Pyridine derivatives, their production and use

Claim 2

A pyridine derivative according to claim 1, R₁ and R₂ are the same or different and are a hydrogen atom, amino group or an acylamino, X is an oxygen or sulfur atom, A is a bivalent C₁₋₆ hydrocarbon residue, Y is an oxygen atom, R₃ is a hydrogen atom, an optionally substituted aralkyl group or an optionally substituted aryl group, R₄′ is a C₂₋₃₀ alkyl group, a halogeno lower alkyl group, an optionally substituted aryl group or an optionally substituted monocyclic or bicyclic heterocyclic group.

Claim 3

A pyridine derivative according to claim 2, wherein A is a C₁₋₄ alkylene.

Claim 4

The pyridine derivative according to claim 1 selected from: 4-[3-(N-benzyl-N-trifluoroacetylamino)propylthio]pyridine hydrochloride; 4-[2-(thianaphthene-2-carbonylamino)ethylthio]pyridine; and 1,2-bis[N-[4-(4-pyridylthio)butyl]-N-propionylamino]benzene dihydrochloride.

Claim 5

A pyridine derivative of the formula (III): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro group, cyano group, amino group, carbamoyl group, an acylamino group, a lower alkylamino group, a lower alkenylamino group or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2; A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, R₅ and R₆ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, or R₅ and R₆ are joined to form a group of the formula: wherein R₇ and R₈ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group or an optionally substituted monocyclic or a bicyclic heterocyclic group, or R₇ and R₈ are linked together to form a ring, B₁ is -(CH₂) p -, wherein p is an integer of 1 to 4, or a group of the formula: wherein R₉ is a hydrogen atom, an optionally substituted lower alkyl, lower alkenyl or aralkyl group, or a salt or solvate thereof.

Claim 6

A pyridine derivative according to claim 5, wherein R₁ and R₂ are the same or different and are a hydrogen atom, amino group or an acylamino group, X is an oxygen or sulfur atom, Y is an oxygen atom, A is a bivalent C₁₋₆ hydrocarbon residue, R₅ and R₆ are the same or different and are a hydrogen atom or a lower alkyl, or R₅ and R₆ are joined to form a group of the formula: wherein R₇ and R₈ are the same or different and are a hydrogen atom, a lower alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group or an optionally substituted monocyclic or bicyclic heterocyclic group, B₁ is -C(=O)-O-, -C(=O)-S-, -C(=O)-CH₂-or -C(=O)-NR₉-, wherein R₉ is as defined in claim 7.

Claim 7

A pyridine derivative according to claim 6, wherein R₁ and R₂ are a hydrogen atom, A is a C₁₋₄ alkylene, B₁ is -C(=O)-S- or -C(=O)-NR₉-.

Claim 8

The pyridine derivative according to claim 5 selected from: 4-[4-(5-benzylidene-2,4-thiazolidinedione)butylthio]pyridine; 4-[4-[5-(4-chlorobenzylidene)-2,4-thiazolidinedione]butylthio]pyridine; 4-[4-(5-(2-thienylmethylene)-2,4-thiazolidinedione]butylthio]pyridine; 4-[4-(5-propylmethylene-2,4-thiazolidinedione)butylthio]pyridine; 4-(5,5-dimethyloxazolidine-2,4-dione)methylthiopyridine; 4-[4-[5-(4-pyridyl)methylene-2,4-thiazolidinedione]butylthio]pyridine; 4-[4-[5-(3-pyridyl)methylene-2,4-thiazolidinedione]butylthio]pyridine; and 4-[4-(5-nonylmethylene-2,4-thiazolidinedione)butylthio]pyridine hydrochloride.

Claim 9

A pyridine derivative of the formula (IV): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro group, cyano group, amino group, carbamoyl group, an acylamino group, a lower alkylamino group, a lower alkenylamino group or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, a group of the formula: is an optionally substituted benzene ring, B₂ is -(CH₂) p -, wherein p is an integer of 1 to 4, or a group of the formula: wherein R₉ is a hydrogen atom, an optionally substituted lower alkyl, lower alkenyl or aralkyl group, or a group of the formula: wherein R₁₂ and R₁₃ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group or an aryl group, or R₁₂ and R₁₃ may be linked together to form a ring, or a salt or solvate thereof.

Claim 10

A pyridine derivative according to claim 9, wherein R₁ and R₂ are the same or different and are a hydrogen atom, amino group or an acylamino group, X is an oxygen or sulfur atom, A is a bivalent C₁₋₆ hydrocarbon residue, Y is an oxygen atom, B₂ is -(CH₂) p -, -(HO-)CH-, -C(=O)-O-, -C(=S)-O-, -SO₂-, -C(=O)-NR₉- or -C(=S)-NR₉- wherein p is an integer of 1 to 4, R₉ is a hydrogen atom or an optionally substituted lower alkyl group.

