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Title:
BENZOXEPINE AND RELATED COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/1989/011477
Kind Code:
A1
Abstract:
A compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof wherein: A represents >C=X or a bond; X represents O or S; Y represents N or N+-O- or a moiety CR10; Z° represents O, CH2, NR or S(O)p; R represents hydrogen, alkyl or alkylcarbonyl; a process for preparing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.

Inventors:
WEBSTER RICHARD ANDREW BENTLEY (GB)
CASSIDY FREDERICK (GB)
Application Number:
PCT/GB1989/000588
Publication Date:
November 30, 1989
Filing Date:
May 30, 1989
Export Citation:
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Assignee:
BEECHAM GROUP PLC (GB)
International Classes:
C07D313/08; C07D405/04; C07D491/052; (IPC1-7): C07D313/08; C07D337/08; C07D405/04; C07D491/04
Foreign References:
EP0234656A21987-09-02
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Claims:
Claims A
1. A compound of formula (I): or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof wherein: A represents >C=X or a bond; X represents 0 or S; Y represents N or N+0~ or a moiety CRχo wherein Rχθ is as defined below; Z° represents O, CH2, NR or S(0)p; R represents hydrogen, alkyl or alkylcarbonyl Rx, R2, 3 and R4 each independently represent hydrogen or alkyl; or Rx and R2 together represent a C27 polymethylene chain; or R3 and R4 together represent a C27 polymethyene chain; R5 represents hydrogen, hydroxy, alkoxy or acyloxy; Rg is hydrogen or R5 and Rg together represent a bond; when A represents >C=X, then R7 is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino .
2. optionally substituted by an alkyl or alkenyl ^..oup or.
3. by an alkanoyl group optionally substituted by up to.
4. three halo atoms, by a phenyl group optionally.
5. substituted by alkyl, alkoxy or halogen; substituted or.
6. unsubstituted aryl or substituted or unsubstituted . 01 heteroaryl; and 0.
7. 8 represents hydrogen or alkyl; 09 or R7 and R8 together represent a linking chain of 10 formula A!A2, A1 being attached to the nitrogen atom 11 of the moiety NA and A2 being attached to the group 12 A on the said moiety, and wherein A1 represents a 13 substituted or unsubstituted methylene group, A2 14 represents 2 or 3 linking members, one of the linking 15 members optionally representing 0, S or NR' and the 16 other linking members each independently representing 17 a substituted or unsubstituted methylene group; 18 R' represents hydrogen, alkyl, alkanoyl, phenyl Cχ_4~ 19 alkyl, arylcarbonyl wherein the aryl group may be 20 substituted or unsubstituted; or R' is mono or 21 bicyclic heteroarylcarbonyl; 22 when A represents a bond, then R7 and R8 together with 23 the nitrogen atom to which they are attached, form an 24 unsaturated heterocyclic ring having 5 to 7 ring atoms, 25 which ring atoms comprise up to 2 further nitrogen 26 atoms and a carbon atom, the carbon atom being 27 substituted with either an oxo group or a thioxo group 28 the remaining ring atoms being substituted or 29 unsubstituted; 30 Rg and R o are each independently selected from the 31 class of hydrogen, substituted or unsubstituted alkyl, 32 alkoxy, C3_8 cycloalkyl, hydroxy, nitro, cyano, halo, 33 formyl, carboxy, a group of formula Raτ!, RbRcNT, 34 RaT2NH, RdCO.O, RdCS.O, Rd(OH)CH, Rd(SH)CH, 35 RdC(=N.0H), RdC(=N.NH2) or alkenyl optionally _6 substituted by alkylcarbonyl, nitro or cyano, providing 37 that when Y is CRχo then at least one of Rg or Rχo is not hydrogen; Ra represents Rd or RdO and R represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, optional substituents for Rd being up to 3 substituents selected from alkyl, alkoxy, halo, haloalkyl, nitro and cyano; R and Rc each independently represent hydrogen, alkyl or alkylcarbonyl; T represents a bond or T1, T1 represents CS or T2 and T2 represents CO, SO or SO2; and p represents zero or an integer 1 or 2.
8. 2 A compound according to claim 1, of formula (IA) , or when the compound of formula (IA) contains a salifiable group, a pharmaceutically acceptable salt thereof: x wherein: X is oxygen or sulphur; Y is CRχo as defined below, or is N or N+0"; R and R2 are independently selected from hydrogen or cl6 alkyl or together are C2_7 polymethylene; R3 and R4 are as defined for and R2 above; R5 is hydrogen, hydroxy, Cχ_g alkoxy or Cχ_7 acyloxy and Rg is hydrogen or R5 and Rg together are a bond; R7 is hydrogen; Cχ_g alkyl optionally substituted by up to three halo atoms, by hydroxy, Cχ_g alkoxy, Cχ_g alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent Cχ_g alkyl groups or disubstituted by C4_5 polymethylene; C2g alkenyl; amino optionally substituted by a Cχ_g alkyl or C2g alkenyl group or by a Cχ_g alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by Cχ_g alkyl, Cχ_g alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of Cχ_g alkyl, Cχ_g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C _ 2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cχ_g alkyl groups; or (when X is 0), R7 is selected from the class of carboxy, Cχ_g alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two Cχ_g alkyl groups; and R8 is hydrogen or Cχ_g alkyl; or R7 and R8 together are CH2(CH2)nz(CH2)m wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH2, 0, S or NRx wherein Rxx is hydrogen, Cχ_g alkyl, C27 alkanoyl, phenyl Cχ_4alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two of Cχ_g alkyl, Cχ_g alkoxy or halogen; or Rxx is heteroarylcarbonyl; when Y is N or N+0", Rg is hydrogen or, when is CRχo, either one of Rg and Rχo is hydrogen and the other is selected from the class of Cχ_g alkylcarbonyl, cχ_g alkoxycarbonyl, Cχ_g alkylcarbonyloxy, Cχ_g alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, Cχ_g alkylsulphinyl, Cχ_g alkylsulphonyl, Cχ_g alkoxysulphiny1, Cχ_g alkoxysulphonyl, Cχ_g alkylcarbonylamino, Cχ_g alkoxycarbonylamino, Cχ_g alkylthiocarbonyl, Cχ_g alkoxythiocarbonyl, Cχ_g alkylthiocarbonyloxy, Cχ_g alkylthiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two Cχ_g alkyl groups, or Cχ_g alkylsulphinylamino, Cχ_g alkylsulphonylamino Cχ_g alkoxysulphinylamino or Cχ_g alkoxysulphonylamino or ethenyl terminally substituted by Cχ_g alkylcarbonyl, nitro or cyano, or C(Cχ_g alkyl)N0H or C(Cχ_g alkyl)NNH2; or one of Rg and R o is nitro, cyano or Cχ_3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two Cχ_g alkyl or by C27 alkanoyl; or Rg is hydrogen and Rχo is Cχ_g alkyl or C3_8 cycloalkyl; suitably R8NCXR7 being trans to the R5 group when R5 is hydroxy, Cχ_g alkoxy or Cχ_7 acyloxy.
9. 3 A compound according to claim 1 or claim 2, wherein Rx, R2, R3 and R4 each represent hydrogen.
10. 4 A compound according to any one of claims 1 to 3, wherein R5 is hydroxy and Rg is hydrogen.
11. 5 A compound according to any one of claims 1 to 4, wherein the moiety R8 AR7 represents a pyrrolidonyl group.
12. 6 A compound according to claim 1, being trt____ 4hydroxy7nitro5(2oxopyrrolidinlyl)2,3,4,5 tetrahydro1benzoxepine; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
13. 7 The preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof which comprises; i) acylating a compound of formula (III): wherein, Y1 is Y or a group convertible thereto, Rg1 is Rg or a group or atom convertible thereto, Rx to R4 and Z° are as hereinbefore defined, R51 is hydroxy, Cχ_g alkoxy or Cχ_7 acyloxy, and Re1 is hydrogen or Cχ_g alkyl, the R8!NH group being trans to the R51 group, a) with an acylating agent of formula (IV): Rχ2CbLχ (IV) wherein x is a leaving group, and Rχ2 is hydrogen; Cχ_g alkoxycarbonyl; Cχ_g alkyl optionally substituted by halogen, hydroxy, Cχ_g alkoxy, Cχ_g alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R7; C26 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R7; or a group convertible to R7 as hereinbefore defined, and thereafter, when R8 is hydrogen and Rχ2 is (CH2)ZL2' where z is 3 or 4 and L2 is a leaving group, cyclising the resultant compound; b) with a compound of formula (V): X=C=N.R13 (V) wherein χ3 is hydrogen, Cχ_g alkyl, C2g alkenyl, Cχ_g alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by Cχ_g alkyl, Cχ_g alkoxy or halogen; and X is oxygen or sulphur, and thereafter when Rχ3 is hydrogen, optionally converting Rχ3; or ii) for compounds of formula (I) wherein R7 and R8 together represent a linking chain of formula A!A2 as defined above in relation to formula (I) by reacting a compound of formula (VI): wherein Rx, R2, R3, R4, Rg1, Y1 and Z° are as hereinbefore defined with a compound of formula (VII) : R15NHC0Rχ4 (VII) wherein Rχ4 and Rχ5 together represent a linki._j chain A1A2; or ϋi) for compounds of formula (I) wherein A represents a bond and R7 and R8 together with the nitrogen to which they are attached form the above defined unsaturated heterocyclic ring, by reacting a compound of formula (VI) as defined above with an activated form of a compound of formula (VIIA) : R3NHR7 (VIIA) wherein R7 and R8 are as defined above; and thereafter if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into a further compound of formula (I); (ii) converting Y1 to Y; (iii) converting Rg1 to Rg; (iv) forming a pharmaceutically acceptable salt of the compound of formula (I); or (v) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
14. 8 A pharmaceutical composition comprising a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
15. A method of treatment of respiratory tract disorders or hypertension in mammals, which comprises administering to the suffering mammal an effe llve amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
16. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders or hypertension.
Description:
NOVEL COMPOUNDS

