaumann (Ed.), 4th Ed. Thieme Verlag, Stuttgart 1994, Volume Es/d, pages 189 et seq.; A. R. Katritzky, C. W. Rees (ed.) "Comprehensive Heterocyclic Chemistry", 1st Ed. and literature cited therein. The process for preparing the compounds comprises

i) reacting a compound of the general formula II: ##STR8## where Y.sup.1 is a conventional leaving group, with a compound of the general formula III: H--B--Ar ii) to prepare a compound of the formula I where A comprises an oxygen or sulfur atom or NR.sup.3, a) reacting a compound of the general formula IV: ##STR9## where Z.sup.1 is O, S or NR.sup.3, and A.sup.1 is C.sub.0 -C.sub.18 -alkylene, with a compound of the general formula VI Y.sup.1 --A.sup.2 --B--Ar where Y.sup.1 has the abovementioned meanings, and A.sup.2 is C.sub.1 -C.sub.18 -alkylene, where A.sup.1 and A.sup.2 together have 7 to 18 carbon atoms; iii) to prepare a compound of the formula I where A comprises the group COO or CONR.sup.3 : a) reacting a compound of the general formula VII: ##STR10## where Y.sup.2 is OH, OC.sub.1 -C.sub.4 -alkyl, Cl or, together with CO, is an activated carboxyl group, and A.sup.1 has the abovementioned meanings, with a compound of the formula VIII: Z.sup.1 --A.sup.2 --B--Ar where A.sup.2 has the abovementioned meanings, and Z.sup.1 is OH or NHR.sup.3, iv) to prepare a compound of the formula I where A comprises the group OCO or NR.sup.3 CO: a) reacting a compound of the formula IV ##STR11## where Z.sup.1 is O, or NR.sup.3, with a compound of the formula X: Y.sup.2 CO--A.sup.2 --B--Ar where A.sup.2 and Y.sup.2 have the abovementioned meanings, and where R.sup.1, R.sup.2, A, B and Ar have the abovementioned meanings.

To treat the abovementioned disorders, the compounds according to the invention are administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which contain the compounds according to the invention. These compositions are in the usual solid or liquid pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. The active substances can in these cases be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount from 1 to 99% by weight.

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

EXAMPLE 1 ##STR12##

a) 2-Amino-5-(6-chlorohexylmercapto)-1,3,4-thiadiazole

5 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 7.5 g of 1,6-bromochlorohexane �sic! and 4.07 g of triethylamine were refluxed in 100 ml of tetrahydrofuran for 1 hour. The mixture was filtered with suction, the filtrate was concentrated, and the residue was washed with water and then dried. 8.2 g (=91% yield) of product remained.

b) 2-Amino-5-(6-(3,5-dichlorophenylpiperazinyl)hexylmercapto)-1,3,4-thiadiazole) �sic!

2.2 g of product from la), 2.08 g of 3,5-dichloro-phenylpiperazine and 1 g of triethylamine in 4 ml of DMF were heated at 100.degree. C. for 1 hour. Water was added to the mixture and, after extracting 3 times with methylene chloride, drying over MgSO.sub.4 and concentrating, the residue was purified by chromatography (mobile phase: CH.sub.2 Cl/CH.sub.3 OH �sic!=9/1). 1.0 g (=25% yield) of product was obtained. Melting point: 130.degree. C.

EXAMPLE 2 ##STR13##

a) 5-Amino-2-(6-bromohexyl)-1,3,4-thiadiazole

5 g of 7-bromoheptanoic acid and 2.17 g of thiosemicarbazide were introduced into 50 ml of dioxane at 90.degree. C. and, at this temperature, 4.0 g of POCl.sub.3 were added dropwise. The mixture was then stirred at 90.degree. C. for 1 hour. Then water was added to the mixture, and extraction 3 times with methylene chloride, drying over MgSO.sub.4 and concentration were carried out. 6.1 g (=96% yield) of product were obtained as residue.

b) 2.5 g of product 2a), 2.18 g of u-trifluoromethylphenylpiperazine and 1.92 g of triethylamine in 3 ml of DMF were stirred at 100.degree. C. for 1 hour. Workup took place as for lb). 1.4 g (=36% yield) of product were obtained. Melting point: 134-136.degree. C.

The compounds indicated in Tables 1 to 3 below were prepared in a similar manner.

The compounds listed in Tables 4 to 8 below can likewise be prepared in a similar manner.