Claim 11

A pyridine derivative according to claim 10, wherein R₁ and R₂ are a hydrogen atom, A is a C₁₋₄ alkylene, B₂ is -CH₂-, -C(=O)-O-, -C(=S)-O-, -SO₂-, -C(=O)-NR₉- or -C(=S)-NR₉-, and the substituent of the lower alkyl group is pyridylthio group.

Claim 12

The pyridine derivative according to claim 9 selected from: 3-[3-(4-pyridylthio)propyl]-2H-1,3-benzoxazine-2-thion-4(3H)-one; 3-[4-(4-pyridylthio)butyl]quinazoline-2,4-(1H,3H)-dione; 1,3-bis[4-(4-pyridylthio)butyl]quinazoline-2,4-(1H,3H)-dione; 3-[4-(4-pyridylthio)butyl]-2H-1,3-benzoxazine-2-thion-4(3H)-one; 4-saccharinmethylthiopyridine; 4-saccharinmethylthiopyridine hydrochloride; 1,3-bis[4-(2-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione; 1-(4-pyridylthio)methyl-3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione dihydrochloride; and 1,3-bis[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4(3H)-one dihydrochloride.

Claim 13

A pyridine derivative of the formula (V): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro croup, cyano group, amino group, carbamoyl group, an acylamino group, a lower alkylamino group, a lower alkenylamino group or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, a group of the formula: is an optionally substituted benzene ring, or a salt or solvate thereof.

Claim 14

A pyridine derivative according to claim 13, wherein R₁ and R₂ are the same or different and are a hydrogen atom, amino group or an acylamino group, X is an oxygen or sulfur atom.

Claim 15

A pyridine derivative according to claim 14, wherein R₁ and R₂ are a hydrogen atom.

Claim 16

The pyridine derivative according to claim 13 which is 4-(phthalimidomethylthio)pyridine, or 4-(phthalimidomethyloxy)pyridine.

Claim 17

A process for producing a pyridine derivative of the formula (II): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro group, cyano group, amino group, carbamoyl group, an acylamino croup, a lower alkylamino group, a lower alkenylamino or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, R₃ is a hydrogen atom or an optionally substituted hydrocarbon atom, R₄′ is (1) a C₂₋₃₀ alkyl group, (2) a C₂₋₃₀ alkenyl group, (3) a lower alkyl group substituted with a halogen atom, an aryl group or a heterocyclic group, (4) an optionally substituted aralkyl group, (5) an optionally substituted aryl group or (6) an optionally substituted monocyclic or bicyclic heterocyclic group, or a salt or solvate thereof, which comprises the steps of: (a) when X is O or S, reacting a compound of the formula: wherein E is a halogen atom and the other symbols are as defined above, with a compound of the formula: wherein X₁ is O or S and the other symbols are as defined above; or (b) when X is O or S, reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: wherein E₂ is a leaving group such as a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy, etc. and the other symbols are as defined above; or (c) when Y is O, reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: wherein E₂ is a halogen atom, O-C(=O)-R₄′ or OH and the other symbols are as defined above; or (d) when X is S and A is CH₂, R₃ is a hydrogen atom and Y is O, reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: R₄′CONHCH₂OH wherein each symbol is as defined above.

Claim 18

A process for producing a pyridine derivative of the formula (III): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro Group, cyano group, amino group, carbamoyl group, an acylamino group, a lower alkylamino group, a lower alkenylamino group or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2; A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, R₅ and R₆ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, or R₅ and R₆ are joined to form a group of the formula: wherein R₇ and R₈ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group or an optionally substituted monocyclic or a bicyclic heterocyclic group, or R₇ and R₈ are linked together to form a ring, B₁ is -(CH₂) p -, wherein p is an integer of 1 to 4, or a group of the formula: wherein R₉ is a hydrogen atom, an optionally substituted lower alkyl, lower alkenyl or aralkyl group, or a salt or solvate thereof, which comprises the steps of: (a) reacting a compound of the formula: wherein each symbol is a defined above, with a compound of the formula: wherein each symbol is as defined above; or (b) when R₅ and R₆ are joined to form the group of the formula: wherein each symbol is as defined above, reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: wherein each symbol is as defined above.

