Aryl derivatives

Claim 2

1) A process for the preparation of a novel compound of formula (I) wherein k,p and q are independently 0 or 1, provided that when k is 1 then p must also be 1; Ar represents either: (i) naphthyl, tetrahydronaphthyl or pyridyl, any of which is optionally substituted by one or more substituents independently selected from C 1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C 1-4 alkoxy, halo, nitro, amino, carboxy, C 1-4 alkoxycarbonyl and hydroxy, or (ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and said optional substituents specified in (i) above; L is selected from -(CH 2 ) r (where r is 1-4), -0-, -CH 2 0-, - CH2S-, -OCH 2- , -CONH-, -NHCO-, -CO-and -CH 2 NH-, and, Ar' represents phenylene, thienylene or pyridylene, any of which may be optionally substituted by one or more substituents independently selected from those specified as optional substituents in definition (i) of Ar; X represents oxygen, sulphur or carbonyl, provided that at least one atom separates said carbonyl group from any carbonyl group in Q as defined below; Y is C 1-10 alkylene or C 1-10 alkenylene; Q represents a non-cyclic moiety selected from groups of. formula in which one of m and n is and the other is 1, and when n is 1 and m is 0, R' and R 2 are independently selected from hydrogen and C 1-4 alkyl, with the possibility that R 2 can also be C 5-7 cycloalkyl, or when n is 0 and m is 1, R' is independently selected from hydrogen, C 1-4 alkyl, groups as defined for Ar above and groups of formula -COR 3 in which R 3 is selected from C 1-4 alkyl (optionally substituted by a carboxy or C 1 . 4 alkoxycarbonyl group) and groups of formula -N(R 4 )R 5 in which R 4 is hydrogen or C 1-4 alkyl and R 5 represents hydrogen C 1-4 alkyl or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in the definition (i) or Ar, and R 2 is selected from hydrogen, C 1-4 alkyl, amino C 1-4 alkylamino, di-C 1 - 4 alkylamino, C 5-7 cycloakylamino, C 5-7 cycloakyl ( 1 . 4 alkyl) amino, anilino, N-C 1-4 alkylanilino and groups as defined for Ar above; or Q represents a cyclic moiety selected from 1-hydroxy-1,3,-dihydro-imidazol-2-one and groups of formula in which Z represents a C 2-5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom; and salts thereof; and salts thereof; with the proviso that- when q is 0, k is 0 or 1 and p is 1, Ar is phenyl or naphthyf, either being optionally substituted by one or more substituents as specified in definition (i) of Ar, and X is oxygen or sulphur (in the case when k is 1) Y is C 1-10 alkylene and Q represents said non-cyclic moiety as hereinbefore defined in which one of R 1 and R 2 is hydrogen or C 1- 4 alkyl; then the other of R' and R 2 is neither hydrogen nor C 1-4 alkyl; comprising:- a) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R' represents hydrogen, reacting a compound of formula (11) with a compound of formula (III) (in which one of R 6 and R 7 is a group R 2 as hereinbefore defined and the other is a group of formula Ar-(L-Ar')q-(X) k -(Y) p-as hereinbefore defined, and R 8 is a group capable of reacting with the NH group in the compound of formula (II) thereby to bring about formation of the corresponding hydroxamic acid or derivative thereof); b) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R' represents hydrogen, n is 1 and m is 0, reacting a compound of formula (IV) (wherein q, k, p, Ar, Ar`, L, X and Y are as hereinbefore defined) with Piloty's acid, i.e. the compound of formula PhSO 2 NHOH, or an appropriate analogue or derivative thereof; c) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R' represents hydrogen, reacting a compound of formula (V) (wherein R' is a group R 2 as hereinbefore defined or a group of formula Ar-(L-Ar')q-(X) k -(Y) p -as hereinbefore defined, as appropriate, and Z' is hydrogen or an appropriate protecting group) with an appropriate acylating agent, and where Z' is a protecting group, subjecting the reaction product to such conditions and/or reacting with one or more reagents as appropriate to effect removal of said protecting group; or d) for the preparation of compounds of formula (I) in which Q represents a cyclic group as hereinbefore defined, treating a compounds of formula (VI) (where Ar, Ar', L, X, Y, q, k and p are as hereinbefore defined and R 10 -R 11 -R 12 are chosen to be capable of cyclisation) with an agent or agents and under such reaction conditions to bring about cyclisation of said R 10 -R 11 -R 12 ; and optionally if desired, effecting one or more of the following inter-conversions in any desired order:- (i) when in the compound of formula (1) so formed, any of R', R Z and (in the definition of R') R 4 and R 5 are hydrogen atoms, converting said compound to a corresponding compound of formula (I) wherein any of said hydrogen atoms as desired, are converted to C 1-4 alkyl groups; (ii) converting the compound of formula (I) to a corresponding salt thereof; (iii) when in the compound of formula (I) so formed, n is 0 and m is 1 and R' is hydrogen, converting said compound to a corresponding compound of formula (I) wherein R' is a group of formula -COR 3 as hereinbefore defined; (iv) when in a compound of formula (I), n is 0, m is 1 and R' is a group of formula -COR a in which R 3 is a C 1-4 alkyl group substituted by carboxy, converting said compound to a corresponding compound in which R 3 is C 1-4 alkyl substituted by C 1-4 alkoxycarbonyl.