TABLE 1__________________________________________________________________________ physical data, H-NMR �&, ppm!No. Example mp. �.degree. C.!__________________________________________________________________________ 3 1 #STR14## 1.8(2H); 2.4(6H); 3.08(2H); 3.13(4H); 6.9(2H); 7.05(1H); 7.12(1H); 7.3(2H) 4 2 #STR15## 1.8(2H; 2.43(6H); 3.1(2H); 3.18(4H); 7.1(1H); 7.25(4H); 7.35(1H) 5 3 #STR16## 191-194 6 4 #STR17## 140-143 7 5 #STR18## 117-119 8 6 #STR19## 1.5(4H); 1.8(2H); 2.4(2H); 2.6(4H); 3.18(2H; 3.22(4H); 5.1(2H); 7.1(3H); 7.3(1H) 9 7 #STR20## 1.8(2H); 2.45(6H); 3.1(2H); 3.15(4H); 6.55(1H; 6.75(2H); 7.2(1H); 7.3(2H)10 8 #STR21## 1.25(3H); 1.5(4H); 1.78(2H); 2.4(2H); 2.6(6H); 3.2(6H); 5.1(2H); 6.75(3H); 7.2(1H)11 9 #STR22## 1.3(9H); 1.5(4H); 1.8(2H); 2.4(2H); 2.6(4H); 3.2(6H); 5.25(2H); 6.75(1H); 6.95(1H); 7.0(1H); 7.21(1H)12 0 #STR23## 1.4(3H); 1.5(4H); 1.8(2H); 2.35(2H); 2.55(4H); 3.18(6H); 4.0(2H); 5.2(2H); 6.4(1H); 6.48(1H); 6.53(1H); 7.15(1H)13 1 #STR24## 1.82(2H); 2.45(6H); 3.1(2H); 3.2(4H); 6.85(1H); 6.95(2H); 7.3(2H)14 2 #STR25## 146-14915 3 #STR26## 1.4(4H); 1.65(2H); 2.25(2H); 2.4(4H); 3.05(2H); 3.2(4H); 6.82(1H); 6.95(2H); 7.3(2H)16 4 #STR27## 96-11017 5 #STR28## 2.0(2H; 2.48(3H); 2.51(2H); 2.58(4H); 3.2(6H); 5.38(2H); 6.75(2H); 6.82(1H); 7.17(1H)18 6 #STR29## 1.5(4H); 1.8(2H); 2.4(2H); 2.48(3H); 2.6(4H); 3.15(6H); 5.2(2H); 6.75(2H); 6.82(1H); 7.2(1H)19 7 #STR30## 1.7(2H); 1.8(2H); 2.4(2H); 2.6(4H); 3.05(3H); 3.15(2H); 3.22(4H); 5.7(1H); 7.1(3H); 7.35(1H)20 8 #STR31## 1.55(4H); 1.8(2H); 2.4(2H); 2.6(4H); 3.2(2H); 3.25(4H); 5.15(2H); 6.6(1H); 7.0(2H); 7.03(1H); 7.32(1H)21 9 #STR32## 2.0(2H); 2.55(2H); 2.6(4H); 3.22(4H) 3.3(2H); 7.1(3H); 7.22(1H); 7.35(1H); 7.7(1H)22 0 #STR33## 1.2(6H); 1.95(2H); 2.5(2H); 2.6(4H); 2.85(1H); 3.15(6H); 6.05(2H); 6.75(2H); 6.8(1H); 6.18(1H)23 1 #STR34## 170-17524 2 #STR35## 220-222 (Hydrochloride)25 3 #STR36## 2.08(2H); 2.55(2H); 2.6(4H); 3.25(4H); 3.45(2H); 7.1(3H), 7.3(1H); 9.0(1H)26 4 #STR37## 1.8(2H); 2.5(2H); 2.6(4H); 2.7(2H); 3.22(4H); 5.6(2H); 7.05(4H); 7.35(1H)27 5 #STR38## 106-11228 6 #STR39## 1.85(2H); 2.5(2H); 2.6(2H); 3.1(4H); 3.35(2H); 6.3(1H); 7.3(2H); 7.6(2H); 7.75(2H)29 7 #STR40## 1.45(4H); 1.68(2H); 2.4(2H); 2.6(2H); 3.05(4H); 3.3(2H); 6.3(1H); 7.28(2H); 7.6(2H); 7.75(2H)30 8 #STR41## 128-130 (Dihydrochloride)31 9 #STR42## 1.83(2H); 2.43(2H); 2.5(4H); 3.1(2H); 3.15(4H), 6.92(1H); 6.96(1H); 7.1(2H); 7.3(2H); 7.35(1H)32 0 #STR43## 129-13033 1 #STR44## 2.55(2H); 2.75(3H); 3.25(2H); 3.45(2H); 3.7(8H); 7.05(1H); 7.13(1H); 7.19(1H); 7.4(1H); (Dihydrochloride)34 2 #STR45## 2.0(2H); 2.55(2H); 2.6(4H); 3.05(3H); 3.2(6H); 7.1(3H); 7.35(1H)35 3 #STR46## 1.6(4H); 2.3(2H); 2.5(4H); 3.05(2H); 3.2(4H); 7.02(1H); 7.1(1H); 7.2(1H); 7.3(2H); 7.4(1H)36 4 #STR47## 1.45(4H); 1.65(2H); 2.3(2H); 2.5(4H); 3.05(2H); 3.2(4H); 7.05(1H); 7.15(1H); 7.2(1H); 7.3(2H); 7.4(1H)37 5 #STR48## 12038 6 #STR49## 188-190 (Trihydrachloride)39 7 #STR50## 107-11040 8 #STR51## 131-13241 9 #STR52## 134-13542 0 #STR53## 108-10943 1 #STR54## 140-14144 2 #STR55## 137-13945 3 #STR56## 127-13046 4 #STR57## 139-142__________________________________________________________________________ TABLE 2______________________________________1 #STR58##Ex. No. R.sup.1 R.sup.6 A mp. �.degree.C.!______________________________________47 NH.sub.2 CF.sub.3 S--CH.sub.2 C(CH.sub.3).dbd.CHCH.sub.2 -- 152-154.degree.48 NH.sub.2 CF.sub.3 S--(CH.sub.2).sub.9 -- 118-123.degree.49 NH.sub.2 iProp S--(CH.sub.2).sub.7 -- 98-101.degree.50 NH.sub.2 CN S--(CH.sub.2).sub.7 -- 162-166.degree.51 NH.sub.2 CN S--(CH.sub.2).sub.8 -- 98-102.degree.52 NH.sub.2 iProp S--(CH.sub.2).sub.8 -- 95-99.degree.