Claim 19

A process for producing a pyridine derivative of the formula (IV): wherein R₁ and R₂ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, hydroxy group, nitro group, cyano group, amino group, carbamoyl group, an acylamino group, a lower alkylamino group, a lower alkenylamino group or an aralkylamino group, X is an oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, a group of the formula: is an optionally substituted benzene ring, B₂ is -(CH₂) p -, wherein p is an integer of 1 to 4, or a group of the formula : wherein R₉ is a hydrogen atom, an optionally substituted lower alkyl, lower alkenyl or aralkyl group, or a group of the formula: wherein R₁₂ and R₁₃ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkenyl group, an optionally substituted aralkyl group or an aryl group, or R₁₂ and R₁₃ may be linked together to form a ring, or a salt or solvate thereof, which comprises the steps of: (a) reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: wherein each symbol is as defined above; or (b) when B₂ is -(CH₂) p - wherein p is as defined above, cyclizing a compound of the formula: wherein each symbol is as defined above, by dehydration; or (c) when B₂ is -C(=Y)-O-, -C(=Y)-S- or -C(=Y)-N(R₉)- wherein each symbol is as defined above, reacting a compound of the formula: wherein each symbol is as defined above, with a compound of the formula: wherein each symbol is as defined above; or (d) when Y is O and B₂ is -C(-OH)H-, reacting a compound of the formula: wherein each symbol is as defined above, with sodium borohydride, or (e) when Y is O and B₂ is -CH₂-, reacting a compound of the formula: wherein each symbol is as defined above, with sodium borohydride in trifluoroacetic acid; or (f) when B₂ is -C(=O)-N(-R₉)- wherein R₉ is as defined above, reacting a compound of the formula: each symbol is as defined above, with a compound of the formula: R₉-E₁ wherein each symbol is as defined above.

Claim 20

A pharmaceutical composition for providing antiinflammatory, antipyretic, analgesic, antiallergic, immunosuppressing or immunomodulating activity which comprises a pyridine derivative of the formula (I): wherein R is an optionally substituted pyridine ring, X is a oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituert, Y is an oxygen or sulfur atom, R₃ is a hydrogen atom or an optionally substituted hydrocarbon residue, R₄ is an optionally substituted hydrocarbon residue or an optionally substituted monocyclic or bicyclic heterocyclic group, R₃ and R₄ may be joined together with the carbamoyl group or the thiocarbamoyl group to which they are attached to form an optionally substituted heterocyclic group, or R₃ or R₄ may be independently attached to A to form a ring, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

Claim 21

A pharmaceutical composition according to claim 20, wherein the pyridine derivative is selected from that of the formula (II) as claimed in claim 1; that of the formula (III) as claimed in claim 5; that of the formula (IV) as claimed in claim 9; and that of the formula (V) as claimed in claim 13.

Claim 22

A pharmaceutical composition for providing adhesive protein expression inhibitory activity which comprises a pyridine derivative of the formula (I): wherein R is an optionally substituted pyridine ring, X is a oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, R₃ is a hydrogen atom or an optionally substituted hydrocarbon residue, R₄ is an optinally substituted hydrocarbon residue or an optionally substituted monocyclic or bicyclic heterocyclic group, R₃ and R₄ may be joined together with the carbamoyl group or the thiocarbamoyl group to which they are attached to form an optionally substituted heterocyclic group, or R₃ or R₄ may be independently attached to A to form a ring, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

Claim 23

A pharmaceutical composition according to claim 22, wherein the pyridine derivative is selected from that of the formula (II) as claimed in claim 1; that of the formula (III) as claimed in claim 5; that of the formula (IV) as claimed in claim 9; and that of the formula (V) as claimed in claim 13.

Claim 24

Use of a pyridine derivative of the formula (I): wherein R is an optionally substituted pyridine ring, X is a oxygen atom or -S(O) n -, wherein n is 0, 1 or 2, A is a bivalent C₁₋₁₅ hydrocarbon residue whose branched moiety may have a substituent, Y is an oxygen or sulfur atom, R₃ is a hydrogen atom or an optionally substituted hydrocarbon residue, R₄ is an optionally substituted hydrocarbon residue or an optionally substituted monocyclic or bicyclic heterocyclic group, R₃ and R₄ may be joined together with the carbamoyl group or the thiocarbamoyl group to which they are attached to form an optionally substituted heterocyclic group, or R₃ or R₄ may be independently attached to A to form a ring, or a pharmaceutically acceptable salt or solvate thereof, in the production of a pharmaceutical composition for providing antiinflammatory, antipyretic, analgesic, antiallergic, immunosuppressing, immunomodulating or adhesive protein expression inhibitory activity.

Claim 25

Use according to claim 24, wherein the pyridine derivative is selected from that of the formula (II) as claimed in claim 1; that of the formula (III) as claimed in claim 5; that of the formula (IV) as claimed in claim 9; and that of the formula (V) as claimed in claim 13.