This invention relates to novel compounds having smooth muscle relaxant activity, to processes for their preparation and to their use as pharmaceuticals.

EP-A-76075, 91748, 93535, 95316, 107423, 120426, 120427, 126311, 126350, 126367, 138134, 205292 and European Patent Application Number 88312288.9 describe benzopyrans and pyrano(3,2-c)pyridine derivatives having inter alia antihypertensive activity.

A group of heterocyclyl derivatives has now been discovered, having smooth muscle relaxant activity, and such compounds are therefore potentially useful as bronchodilators in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma, and also in the treatment of hypertension. Such compounds are also indicated as of potential use in the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, uterus or the urinary tract including the ureter. Such disorders respectively include irritable bowel syndrome and diverticular disease; premature labour; incontinence; renal cholic and disorders associated with the passage of kidney stones. They are also indicated as of potential use in the treatment of cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease; and also in the treatment and/or prophylaxis of disorders associated with pulmonary hypertension and of disorders associated with right heart failure.

Accordingly, the present invention provides a .—π.pound of formula (I):

(I)

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein: A represents >C=X or a bond; X represents O or S; Y represents N or N + -0 ~ or a moiety CRIQ wherein R l O is as defined below; Z° represents O, CH2, NR or S(0)p; R represents hydrogen, alkyl or alkylcarbonyl R_, R2, R3 and R each independently represent hydrogen or alkyl; or R_ and R2 together represent a C2-7 polymethylene chain; or R3 and R together represent a 2- 7 polymethyene chain; R5 represents hydrogen, hydroxy, alkoxy or acyloxy; Rg is hydrogen or R5 and Rζ together represent a bond; when A represents >C=X, then R7 is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalk lamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or