______________________________________ TABLE 3______________________________________2 #STR59##Ex.No. R.sup.1 R.sup.6 R.sup.8 D A mp. �.degree.C.!______________________________________53 NH.sub.2 CF.sub.3 H CH S--CH.sub.2 CH.dbd.CHCH.sub.2 -- 116-119.degree.54 NH.sub.2 1- CH.sub.3 N S--(CH.sub.2).sub.5 -- 145-148.degree. Pyrrolyl55 NH.sub.2 tBut CF.sub.3 N S--(CH.sub.2).sub.3 -- 128-130.degree.56 NH.sub.2 1- CH.sub.3 N S--(CH.sub.2).sub.3 -- 130-132.degree. Pyrrolyl57 NH.sub.2 iProp CF.sub.3 N S--(CH.sub.2).sub.3 -- 109-111.degree.58 NH.sub.2 tBut tBut N S--(CH.sub.2).sub.3 -- 142-145.degree.______________________________________ TABLE 4__________________________________________________________________________3 #STR60##Ex. No. R1 R5 R6 R7 R8 R9 X--Y A__________________________________________________________________________59 NH.sub.2 H tBut H Me H CH.sub.2 --N S--(CH.sub.2).sub.3 --60 NH.sub.2 H tBut H Ph H CH.sub.2 --N S--(CH.sub.2).sub.3 --61 NH.sub.2 H tBut H 1-Pyrrolyl H CH.sub.2 --N NH--(CH.sub.2).sub.3 --62 NH.sub.2 H iProp H 2-Napht H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --63 NH.sub.2 H Et H tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --64 NH.sub.2 OMe tBut H H H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --65 NH.sub.2 OMe CF.sub.3 H H H CH.dbd.C S--(CH.sub.2).sub.3 --66 NH.sub.2 H CF.sub.3 H tBut H CH.sub.2 --N NH--(CH.sub.2).sub.3 --67 NH.sub.2 OiProp iProp H H H CH.sub.2 --N S--(CH.sub.2).sub.3 --68 NH.sub.2 H H CN tBut H CH.sub.2 --N O--(CH.sub.2).sub.3 --69 NH.sub.2 H H F tBut H CH.dbd.C S--(CH.sub.2).sub.3 --70 NH.sub.2 H H Cl iProp H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --71 NH.sub.2 H tBut H H OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --72 NH.sub.2 OMe tBut H tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --73 NH.sub.2 OMe tBut H CF.sub.3 H CH.sub.2 --N S--(CH.sub.2).sub.3 --74 NH.sub.2 OMe CF.sub.3 H tBut H CH.sub.2 --N NH--(CH.sub.2).sub.3 --75 NH.sub.2 H nProp CN tBut H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --76 NH.sub.2 H CF.sub.3 CN iProp H CH.sub.2 --N S--(CH.sub.2).sub.3 --77 NH.sub.2 H Ph C.dbd.CH tBut H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --78 NH.sub.2 OMe tBut CN H H CH.dbd.C S--(CH.sub.2).sub.3 --79 NH.sub.2 H tBut CN CF.sub.3 OMe CH.sub.2 --N NH--(CH.sub.2).sub.3 --80 NH.sub.2 OMe nProp F tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --81 NH.sub.2 H Ph CN tBut Me CH.sub.2 --N O--(CH.sub.2).sub.3 --82 NH.sub.2 OMe tBut F H H CH.dbd.C S--(CH.sub.2).sub.3 --83 NH.sub.2 H iProp H H OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --84 NH.sub.2 H tBut H Me H CH.sub.2 --N S--(CH.sub.2).sub.3 --85 NH.sub.2 H tBut H Ph H CH.sub.2 --N NH--(CH.sub.2).sub.4 --86 NH.sub.2 H tBut H 1-Pyrrolyl H CH.sub.2 --N S--(CH.sub.2).sub.4 --87 NH.sub.2 H iProp H 2-Napht H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --88 NH.sub.2 H Et H tBut H CH.sub.2 --N S--(CH.sub.2).sub.5 --89 NH.sub.2 OMe tBut H H H CH.sub.2 --N O--(CH.sub.2).sub.5 --90 NH.sub.2 OMe CF.sub.3 H H H CH.dbd.C NH--(CH.sub.2).sub.4 --91 NH.sub.2 H CF.sub.3 H tBut H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.4 --92 NH.sub.2 OiProp iProp H H H CH.dbd.C S--(CH.sub.2).sub.3 --93 NH.sub.2 H H CN tBut H CH.sub.2 --N NH--(CH.sub.2).sub.3 --94 NH.sub.2 H H F tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --95 NH.sub.2 H H Cl iProp H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --96 NH.sub.2 H tBut H H OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --97 NH.sub.2 OMe tBut H tBut H CH.sub.2 --N S--(CH.sub.2).sub.4 --98 NH.sub.2 OMe tBut H CF.sub.3 H CH.sub.2 --N S--(CH.sub.2).sub.3 --99 NH.sub.2 OMe CF.sub.3 H tBut H