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US 6,297,264 B1Granted
Trisubstituted phenyl derivatives and process for their preparation
AssigneeCelltech Therapeutics Limited
InventorsJohn Clifford Head, Graham John Warrellow, Rikki Peter Alexander
Life of this patent
Estimating the term…
Abstract
Compounds of the general formula (1) are described wherein W is a ═N—, and Z and L are described in the specifications. These compounds are phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of diseases such as asthma where an unwanted inflammatory response or muscular spasm is present.
Claims6
A compound of formula (1)
- wherein
- ═W— is ═N—;
- L is —XR, —C(R11)═C(R1)(R2) or —(CHR11)nCH(R1)(R2), wherein n is zero or the integer 1;
- Z is (1) a group —C(R3)(R4)C(R5)(R6)(R7) or —C(R4)═C(R5)(R6);
- X is —O—, —S(O)m—, or —N(Rb)—, wherein m is zero or an integer 1 or 2;
- R is an optionally substituted alkyl or alkenyl group;
- Rb is hydrogen or an optionally substituted alkyl group;
- R1 and R2 are independently hydrogen, fluorine, —CN, —NO2, or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO2R8, —CONR9R10 or —CSNR9R10 group;
- R3 is hydrogen, fluorine, or an optionally substituted straight or branched alkyl group;
- R4 is —XaL1R12, —Alk1R12, —CH2L1R12a, —XaR12a or —C(Xb)R12a, wherein:
- Xa is —O—, —S(O)m— or —N(Rb)—;
- Xb is —O— or —S—;
- L1 is —(Alk2)r(Xa)s(Alk3)t— where r, s and t are zero or the integer 1;
- R12 and R12a are independently an optionally substituted cycloaliphatic group or an optionally substituted monocyclic or bicyclic aryl group;
- Alk1 is an optionally substituted straight or branched alkenylene or alkynylene chain optionally interrupted by one or more —O— or —S— atoms or —N(Rb)—, carbocyclic or heteroatom-containing groups;
- and
- Alk2 and Alk3 are independently an optionally substituted straight or branched alkylene, alkenylene or alkynylene chain optionally interrupted by one or more heteroatoms or carbocyclic or heteroatom-containing groups;
- R5 is a —(CH2)pAr group where p is zero or an integer 1, 2 or 3 and Ar is an optionally substituted six-membered heteroaryl group containing one nitrogen atom;
- R6 is hydrogen, fluorine, or an optionally substituted alkyl group;
- R7 is hydrogen, fluorine, an optionally substituted straight or branched alkyl group, or —ORc, where Rc is hydrogen, formyl, alkoxyalkyl, alkanoyl, carboxamido, thiocarboxamido or an optionally substituted alkyl or alkenyl group;
- R8, R9 and R10 are independently hydrogen or an optionally substituted alkyl group;
- and
- R11 is hydrogen, fluorine or methyl;
- or
- Z is (2) a group —C(R4)C(R5)(R6)(R7), where R4 is ═CH2, or —CH(L1)nR12;
- with the provisos that when one of r, s and t is 0, then at least one of the other of r, s and t is 1, when s is 1, then r is 1, and when L1 is adjacent to Xa and s is 1, then r is also 1;
- and the salts, solvates, hydrates and N-oxides thereof.
24 more elements
A pharmaceutical composition comprising a compound of formula (1)
- wherein
- ═W— is ═N—;
- L is —XR, —C(R11)═C(R1)(R2) or —(CHR11)nCH(R1)(R2), wherein n is zero or the integer 1;
- Z is (1) a group —C(R3)(R4)C(R5)(R6)(R7) or —C(R4)═C(R5)(R6);
- X is —O—, —S(O)m—, or —N(Rb)—, wherein m is zero or an integer 1 or 2;
- R is an optionally substituted alkyl or alkenyl group;
- Rb is hydrogen or an optionally substituted alkyl group;
- R1 and R2 are independently hydrogen, fluorine, —CN, —NO2, or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO2R8, —CONR9R10 or —CSNR9R10 group;
- R3 is hydrogen, fluorine, or an optionally substituted straight or branched alkyl group;
- R4 is —XaL1R12, —Alk1R12, —CH2L1R12a, —XaR12a or —C(Xb)R12a, wherein:
- Xa is —O—, —S(O)m— or —N(Rb)—;
- Xb is —O— or —S—;
- L1 is —(Alk2)r(Xa)s(Alk3)t— where r, s and t are zero or the integer 1;
- R12 and R12a are independently an optionally substituted cycloaliphatic group or an optionally substituted monocyclic or bicyclic aryl group;
- Alk1 is an optionally substituted straight or branched alkenylene or alkynylene chain optionally interrupted by one or more —O— or —S— atoms or —N(Rb)—, carbocyclic or heteroatom-containing groups;
- and
- Alk2 and Alk3 are independently an optionally substituted straight or branched alkylene, alkenylene or alkynylene chain optionally interrupted by one or more heteroatoms or carbocyclic or heteroatom-containing groups;
- R5 is a —(CH2)pAr group where p is zero or an integer 1, 2 or 3 and Ar is an optionally substituted six-membered heteroaryl group containing one nitrogen atom;
- R6 is hydrogen, fluorine, or an optionally substituted alkyl group;
- R7 is hydrogen, fluorine, an optionally substituted straight or branched alkyl group, or —ORc, where Rc is hydrogen, formyl, alkoxyalkyl, alkanoyl, carboxamido, thiocarboxamido or an optionally substituted alkyl or alkenyl group;
- R8, R9 and R10 are independently hydrogen or an optionally substituted alkyl group;
- and
- R11 is hydrogen, fluorine or methyl;
- or
- Z is (2) a group —C(R4)C(R5)(R6)(R7), where R4 is ═CH2, or —CH(L1)nR12;
- with the provisos that when one of r, s and t is 0, then at least one of the other of r, s and t is 1, when s is 1, then r is 1, and when L1 is adjacent to Xa and s is 1, then r is also 1;
- and the salts, solvates, hydrates and N-oxides thereof;
- together with one or more pharmaceutically acceptable carriers, excipients or diluents.
25 more elements
Dependencies are inferred from the claim text.