Claim 3

2) A process as claimed in claim 1(a) wherein the compound of formula (II) is used in the form of a salt thereof and the compound of formula (III) is an appropriate mixed anhydride or activated acid such as an acid halide and the reaction is effected in a suitable solvent in the presence of a base, such as an appropriate amine, to liberate the free hydroxylamine compound in situ .

Claim 4

3) A process as claimed in claim 1(b) wherein the reaction is effected in the presence of a base such as an alkali metal hydroxide or alkoxide.

Claim 5

4) A process as claimed in claim 1 (c) wherein the group Z' in the compound of formula (V) is a protecting group, and is selected from and acetyl, benzyl, O-benzyt, trityl, tetrahydropyranyl, O-tetrahydropyranyl, O-t-butyl and benzoyl.

Claim 6

5) A process as claimed in claim 1(c) when used to prepare a compound of formula (I) wherein Q represents a non-cyclic moiety (as defined in claim 1) in which n is 0 and m is 1, R' is an amino group or a mono-amine derivative and Z' is a protecting group and the acylating agent is an isocyanate of formula (VII). (wherein Q' is said R 2 group minus the -NH portion).

Claim 7

6) A process as claimed in claim 1(c) when used to prepare a compound of formula (I) in which Q represents a non-cyclic moiety (as defined in claim 1) and R 2 is other than as specified in claim 5 (whether Z is hydrogen or a protecting group) and, the acylating agent an appropriate mixed anhydride or activated acid, such as an acid halide.

Claim 8

7) A process as claimed in claim 1 (d) when used to prepare a compound of formula (I) in which Q is a group formula (wherein Z is as defined in claim 1) and one of the groups R 10 and R" terminates with a group of formula -CO 2 Q 2 - (where Q 2 is hydrogen, amino C 1-6 alkyl or aryl, and the other then terminates with an appropriate reactive group of formula -OQ 3 (wherein Q 3 is hydrogen or a protecting group such as benzyl or any of those defined above in respect of Z) or else the other terminates with a group of formula -NO 2 or -NHOH.

Claim 9

8) A process as claimed in claim 1(d) when used to prepare a compound of formula (I) in which Q is 1-hydroxy-1,3-dihydro-imidazol-2-one and, the compound of formula - (VI) is a compound of formula (VIII) (wherein Ar, Ar', L, X, Y, q, k and p are as defined in claim 1), the cyclisation being initiated by removal of the acetal group with an appropriate reagent such as trifluoroacetic acid.

Claim 10

9) A process as claimed in claim 1 wherein optional conversion (iii) is used for the preparation of compounds wherein R 3 is an alkyl group optionally substituted by a carboxy group or a C 1-4 alkoxycarbonyl group, and comprises reacting the compound of formula (I) with an appropriate acylating agent such as a mixed anhydride or a suitable activated acid.