CH.sub.2 --N NH--(CH.sub.2).sub.5 --100 NH.sub.2 H nProp CN tBut H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --101 NH.sub.2 H CF.sub.3 CN iProp H CH.sub.2 --N S--(CH.sub.2).sub.4 --102 NH.sub.2 H Ph C.dbd.CH tBut H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --103 NH.sub.2 OMe tBut CN H H CH.dbd.C S--(CH.sub.2).sub.6 --104 NH.sub.2 H tBut CN CF.sub.3 OMe CH.sub.2 --N NH--(CH.sub.2).sub.3 --105 NH.sub.2 OMe nProp F tBut H CH.sub.2 --N S--(CH.sub.2).sub.5 --106 NH.sub.2 H Ph CN tBut Me CH.sub.2 --N O--(CH.sub.2).sub.3 --107 NH.sub.2 OMe tBut F H H CH.dbd.C S--(CH.sub.2).sub.4 --108 NH.sub.2 H iProp H H OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --109 NHMe H tBut H Me H CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --110 NHMe H tBut H Ph H CH.sub.2 --N --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --111 NHMe H tBut H 1-Pyrrolyl H CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --112 NHMe H iProp H 2-Napht H CH.sub.2 --N NH--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub. 2 --113 NHMe H Et H tBut H CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --114 OH OMe tBut H H H CH.sub.2 --N --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH --CH.sub.2 --115 OH OMe CF.sub.3 H H H CH.sub.3 --N NH--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub. 2 --116 OH H CF.sub.3 H tBut H CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --117 OH OiProp iProp H H H CH.dbd.C --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --118 OMe H H CN tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --119 OMe H H F tBut H CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --120 OMe H H Cl iProp H CH.dbd.C O--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --121 OMe H tBut H H OMe CH.dbd.C NH--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub. 2 --122 NHMe OMe tBut H tBut H CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --123 NHMe OMe tBut H CF.sub.3 H CH.sub.2 --N --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --124 NHMe OMe CF.sub.3 H tBut H CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --125 NHMe H nProp CN tBut H CH.sub.2 --N NH--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub. 2 --126 NHMe H CF.sub.3 CN iProp H CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --127 OH H Ph C.dbd.CH tBut H CH.sub.2 --N --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH --CH.sub.2 --128 OH OMe tBut CN H H CH.sub.2 --N NH--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub. 2 --129 OH H tBut CN CF.sub.3 OMe CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --130 OH OMe nProp F tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --131 OMe H Ph CN tBut Me CH.dbd.C --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub. 2 --132 OMe OMe tBut F H H CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --133 OMe H iProp H H OMe CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --__________________________________________________________________________ TABLE 5__________________________________________________________________________4 #STR61##Ex. No. R1 R6 R7 R8 R9 X--Y A__________________________________________________________________________134 NH.sub.2 tBut H tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --135 OH tBut CN H H CH.sub.2 --N S--(CH.sub.2).sub.3 --136 NHMe tBut H H OMe CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --137 NH.sub.2 H CN tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH.s ub.2 --138 NHMe CF.sub.3 H tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --139 NH.sub.2 nProp H iProp H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --140 NHMe H