02 by an alkanoyl group optionally substituted by to

03 three halo atoms, by a phenyl group optionally

04 substituted by alkyl, alkoxy or halogen; substituted or ,5 unsubstituted aryl or substituted or unsubstituted 6 heteroaryl; and 7 Rø represents hydrogen or alkyl; 8 or R 7 and R β together represent a linking chain of 9 formula -A 1 -A 2 -, A 1 being attached to the nitrogen atom 0 of the moiety -N-A- and A 2 being attached to the group 1 A on the said moiety, and wherein A 1 represents a 2 substituted or unsubstituted methylene group, A 2 3 represents 2 or 3 linking members, one of the linking 4 members optionally representing O, S or NR' and the 5 other linking members each independently representing 6 a substituted or unsubstituted methylene group; 7 R' represents hydrogen, alkyl, alkanoyl, phenyl Cτ__4- 8 alkyl, arylcarbonyl wherein the aryl group may be 9 substituted or unsubstituted; or R' is mono- or 0 bi-cyclic- heteroarylcarbonyl; 1 when A represents a bond, then R7 and R Q together with 2 the nitrogen atom to which they are attached, form an 3 unsaturated heterocyclic ring having 5 to 7 ring atoms, 4 which ring atoms comprise up to 2 further nitrogen 5 atoms and a carbon atom, the carbon atom being 6 substituted with either an oxo group or a thioxo group 7 the remaining ring atoms being substituted or 8 unsubstituted; 9 R9 and RT_ Q are each independently selected from the 0 class of hydrogen, substituted or unsubstituted alkyl, 1 alkoxy, 03.3 cycloalkyl, hydroxy, nitro, cyano, halo, 2 formyl, carboxy, a group of formula R a !-, R*°R C NT-, 3 R a T 2 NH-, R d CO.O-, R d CS.O-, R d (OH)CH-, R d (SH)CH-, * 4 R d C(=N.0H)-, R d C(=N.NH 2 )- or alkenyl optionally 5 substituted by alkylcarbonyl, nitro or cyano, providing ' 6 that when Y is CR]_o then at least one of R9 or Rχo is

not hydrogen; R a represents R or R 0- and R d represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, optional substituents for R d being up to 3 substituents selected from alkyl, alkoxy, halo, haloalkyl, nitro and cyano; B and R c each independently represent hydrogen, alkyl or alkylcarbonyl; T represents a bond or T 1 , T 1 represents -CS- or T 2 and T 2 represents -CO-, -SO- or -SO2-; and p represents zero or an integer 1 or 2.

Suitable substituents for any aryl or heteroaryl group represented by R7 include one or more groups or atoms selected from alkyl, alkoxy, hydroxy, halogen, fluoroalkyl, nitro, cyano, carboxy or an ester thereof, alkylcarbonyloxy, amino, monoalkylamino , dialkylamino, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl.

When the linking chain -A 1 -A 2 - comprises substituted methylene groups it is favoured if one or two of methylene groups are substituted, in particular it is favoured if the methylene group represented by -A 1 - is substituted.

Suitable substituents for any methylene group in -A 1 -A 2 - include alkyl groups, especially methyl or ethyl and in particular methyl.

In one particular aspect when A •represents >C=X, the linking chain -A 1 -A 2 - (and thus R7 and R3 together) represent a moiety of formula -CH2 ~ ( CH 2)n~ z ~( CH 2)m~ wherein m and n are 0 to 2 such that m + n is 1 or 2

and Z is CH2 , O , S or NR ' wherein R ' is as deHned above.

Suitably R' represents hydrogen, Cι_g alkyl, C2-7 alkanoyl, phenyl-Cι_4~ alkyl, naphthylearbony1, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthy1 ring by one or two of Cι_s alkyl, Cι_g alkoxy or halogen; or R' is mono- or bi-cyclic- heteroarylcarbonyl.

Suitably, when Y is N or N + -0 ~ , Rg is hydrogen.

Suitably, when Y is CRIQ, then one of R9 and Rτ_o is hydrogen.

In particular, when Y is C χo, one of Rg and Rτ__ is hydrogen and the other is selected from substituted or unsubstituted alkyl, alkoxy, C3..8 cycloalkyl, hydroxy, nitro, cyano, halo, formyl, carboxy, a group of formula R 3 ! 1 -, R b R c NT-, R a T 2 NH-, R d C0.0-, R d CS.O-, R d (OH)CH-, R d (SH)CH-, R d C(=N.0H)-, R d C(=N.NH 2 )- or alkenyl optionally substituted by alkylcarbonyl, nitro or cyano, wherein R a , R* 3 , R c , R , T, T 1 and T 2 are as defined in relation to formula (I).