Claim 11

10) A process as claimed in any of claims 1-9 when used to prepare a compound of formula (I) or salt thereof with the further proviso that when Q represents said non-cyclic moiety as defined in claim 1, (i) then whenn is 1 and m is 0, when q is 0 and Ar is as definition (ii) or q is 1, Ar is as definition (i) and L is -CH 2 -, -0-or -CH 2 0-and Ar' is phenylene optionally substituted as defined, then at least one or k and p must be 1; (ii) and when n is 0 and m is 1, when R' is hydrogen or C 1-4 alkyl and R 2 is phenyl optionally substituted by a single substituent selected from C 1-4 alkyl, C 1 . 4 alkoxy and phenyl optionally substituted by one or more substituents independently selected from these specified as optional substituents in definition (i) of Ar, then at least one of k and p must be 1, and in the case when k is 0 and p is 1, Y must be C 1-10 alkenylene.

Claim 12

11) A process as claimed in any of claim 1-10 when used to prepare a compound of formula (I) or salt thereof, with the further proviso that when q and p are 1, k is 0, Ar is unsubstituted phenyl, L is -0-, Q is said non-cyclic moiety as defined in claim 1, m is 0 and n is 1, L and -(Y)p-are meta-substituted relative to one another on the Ar', Ar' is phenylene and is unsubstituted or bears a substituent selected from hydroxy, amino, nitro, halo, methyl, ethyl, and C 1 - 3 alkoxy and/or a substituent selected from hydroxy, halo, methyl and ethyl, R 2 is hydrogen or C 1-4 alkyl and Y is a group of formula -CHG-(CH2) s -in which G is hydrogen or C 1 - 5 alkyl and s is 0-3; then R' is other than hydrogen.

Claim 13

12) A process as claimed in any of claims 1-11 when used to prepare a compound of formula (I) or salt thereof, with the further proviso that q is 0 and p is 1; Ar represents napthyl optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar, X (in the case when k is 1) is oxygen; and Q is said non-cyclic moiety as defined in claim 1, in which n is 0, m is 1 and R 2 is C 1-4 alkyl.

Claim 14

1 3) A process as claimed in any of claims 1- 1 2 when used to prepare a compound of formula (I) or salt thereof, with the further proviso that Ar represents phenyl optionally substituted by one or more substituents independently selected from those defined in definition (ii) of Ar; L is -O-or -CH 2 O-; Ar' is phenylene optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar; and Q is said non-cyclic moiety-as defined in claim 1, provided that when L is -CH 2 0-and y is C 1-6 alkenylene, then m is 1 and n is 0.

Claim 15

14) A process as claimed in claim 1, when used to prepare a compound of formula (1) selected from 3-pfienoxy-N-metfiylcinnamofiydroxamic acid, N-(3-phenoxycinnamyl)acetohydroxamic acid, N-(4-benzyioxybenryl)acetohydroxamic acid, N-[2-(5,6,7,8-tefrahydro-2-naphthyloxy)ethyl]-acetohydroxamic acid and N-(5,6,7,8-Tetrahydro-2-naphthylallyl)acetohydroxamic acid and salts thereof.

Claim 16

15) A method of preparing a pharmaceutical formulation, comprising a) preparing a compound of formula (I) or a physiologically acceptable salt thereof by a process as claimed in any of claims 1-14; and b) admixing the product of a) with a pharmaceutically acceptable carrier therefor and opfionally, one or more other pharmacologically active ingredients.

Claim 17

16) A method of delaying senescence in cut or picked plant matter or for regulating plant growth, by application to said matter or plant (before or after cutting or picking) of an effective amount of a compound of formula (I) as defined in claim 1 or a salt thereof.