H iProp OMe CH.dbd.C S--(CH.sub.2).sub.3 --141 NH.sub.2 tBut H tBut H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --142 NH.sub.2 tBut CN H H CH.sub.2 --N S--(CH.sub.2).sub.4 --143 NHMe tBut H H OMe CH.sub.2 --N O--(CH.sub.2).sub.3 --144 OH H CN tBut H CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --145 NH.sub.2 CF.sub.3 H tBut H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --146 NH.sub.2 nProp H iProp H CH.sub.2 --N S--(CH.sub.2).sub.3 --147 NH.sub.2 nProp CN tBut H CH.sub.2 --N S--(CH.sub.2).sub.4 --148 OH CF.sub.3 CN iProp H CH.sub.2 --N S--(CH.sub.2).sub.3 --149 NHMe Ph C.dbd.CH tBut H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --150 NH.sub.2 tBut CN tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH.s ub.2 --151 NHMe tBut H nProp OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --152 NH.sub.2 Ph H tBut OMe CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.5 --153 NHMe CF.sub.3 H tBut OMe CH.dbd.C S--(CH.sub.2).sub.3 --154 NH.sub.2 tBut F H Me CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --155 NH.sub.2 nProp CN tBut Me CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --156 OH nProp C.dbd.CH tBut OMe CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH.s ub.2 --157 NHMe tBut CN H OMe CH.sub.2 --N S--(CH.sub.2).sub.4 --158 OH H H iProp OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --__________________________________________________________________________ TABLE 6__________________________________________________________________________5 #STR62##Ex. No. R1 R5 R7 R8 R9 X--Y A__________________________________________________________________________159 NH.sub.2 OMe H tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --160 OH OMe H CF.sub.3 H CH.sub.2 --N S--(CH.sub.2).sub.3 --161 NHMe OMe H tBut H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --162 NH.sub.2 H CN tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub .2 --163 NHMe H F tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --164 NH.sub.2 Me Cl iProp H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --165 NHMe H H iProp OMe CH.dbd.C S--(CH.sub.2).sub.3 --166 NH.sub.2 H H tBut OMe CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --167 NH.sub.2 CN H CF.sub.3 H CH.sub.2 --N S--(CH.sub.2).sub.4 --168 NHMe H CN H OMe CH.sub.2 --N O--(CH.sub.2).sub.3 --169 OH H H tBut OEt CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --170 NH.sub.2 H CN tBut H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --171 NH.sub.2 Me H iProp H CH.sub.2 --N S--(CH.sub.2).sub.3 --172 NH.sub.2 OMe CN tBut H CH.sub.2 --N S--(CH.sub.2).sub.4 --173 NH.sub.2 OMe Me tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --174 NHMe H CN tBut OMe CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --175 NH.sub.2 Me H tBut OMe CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub .2 --176 NH.sub.2 H Cl CF.sub.3 Me CH.sub.2 --N S--(CH.sub.2).sub.5 --177 NHMe OMe CN tBut Me CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --178 OH Me Me iProp Me CH.dbd.C S--(CH.sub.2).sub.4 --179 OH OMe H iProp H CH.sub.2 --N S--(CH.sub.2).sub.3 --__________________________________________________________________________ TABLE 7__________________________________________________________________________6 #STR63##Ex. No. R1 R5 R6 R8 R9 X--Y A__________________________________________________________________________180 NH.sub.2 H tBut tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --181 OH H tBut Ph H CH.sub.2 --N S--(CH.sub.2).sub.3 --182 NHMe H tBut 1-Pyrrolyl H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --183 NH.sub.2 H nPropyl tBut H CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH .sub.2 --184 NHMe H CF.sub.3 tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --185 NH.sub.2 H 2-Napht tBut H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --186 NHMe OMe tBut H H CH.dbd.C S--(CH.sub.2).sub.3 --187 NH.sub.2 OMe iProp H H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --188 NH.sub.2 OMe H CF.sub.3 H CH.sub.2 --N S--(CH.sub.2).sub.4 --189 NHMe H tBut H OMe CH.sub.2 --N O--(CH.sub.2).sub.3 --190 OH H iProp H Me CH.dbd.C S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --191 NH.sub.2 CN tBut H H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --192 NH.sub.2 H H CF.sub.3 Me CH.sub.2 --N S--(CH.sub.2).sub.3 --193 NHMe OMe tBut iProp H CH.sub.2 --N S--(CH.sub.2).sub.4 --194 OH OMe CF.sub.3 tBut H CH.sub.2 --N NH--CH.sub.2 --CH.dbd.CH--CH.sub.2 --195 NH.sub.2 Me tBut nProp H CH.dbd.C --CH.sub.2 --CH.sub.2 --C(CH.sub.3).dbd.CH--CH .sub.2 --196 NH.sub.2 Me tBut H OMe CH.sub.2 --N S--(CH.sub.2).sub.5 --197 NH.sub.2 OMe tBut tBut OMe CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --198 NH.sub.2 Me CF.sub.3 tBut OMe CH.dbd.C S--(CH.sub.2).sub.4 --199 OH H nProp tBut H CH.sub.2 --N S--(CH.sub.2).sub.3 --__________________________________________________________________________ TABLE 8__________________________________________________________________________7 #STR64##Ex. No. R1 R6 R8 R9 X--Y A__________________________________________________________________________200 NH.sub.2 tBut Ph H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --201 NH.sub.2 tBut 2-Napht H CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --202 NH.sub.2 tBut 1-Pyrrolyl H CH.sub.2 --N S--(CH.sub.2).sub.3 --203 NHMe tBut cHex H CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --204 NH.sub.2 tBut nHex H CH.sub.2 --N S--(CH.sub.2).sub.5 --205 NH.sub.2 tBut H OMe CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --206 NHMe iProp H OMe CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --207 NH.sub.2 H CH.sub.3 OMe CH.dbd.C NH--(CH.sub.2).sub.3 --208 NH.sub.2 H iProp OMe CH.sub.2 --N O--CH.sub.2 --CH.dbd.CH--CH.sub.2 --209 NH.sub.2 tBut tBut OMe CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --210 NHMe tBut iProp OMe CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --211 NH.sub.2 Ph tBut Cl CH.sub.2 --N S--(CH.sub.2).sub.4 --212 NH.sub.2 2-Napht tBut Me CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --213 NH.sub.2 tBut CF.sub.3 OMe CH.sub.2 --N S--(CH.sub.2).sub.3 --214 NH.sub.2 tBut H CH.sub.3 CH.sub.2 --N S--(CH.sub.2).sub.3 --215 NH.sub.2 tBut Ph H CH.sub.2 --N S--(CH.sub.2).sub.3 --216 NH.sub.2 tBut 2-Napht H CH.dbd.C NH--(CH.sub.2).sub.3 --217 NH.sub.2 tBut 1-Pyrrolyl H CH.sub.2 --N O--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --218 NH.sub.2 tBut cHex H CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --219 OH tBut nHex H CH.sub.2 --N S--(CH.sub.2).sub.4 --220 OH tBut H OMe CH.dbd.C S--(CH.sub.2).sub.4 --221 OMe iProp H OMe CH.sub.2 --N --CH.sub.2 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --222 OMe H CH.sub.3 OMe CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.3 --223 NCH.sub.2 Ph H iProp OMe CH.sub.2 --N S--CH.sub.2 --C(CH.sub.3).dbd.CH--CH.sub.2 --224 OH tBut tBut OMe CH.sub.2 --N --CH.sub.2 --(CH.sub.2).sub.4 --225 OH tBut iProp OMe CH.sub.2 --N S--CH.sub.2 --CH.dbd.CH--CH.sub.2 --226 OMe Ph tBut Cl CH.sub.2 --N S--(CH.sub.2).sub.5 --227 OMe 2-Napht tBut Me CH.dbd.C --CH.sub.2 --(CH.sub.2).sub.3 --228 NCH.sub.2 Ph tBut CF.sub.3 OMe CH.sub.2 --N S--(CH.sub.2).sub.4 --229 NHMe tBut H CH.sub.3 CH.dbd.C S--(CH.sub.2).sub.3 --__________________________________________________________________________

