Novel compounds

Claim 2

A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein L is NH or O; X is a moiety capable of hydrogen bonding to the NH group depicted in formula (I); R₁ and R₂ are independently selected from hydrogen, halogen, CF₃, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-7 acyl, C 1-7 acylamino, C 1-6 alkylsulphonylamino, N-(C 1-6 alkylsulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphinyl, carboxy, C 1-6 alkoxycarbonyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, phenyl or phenyl C 1-4 alkyl groups or optionally N-disubstituted by C 4-5 polymethylene; and Z is a group of formula (a), (b) or (c) wherein n is 2 or 3; p is l or 2; q is l to 3; r is l to 3; and R₃ or R₄ is C 1-7 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl or C 2-7 alkenyl-C 1-4 alkyl.

Claim 3

A compound according to claim l or formula (II): wherein X¹ is COR₅ or a group C-R₆ as defined in claim l; and the remaining variables are as defined in claim l.

Claim 4

A compound according to claim 2 wherein n is 2.

Claim 5

A compound according to claim 2 or 3 wherein R₃ is methyl or ethyl.

Claim 6

A compound according to claim l of formula (IV): wherein r¹ is l or 2 and the remaining variables are as defined in claims l and 2.

Claim 7

A compound according to claim 5 wherein r is 2.

Claim 8

A compound according to any one of claims l to 6 wherein L is NH.

Claim 9

A compound according to any one of claims l to 7 wherein R₁ and R₂ are both hydrogen.

Claim 10

A compound according to any one of claims l to 8 wherein X is C-OCH₃, C-OC₂H₅, C-OC₃H₇, C-CO₂CH₃, C-CO₂C₂H₅ or SO₂N(CH₃)₂.

Claim 11

l0. (endo)-N-(9-Methyl-9-azabicyclo[3.3.l]non-3-yl)-­N′-2-methoxyphenyl urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-2-­methoxyphenyl urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′(2-­pyridyl-l-oxide)urea, (endo)-O-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N-(2-­methoxyphenyl)carbamate, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(5-­fluoro-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N-(2,4-­dimethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(2-­methoxy-5-methylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(5-­chloro-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2,5-dimethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(2-­methoxy-5-nitrophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(2-­methoxy-4-methoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(2-­ethoxy-5-fluorophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(4-fluoro-2-methoxyphenyl)urea, N-(l-azabicyclo[2,2,2]oct-3-yl)-N′-(2-methoxyphenyl)­urea, O-(l-azabicyclo[2,2,2]oct-3-yl)-N-(2-methoxyphenyl)­carbamate, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-n-propyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-ethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(5-­dimethylaminocarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-methoxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- iso propoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-benzyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-hydroxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- sec -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- n -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- tert -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-allyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-phenoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-hydroxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl]-N′-­(4-hydroxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-methylaminocarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-hydroxy-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-ethoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-dimethylaminocarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-dimethylaminosulphonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-nitrophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methoxymethylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methylthiophenyl)urea, or a hydrochloride salt of any of the foregoing.

Claim 12

l0. (endo)-N-(9-Methyl-9-azabicyclo[3.3.l]non-3-yl)-­N′-2-methoxyphenyl urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-2-­methoxyphenyl urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′(2-­pyridyl-l-oxide)urea, (endo)-O-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N-(2-­methoxyphenyl)carbamate, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(5-­fluoro-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N-(2,4-­dimethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(2-­methoxy-5-methylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(5-­chloro-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2,5-dimethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(2-­methoxy-5-nitrophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(2-­methoxy-4-methoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-(2-­ethoxy-5-fluorophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(4-fluoro-2-methoxyphenyl)urea, N-(l-azabicyclo[2,2,2]oct-3-yl)-N′-(2-methoxyphenyl)­urea, O-(l-azabicyclo[2,2,2]oct-3-yl)-N-(2-methoxyphenyl)­carbamate, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-n-propyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-ethoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3- yl)-N′-(5-­dimethylaminocarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-methoxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- iso propoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-benzyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-hydroxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- sec -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- n -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2- tert -butyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-allyloxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(2-phenoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-hydroxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl]-N′-­(4-hydroxycarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-methylaminocarbonyl-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-N′-­(5-hydroxy-2-methoxyphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-ethoxycarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-dimethylaminocarbonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-dimethylaminosulphonylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-nitrophenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methoxymethylphenyl)urea, (endo)-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl)-N′-­(2-methylthiophenyl)urea, or a hydrochloride salt of any of the foregoing.

Claim 13

A process for the preparation of a compound of formula (I), as defined in Claim l, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (V): with a compound of formula (VI): J-Z¹      (VI) wherein E is: wherein X′ is X as defined, or N, and Y is hydrogen or joined to G as defined, or (when X is N⁺⁻O⁻) E and Y together are joined to G to form (V)′: G is COQ₁ where Q₁ is a group displaceable by a nucleophile, G and Y together =C=O or G is joined to E as defined, or G is hydrogen (when Y is hydrogen); and, when G is COQ₁ or G-N-Y is N=C=O, J is NH₂, or OH or a reactive derivative thereof or, when G is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-L-linkage with the compound of formula (V); Z¹ is Z as defined or Z wherein R₃/R₄ is replaced by a hydrogenolysable protecting group; and the remaining variables are as defined in claim l; and thereafter optionally converting any R₁ and R₂ group to another R₁ and R₂ group respectively, converting Z¹, when other than Z, to Z; converting X′ when N to N⁺-O⁻ or X to other X: and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

Claim 14

A process for the preparation of a compound of formula (I), as defined in Claim l or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (X): with a compound of formula (XI): MHN -L-Z      (XI) wherein M is a metal ion and the remaining variables are as defined in claim l; and thereafter optionally converting Z¹,when other than Z, to Z¹; converting X′ when N to N⁺-O⁻ or X to other X; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

Claim 15

A pharmaceutical composition comprising a compound according to any one of claims l to l0, and a pharmaceutically acceptable carrier.

Claim 16

A compound according to any one of claims l to l0, for use as an active therapeutic substance.

Claim 17

A compound according to any one of claims l to l0 for use in the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.

Claim 18

Use of a compound according to any one of claims l to l0 in the preparation of a medicament for the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.