Claim 18

1) Any novel compound of formula (I) wherein:- k,p and q are independently 0 or 1, provided that when k is 1 then p must also be 1; Ar represents erfher (i) naphthyl, tetrahydronaphthyl or pyridyl, any of which is optionally substituted by one or more substituents independently selected from C 1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C 1-4 alkoxy, halo, nitro, amino, carboxy, C 1-4 alkoacycarbonyl and hydroxy, or (ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and said optional substituents specified in (i) above; L is selected from -(CH 2 ) r -where r is 1-4), -0-, -CH 2 0-, -CH 2 S-, -OCH 2 -, -CONH-, -NHCO-, -CO-and -CH 2 NH-, and, Ar' represents phenylene, thienylene or pyridylene, any of which may be optionally substituted by one or more substituents independently selected from those specified as optional substituents in definition (i) of Ar; X represents oxygen, sulphur or carbonyl, provided that at least one atom separates said carbonyl group from any carbonyl group in Q as defined below; Y is C 1-10 alkylene or C 1-10 alkenylene; Q represents a non-cyclic moiety selected from groups of formula in which one of m and n is 0 and the other is 1, and when n is 1 and m is 0, R' and R 2 are independently selected from hydrogen and C 1-4 alkyl, with the possibility that R 2 can also be C 5-7 cycloalkyl, or when n is 0 and m is 1, R' is independently selected from hydrogen, C 1-4 alkyl, groups as defined for Ar above and groups of formula -COR 3 in which R 3 is selected from C 1-4 alkyl (optionally substituted by a carboxy or C 1-4 alkoxycarbonyl group) and groups of formula -N(R 4 )R 5 in which R 4 is hydrogen or C 1-4 alkyl and R 5 represents hydrogen C 1-4 alkyl or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in the definition (i) of Ar, and R 2 is selected from hydrogen, C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 5-7 cycloalkylamino, C 5-7 cycloakyl ( 1-4 alkyl) amino, anilino, N -C 1-4 alkylanilino and groups as defined for Ar above; or Q represents a cyclic moiety selected from 1-hydroxy-1,3,-dihydro-imidazol-2-one and groups of formula in which Z represents a C 2-5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom; and salts thereof; with the proviso that- when q is 0, k is 0 or 1 and p is 1, Ar is phenyl or naphthyl, either being optionally substituted by one or more substituents as specified in definition (i) of Ar, and X is oxygen or sulphur (in the case when k is 1) Y is C 1-10 alkylene and Q represents said non-cyclic moiety as hereinbefore defined in which one of R' and R 2 is hydrogen or C 1 . 4 alkyl; then the other of R' and R 2 is neither hydrogen nor C 1-4 alkyl.

Claim 19

2) A compound or salt as claimed in claim 1, with the further proviso that when Q represents said non-cyclic moiety as defined in claim 1, (i) then when n is 1 and m is 0, when q is 0 and Ar is as definition (ii) or q is 1, Ar is as definition (i) and L is -CH 2- , -0-or -CH 2 0-and Ar' is phenylene optionally substituted as defined, then at least one or k and p must be 1; (ii) and when n is 0 and m is 1, whenR' is hydrogen or C 1-4 alkyl and R 2 is phenyl optionally substituted by a single substituent selected from C 1-4 alkyl, C 1-4 alkoxy and phenyl optionally substituted by one or more substituents independently selected from these specified as optional substituents in definition (i) of Ar, then at least one of k and p must be 1, and in the case when k is 0 and p is 1, Y must be C 1-10 alkenylene.

Claim 20

3) A compound or salt as claimed in claim 1 or claim 2, with the further proviso that when q and p are 1, k is 0, Ar is unsubstituted phenyl, L is -0-, Q is said non-cyclic moiety as defined in claim 1, m is 0 and n is 1, L and -(Y)p -are meta-substituted relative to one another on the Ar', Ar' is phenylene and is unsubstituted or bears a substituent selected from hydroxy, amino, nitro, halo, methyl, ethyl and C 1-3 alkoxy and/or a substituent selected from hydroxy, halo, methyl and ethyl, R' is hydrogen or C 1-4 alkyl and Y is a group of formula -CHG-(CH 2 ) s -in which G is hydrogen or C 1-5 alkyl and s is 0-3; thenR' is other than hydrogen. 4) A compound or salt as claimed in any of claim 1-3 wherein q is 0 and p is 1; Ar represents naphthyl optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar; X (in the case when k is 1) is oxygen; and Q is said non-cyclic moiety as defined in claim 1, in which n is 0, m is 1 and R 2 is C 1-4 alkyl. 5) A compound or salt as claimed in any of claims 1-4 wherein Ar represents phenyl optionally substituted by one or more substituents independently selected from those defined in definition (ii) of Ar; L is -0-or -CH 2 O-; Ar' is phenylene optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar; and Q is said non-cyclic moiety as defined in claim 1, provided that when L is -CH 2 O-and y is C 1-6 alkenylene, then m is 1 and n is 0.