Examples of Pharmaceutical forms:

A) Tablets

Tablets of the following composition were compressed in a tabletting machine in a conventional manner

40 mg of substance of Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil.RTM. (chemically pure silica in submicroscopically fine dispersion)

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

B) Sugar-coated tablets

20 mg of substance of Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition comprises 5 parts of sucrose, �lacuna! parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.

Biological investigations - receptor-binding studies

1) D.sub.3 binding assay

Cloned human D.sub.3 receptor-expressing CCL 1.3 mouse fibroblasts obtained from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell preparation

The D.sub.3 -expressing cells were grown in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300.times.g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4, with 10% glycerol) and then incubated in a concentration of 10.sup.7 cells/ml of lysis buffer at 4.degree. C. for 30 min. The cells were centrifuged at 200.times.g for 10 min and the pellet was stored in liquid nitrogen.

Binding assays

For the D.sub.3 receptor-binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 120 mM NaCl, 5 mM KCl, 2 mM CaCl.sub.2, 2mM MgCl.sub.2, 10 .mu.M quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of about 10.sup.6 cells/250 .mu.l of assay mixture and incubated at 30.degree. C. with 0.1 nM .sup.125 iodosulpiride in the presence and absence of test substance. The non-specific binding was determined using 10.sup.-6 M spiperone.

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

The K.sub.i values were determined by non-linear regression analysis using the LIGAND program.

2) D.sub.2 binding assay

Membrane preparation

a) Nucleus caudatus (bovine)

Nucleus caudatus was removed from bovine brain and washed with ice-cold 0.32 M sucrose solution. After determination of the weight, the material was comminuted and homogenized in 5-10 volumes of sucrose solution using a Potter-Evehjem �sic! homogenizer (500 rpm). The homogenate was centrifuged at 3,000.times.g for 15 minutes (4.degree. C.), and the resulting supernatant was subjected to another 15-minute centrifugation at 40,000.times.g. The residue was then washed twice, by resuspension and centrifugation, with 50 mM tris-HCl, pH 7.4. The membranes were stored in liquid nitrogen until used.

b) Striatum (rat)

Striati from Sprague-Dawley rats were washed in ice-cold 0.32 M sucrose solution. After determination of the weight, the parts of the brain were homogenized in 5-10 volumes of sucrose solution using a Potter-Elvehjem homogenizer (500 rpm). The homogenate was centrifuged at 40,000.times.g for 10 minutes (4.degree. C.), and then the residue was washed several times, by resuspension and centrifugation, with 50 mM tris-HCl, 0.1 mM EDTA and 0.01% ascorbic acid (pH 7.4). The washed residue was resuspended in the abovementioned buffer and incubated at 37.degree. C. for 20 minutes (to break down the endogenous dopamine). The membranes were then washed twice with buffer and portions were frozen in liquid nitrogen. The membrane preparation was stable for a maximum of one week.

Binding assay

a) .sup.3 H-Spiperone (D.sub.2low)

Nucleus caudatus membranes were taken up in incubation buffer (mM: tris-HCl 50, NaCl 120, KCl 5, MgCl.sub.2 1, CaCl.sub.2 2, pH 7.4). Various mixtures, each of 1 ml, were prepared:

Total binding: 400 .mu.g of membranes+0.2 nmol/l .sup.3 H-spiperone (Du Pont de Nemours, NET-565). Non-specific binding: as mixtures for total binding+10 .mu.M (+)-butaclamol. Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25.degree. C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K.sub.i values were determined by non-linear regression analysis using the LIGAND program or by conversion of the IC.sub.50 values using the formula of Cheng and Prusoff.

b) .sup.3 H-ADTN (D.sub.2high)

Striatum membranes were taken up in incubation buffer (50 mM tris-HCl, pH 7.4, 1 mM MnCl.sub.2 and 0.1% ascorbic acid).

Various mixtures, each of 1 ml, were prepared.

Total binding: 300 .mu.g wet weight+1 nM .sup.3 H-ADTN (Du Pont de Nemours, customer synthesis)+100 nM SCH 23390 (occupation of D.sub.1 receptors). Non-specific bindings: as mixtures for total binding+50 nM spiperone. Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25.degree. C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4.

The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The evaluation took place as under a).

In these assays, the compounds according to the invention show very good affinities and high selectivities for the D.sub.3 receptor. The results obtained for representative compounds are compiled in the following Table 9.

