Heterocyclic derivative, pharmaceutical composition, containing, and intermediate product

 

Describes new heterocyclic compounds of General formula Iwhere R is cyano or a nitro-group; R1is a hydrogen atom, halogen atom, cyano, halogen(lower)alkyl, lower alkyl, or R6-A-; R2and R3independently mean a hydrogen atom or a lower alkyl group; R4is a hydrogen atom, a lower alkyl, -C(O)lower alkyl, R3is lower alkyl, phenyl (lower)alkyl-O-, -C(O)-O-(lower)alkyl, phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, isoxazolyl, hinely, benzofurazanyl, benzoimidazolyl, benzothiazolyl, tetrazolyl, tetrahydrofuranyl, morpholinyl, thiomorpholine or cycloalkyl, which may be substituted; R6- lower alkyl, possibly substituted by a group lower alkyl-O -, - N(R9R10where R9and R10together with the nitrogen atom to which they are attached, form morpholinyl; k is 1, 2, 3 and n is 1; m is 1 or 0; R means 0,1 or 2; And a is an oxygen atom or NR8where R8is hydrogen or lower alkyl; X is-C(=O)- or-S(O)2-; Z1and Z2independently denote CH or N; Y is a simple link, the lower alkylene, -C(=O)-, provided that when R5is lower alkyl, Y represents a group other than lower alkalmaval find application as antiandrogenna funds. 4 C. and 3 h.p. f-crystals, 13 tables.

Description text in facsimile form (see graphic part)and

Claims

1. Heterocyclic derivative represented by the following General formula (I) or its salt:

in which R represents cyano or a nitro-group,

R1represents a hydrogen atom, halogen atom or cyano, halogenosilanes, lower alkyl, R6-A-;

R2, R3may be the same or different and mean a hydrogen atom or a lower alkyl group;

R4represents a hydrogen atom, a lower alkyl, -C(O)- lower alkyl;

R5represents lower alkyl, familystyle-O-, C(O)-O-nishiuchi or phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, isoxazolyl, hinely, benzofurazanyl, benzoimidazolyl, benzothiazolyl, tetrazolyl, tetrahydrofuranyl, morpholinyl, thiomorpholine or cycloalkyl that may have a group-assistant selected from the group comprising: halogen atom, halogenosilanes, lower alkyl, lower alkyl-O -, lower alkyl-S-, lower alkyl-S(O)-, lower alkyl-S(O)2, sulfamoyl, which can be substituted which may be substituted by one or two lower alkyl groups or by a group of lower alkyl-C(=O)- or lower alkyl-O-C(=O)-, phenyl-O-, phenyl-C(O)-, amino-O-, carbarnoyl (which may be substituted by a lower alkyl group), carboxyl, lower alkyl-O-C(=O)-, morpholinyl, morpholinoethyl-O-, imidazolyl, cyclopropyl and HE-group;

R6represents lower alkyl which may be substituted by a group lower alkyl-O -, - N(R9R10where R9and R10together with the nitrogen atom to which they are attached, form morpholinyl;

k is 1, 2, 3;

n means 1;

m means 1 or 0;

p denotes 0, 1 or 2;

And represents an oxygen atom or NR8where R8means hydrogen or lower alkyl;

X represents-C(=O)- or-S(O)2-;

Z1and Z2may be the same or different, and each denotes CH or N;

Y represents a simple bond, a lower alkylene, -C(=O)-, provided that when R5represents a lower alkyl group, Y represents a group other than lower alkylene;

provided that (1) when R1represents a hydrogen atom, at least one of R2and R3represents lower alkyl, (2) when R is a nitro-group, k is 2 and m is 0, at least one of R2and R3represents a lower alkyl,-, and n is 1, k is 2 and m is 0, and R5represents a methyl group, R1represents a group other than a fluorine atom.

2. Heterocyclic derivative or its salt under item 1, where R represents the cyano.

3. Heterocyclic derivative or its salt under item 2, where R1represents a halogen atom, cyano, halogenized alkyl, at least one of R2and R3represents a lower alkyl group, R4represents a hydrogen atom or a lower alkyl group; R5represents phenyl, naphthyl, furanyl, thienyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, isoxazolyl, hinely, benzofurazanyl, benzoimidazolyl, benzothiazolyl, tetrazolyl, tetrahydrofuranyl, morpholinyl, thiomorpholine or cycloalkyl, which may contain the group-Deputy as defined in paragraph 1, k is 2, n is 1, m is 1, X represents-C(=O)-group, Y represents a simple bond; and Z1or Z2both mean SN.

4. The compound or its salt selected from the group including

(2R,5S)-4-(4-cyano-3-triptoreline)-N-(6-methoxy-3-pyridyl)-2,5-dimethylpiperazine-1-carboxamide,

(2R,5S)-N-(2-aminopyrimidine-4-yl)-4-(4-cyano-3-triptoreline)piperazine-1-carboxamide,

(2R,5S)-4-(4-cyano-3-triptoreline)-N-(2-fluoro-4-pyridyl)-2,5-dimethylpiperazine-1-carboxamide, and

(2R,5S)-N-(2-bromo-4-pyridyl)-4-(4-cyano-3-triptoreline)-2,5-dimethylpiperazine-1-carboxamide.

5. Pharmaceutical composition having antiandrogenna action, which includes as an active ingredient derived heterocycle under item 1 or its salt.

6. Heterocyclic derivative represented by the following General formula (II) or its salt

which groups have the following meanings: R is a cyano or a nitro-group,

R1represents a hydrogen atom, halogen atom, cyano, halogenized alkyl, lower alkyl, R6-A-;

R2and R3may be the same or different and each means a hydrogen atom or a lower alkyl group;

R6represents lower alkyl which may be substituted by N(R9R10- where R9and R10together with the nitrogen atom to which they are attached can form morpholinyl, or lower alkyl-O-;

k represents 2 or 3;

n means 1;

And represents an oxygen atom;

Z1or Z2the same or different and each represent CH or a nitrogen atom,

the>represents a halogen atom or a cyano, at least one of R2and R3represents a group other than a hydrogen atom, (ii) when R represents CN, and R1represents a hydrogen atom, then both R2and R3are not hydrogen atoms, or one of R2and R3represents a methyl group and the other represents a group which is other than a hydrogen atom, (iii) when R is a nitro-group, and R1represents a methyl group, a methoxy group, CF3at least one of R2and R3is a group that is other than a hydrogen atom, (iv) when R is a nitro-group, and R1represents a hydrogen atom, at least one of R2and R3is a group that is other than a hydrogen atom and methyl group, (v) when R and R1represent the nitrogroup, at least one of R2and R3is a group that is other than a hydrogen atom and a methyl group; (2) when Z1=Z2=CH, n is 1, and k is 3: when R represents cyano, and R1represents a hydrogen atom, or when R p is Milou or methyl group, at least one of R2and R3is a group that is other than a hydrogen atom; (3) when Z1=N, Z2=CH, n is 1 and k is 2: when R and R1represent the nitrogroup, at least one of R2and R3is a group that is other than a hydrogen atom.

7. Heterocyclic derivative according to p. 6, as intermediate compounds for connection on p. 1.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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