Claim 21

6) A compound selected from the following 3-phenoxy-N-methylcinnamohydroxamic acid, N-(3-phenoxycinnamyl)acetohydroxamic acid, N-(4-benzyloxybenryl)acetohydroxamic acid, N -[2-(5,6,7,8-tetrahydro-2-naphthyloxy)ethyl]-acetohydroxamic acid N-(5,6,7,8-Tetrahydro-2-naphthylallyl)acetohydroxamic acid and salts thereof.

Claim 22

7) A pharmaceutical formulation comprising a compound as claimed in claim 3 when dependent on claim 2 or a physiologically acceptable salt thereof, optionally one or more other pharmacologically active agents, and a pharmaceutically acceptable carrier therefor.

Claim 23

8) A pharmaceutical formulation as claimed in claim 7, wherein the formulation is adapated for pulmonary administration and the compound of formula (I) is 3-phenoxy-N-methylcinnamohydroxamic acid.

Claim 24

9) A process for the preparation of a compound of formula - (I) as defined in claim 1 or a salt thereof, comprising:- a) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as defined in claim 1) in which R' represents hydrogen, reacting a compound of formula (II) with a compound of formufa (III) (in which one of R 6 and R 7 is a group R 2 as defined in claim 1 and the other is a group of formula Ar-(L-Ar') q -(X) k -(Y) p - as definedin claim 1, and R 5 is a group capable of reacting with the NH group in the compound of formula (II) thereby to bring about formation of the corresponding hydroxamic acid or derivative thereof); b) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as defined in claim 1) in which R' represents hydrogen, n is 1 and m is 0, reacting a compound of formula (IV) (wherein q, k, p, Ar, Ar 2 , L, X and Y are as defined in claim 1) with Piloty's acid, i.e. the compound of formula PhSO 2 NHOH, or an appropriate analogue or derivative thereof; c) For the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as defined in claim 1) in which R' represents hydrogen, reacting a compound of formula (V) (wherein R 9 is a group R 2 as defined in claim 1 or a group of formula Ar-(L-Ar')q-(X) k -(Y) p -as defined in claim 1, as appropriate, and Z' is hydrogen or an appropriate protecting group) with an appropriate acylating agent, and where Z' is a protecting group, subjecting the reaction product to such conditions and/or reacting with one or more reagents as appropriate to effect removal of said protecting group; or; d) for the preparation of compounds of formula (1) in which Q represents a cyclic group as defined in claim 1, treating a compounds of formula (VI) (where Ar, Ar', L, X, Y, q, k and p are as defined in claim 1 and R 10 -R 11 -R 12 are chosen to be capable of cyclisation) with an agent or agents and under such reaction conditions to bring about cyclisation of said R 10 -R 11 -R 12 ; and optionally if desired, effecting one or more of the following inter-conversions in any desired order:-(i) when in the compound of formula (I) so formed, any of R', R 2 and (in the definition of R') R 4 and R 5 are hydrogen atoms, converting said compound to a corresponding compound of formula (I) wherein any of said hydrogen atoms as desired, are converted to C 1-4 alkyl groups; (ii) converting the compound of formula (I) to a corresponding salt thereof; (iii) when in the compound of formula (I) so formed, n is 0, m is 1 and R' is hydrogen, converting said compound to a corresponding compound of formula (I) wherein R' is a group of formula -COR 3 as'defined in claim 1; (iv) when in a compound of formula (I), n is 0, m is 1 and R' is a group of formula -COR 3 in which R 3 is a C 1-4 alkyl group substituted by carboxy, converting said compound to a corresponding compound in which R' is C 1-4 alkyl substituted by C 1-4 alkoxycarbonyl.

Claim 25

10) A compound or physiologically acceptable salt as claimed in claim 3 when dependent on claim 2, for use in medical therapeutic treatment or prophylaxis.

Claim 26

11) Use of a compound or physiologically acceptable salt as claimed in claim 2 in the manufacture of anti-spasmogenic agents.

Claim 27

12) Use as claimed in claim 11 wherein the agents are anti- asthmatic.

Claim 28

13) Use of a compound or physiologically acceptable salt as claimed in claim 3 when dependent on claim 1 in the manufacture of anti-inflammatory, analgesic or anti-pyretic agents.