TABLE 9______________________________________Receptor binding D.sub.3 D.sub.2Example .sup.125 I-sulpiride .sup.3 H-spiperone SelectivityNo. K.sub.i �nM! K.sub.i �mM! K.sub.i D.sub.2 /K.sub.i D.sub.3______________________________________ 2 1.4 65 4613 0.6 25 4116 10.9 402 3623 6.3 200 3149 6.5 560 8651 8.3 500 6253 2.95 145 5056 27.0 3,500 7058 1.7 225 132______________________________________

Claims

1. A method for treating disorders which respond to dopamine D.sub.3 receptor antagonists or agonists which comprises administering to a person requiring such treatment an effective amount of a member selected from the group consisting of thiazole and thiadiazole compounds of the formula I: ##STR65## where A is a straight-chain or branched C.sub.3 -C.sub.14 -alkylene group which comprises at least one group selected from O, S, and NR,

B is a radical of the formula: ##STR66## R.sup.1 is H, NR.sup.2 R.sup.3, or C.sub.1 -C.sub.8 -alkyl; R.sup.2 is H or C.sub.1 -C.sub.8 -alkyl, which is unsubstituted or substituted by OH;

R.sup.3 has the meanings indicated for R.sup.2 ;

X is N;

Ar is phenyl, pyridyl or pyrimidyl where Ar may have one or two substituents which are selected, independently of one another, from OR.sup.3, C.sub.1 -C.sub.8 -alkyl, halogen, CN, NO.sub.2, CF.sub.3, CHF.sub.2, phenyl, and a 5-membered heterocyclic aromatic ring having 1 or 2 hetero atoms selected from O, S and N,

and the salts thereof with physiologically tolerated acids.

2. A method as claimed in claim 1 which comprises administering a member selected from the group consisting of compounds of the formula I where R.sup.1 is H, or NR.sup.2 R.sup.3, where R.sup.2 and R.sup.3 are, independently of one another, H or C.sub.1 -C.sub.8 -alkyl; and A is C.sub.3 -C.sub.12 -alkylene which comprises at least one group selected from O, S, and NR.sup.3.

3. A method as claimed in claim 1 of compounds of the formula I where

B is ##STR67##

4. A method as claimed in claim 1 of compound of the formula I where Ar is phenyl which has one or two substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl, phenyl, pyrrolyl, CHF.sub.2, CF.sub.3, halogen, NO.sub.2, CN, OH, OC.sub.1 -C.sub.8 -alkyl.

5. A method as claimed in claim 4, where Ar has one or two substituents which are in position 3 or position 3,5.

6. A method as claimed in any of claims 1 to 5 of compounds of the formula I where Ar is pyrimidinyl which has one or two substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.8 -alkyl, phenyl, pyrrolyl, OH, OC.sub.1 -C.sub.8 -alkyl, CHF.sub.2, CF.sub.3 and halogen.

7. A method as claimed in claim 1 of compounds of the formula I where Ar is pyridinyl which has one or two substituents which are selected, independently of one another, from H, C.sub.1 -C.sub.1 -alkyl, phenyl, pyrrolyl, OH, OC.sub.1 -C.sub.8 -alkyl, CHF.sub.2, CF.sub.3, CN and halogen.

8. A compound of the formula I: ##STR68## where A is a straight-chain or branched C.sub.7 -C.sub.14 -alkylene group which comprises a group which is selected from O, S, and NR.sup.3 and, R.sup.1, R.sup.2, R.sup.3, B and Ar have the meanings stated in claim 1.

9. A process for preparing compounds as claimed in claim 8, which comprises

i) reacting a compound of the general formula II: ##STR69## where Y' is a conventional leaving group, with a compound of the general formula III:

H--B--Ar

ii) to prepare a compound of the formula I where A comprises an oxygen or sulfur atom or NR.sup.3,

a) reacting a compound of the general formula IV: ##STR70## where Z.sup.1 is O, S or NR.sup.3, and A.sup.1 is C.sub.0 -C.sub.18 -alkylene, with a compound of the general formula VI

Y.sup.1 --A.sup.2 --B--Ar

where Y.sup.1 has the abovementioned meanings, and A.sup.2 is C.sub.1 -C.sub.14 -alkylene, where A.sup.1 and A.sup.2 together have 7 to 14 carbon atoms;

and all the other substituents have the same meaning as defined in claim 1.

10. A pharmaceutical composition containing at least one compound of the formula I as claimed in claim 8 with or without physiologically acceptable salts.

11. A process for preparing compounds as claimed in claim 8, which comprises

i) reacting a compound of the general formula II: ##STR71## where Y.sup.1 is a conventional leaving group, with a compound of the general formula III:

H--B--Ar.