Tetrahydrofuran derivatives and their use as nk-1 antagonists

A compound of the formula (I):

• 29
• wherein
• R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
• R2 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
• R3 is hydrogen, halogen or fluoroC1-6alkyl;
• R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
• R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
• R6 represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
• R7 represents halogen, hydroxy, C2-4alkenyl, C2-4alkynyl, N3, —NR10R11, NRaCORb, —OSO2Ra, —(CH2)pNRa(CH2)qCOORb, CORa, COORa, —N═C═O, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from ═O, ═S, halogen, hydroxy, —SH, CORa, CO2Ra, -ZNR10R11, C1-4alkyl, hydroxyC1-4alkyl, fluoroC1-4alkyl, chloroC1-4alkyl, C1-4alkoxy, fluoroC1-4alkoxy or C1-4alkoxy substituted by a C1-4alkoxy or hydroxyl group, and wherein said C2-4alkenyl and C2-4alkynyl groups are optionally substituted by a substituent selected from halogen, hydroxy, N3, —NR10R11, —NRaCORb, —OSO2Ra, —(CH2)pNRa(CH2)qCOORb, CORa or COORa;
• or R7 represents a C-linked nitrogen-containing ring of the formula
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• wherein A represents NR14 or O, and B represents a bond, CH2, NR14 or O, wherein one or both hydrogen atoms in said CH2 moiety may be replaced with one or both of R12 and R13, or alternatively, one of the hydrogen atoms in said CH2 moiety together with a hydrogen atom from an adjacent carbon are replaced by a double bond;
• with the proviso that when A is O, then B is NR14;
• and with the further proviso that when R7 represents said C-linked nitrogen-containing ring, n is zero and R8 is hydrogen;
• R8 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, hydroxy, C1-6alkoxy or hydroxyC1-6alkyl;
• R9 represents hydrogen, halogen, C1-6alkyl, CH2ORc, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, C1-6alkyl or phenyl;
• R10 is hydrogen, C1-4alkyl, C3-7cycloalkyl, C3-7cycloallylC1-4alkyl, C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group, or R10 is a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined;
• R11 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloaIkylC1-4alkyl, or C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group;
• or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, CORe, CO2Re, C1-4alkyl optionally substituted by a C1-4alkoxy or hydroxyl group, or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, or a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined, or said heteroaliphatic ring is substituted by a spiro-fused lactone ring or a spiro-fused ring of the formula —(CH2)rO(CH2)s— (where r and s are each independently zero, 1, 2 or 3 and the sum total of r and s is 3), and said heteroaliphatic ring optionally containing a double bond, which heteroaliphatic ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRd moiety, where Rd is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, and where Re is hydrogen, C1-4alkyl or benzyl;
• or R10, R11 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
• or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S;
• R12 and R13 each independently represent hydrogen, hydroxy, CORe, CO2Re, C1-4alkyl optionally substituted by a C1-4alkoxy or hydroxyl group, or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group;
• or, when they are attached to the same carbon atom, R12 and R13 may together represent ═O, ═CHCO2Ra, —O(CH2)mO—, —CH2O(CH2)k—, —CH2OCH2C(O)—, —CH2OCH2CH(OH)—, —CH2OCH2C(CH3)2—, —CH2OC(CH3)2CH2—, —C(CH3)2OCH2CH2—, —CH2C(O)OCH2—, —OC(O)CH2CH2—, —C(O)OCH2CH2—, —C(O)OC(CH3)2CH2—, —C(O)OCH2C(CH3)2—, —OCH2(CH2)k—, —OC(CH3)2CH2CH2—, —OCH2C(OCH3)2CH2—, —OCH2CH2C(CH3)2—, —OCH2CH═CHCH2—, —OCH2CH(OH)CH2CH2—, —OCH2CH2CH(OH)CH2—, —OCH2C(O)CH2CH2—, —OCH2CH2C(O)CH2—, or a group of the formula
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• or, where they are attached to adjacent carbon atoms, R12 and R13 may together represent —OCH2CH2— or —OCH2CH(OH)—, or R12 and R13 may together form a fused benzene ring;
• or, R12 and R13 together form a C1-2alkylene bridge across the pyrrolidine, piperidine, morpholine or piperazine ring to which they are attached;
• R14 represents hydrogen, benzyl, C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkyl C1-4alkyl, or C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group;
• R15 represents hydrogen, halogen, hydroxy, C1-4alkyl, hydroxyC1-4alkyl or fluoroC1-4alkyl;
• Z represents a bond, C1-6alkylene or C3-6cycloalkylene;
• k is 1, 2 or 3;
• m is 1 or 2;
• n is zero, 1 or 2;
• p is 1 or 2;
• and
• q is 1 or 2;
• or a pharmaceutically acceptable salt thereof.