Also to be mentioned are those compounds wherein one of Rg and Rχo is hydrogen and the other is selected from the class of Cι_s alkylcarbonyl, C -Q alkoxycarbonyl, c l -6 alkylcarbonyloxy, C -Q alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C]__6 alkylsulphinyl, Cτ__6 alkylsulphonyl, Cτ__6 alkoxysulphiny1, Cτ._6 alkoxysulphonyl, Cι_6 alkylcarbonylamino, C]__6 alkoxycarbonylamino, Cχ_6 alkyl-thiocarbonyl, Cτ__6 alkoxy-thiocarbonyl, Cι_β alkyl-thiocarbonyloxy, C -s alkyl-thiomethyl, formyl or a inosulphinyl,

aminosulphonyl or aminocarbonyl, the amino moi-^y being optionally substituted by one or two Cχ_g alkyl groups, or C _6 alkylsulphinylamino, Cχ_g alkylsulphonylamino

Cχ_g alkoxysulphinylamino or Cχ_g alkoxysulphonylamino or ethenyl terminally substituted by Cχ_g alkylcarbonyl, nitro or cyano, or -C(Cχ_g alkyl)N0H or

-C(Cχ_g alkyl)NNH 2 .

In one aspect, the present invention provides a compound of formula (IA) following wholly within the scope of the abovementioned formula (I) or, when the compound of formula (IA) contains a salifiable group, a pharmaceutically acceptable salt thereof:

wherein:

X is oxygen or sulphur;

Y is CRio as defined below, or is N or N+-0";

Rl and R2 are independently selected from hydrogen or Cχ_6 alkyl or together are C2-7 polymethylene;

R3 and R4 are as defined for R and R2 above;

R5 is hydrogen, hydroxy, Cχ_6 alkoxy or Cχ_7 acyloxy and Rg is hydrogen or R5 and Rg together are a bond;

R7 is hydrogen; Cχ_g alkyl optionally substit - ^ d by up to three halo atoms, by hydroxy, Cχ_g alkoxy, Cχ_g alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent Cχ_g alkyl groups or disubstituted by C4_5 polymethylene; C2-6 alkenyl; amino optionally substituted by a Cχ_g alkyl or C2-6 alkenyl group or by a Cχ_g alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by Cχ_g alkyl, Cχ_g alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of Cχ_g alkyl, Cχ_g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, Cχ_ 2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cχ_g alkyl groups; or (when X is 0), R7 is selected from the class of carboxy, Cχ_g alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two Cχ_g alkyl groups; and

Rβ is hydrogen or Cχ_g alkyl; or

R7 and RQ together are -CH2-(CH2)n -Z -( H2) m - wherein m and n are 0 to 2 such that + n is 1 or 2 and Z is CH2, O, S or NRxx wherein Rxx is hydrogen, Cχ_g alkyl, C2-7 alkanoyl, phenyl Cχ_4-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of Cχ_g alkyl, Cχ_g alkoxy or halogen; or Rxx is heteroarylcarbonyl;

when Y is N or N + -0 ~ , Rg is hydrogen or, when Y is CR ø either one of Rg and Rχo is hydrogen and the other is selected from the class of Cχ_g alkylcarbonyl, Cχ_g alkoxycarbonyl, Cχ_g alkylcarbonyloxy, Cχ_g alkylhydroxymethyl, nitro, cyano, chloro,

trifluoromethyl, Cχ_g alkylsulphinyl, Cχ_g alkylsulphonyl, Cχ_g alkoxysulphiny1, Cχ_g alkoxysulphonyl, Cχ_g alkylcarbonylamino, Cχ_g alkoxycarbonylamino, Cχ_g alkyl-thiocarbonyl, Cχ_g alkoxy-thiocarbonyl, Cχ_g alkyl-thiocarbonyloxy, Cχ_g alkyl-thiomethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two Cχ_g alkyl groups, or Cχ_g alkylsulphinylamino, Cχ_g alkylsulphonylamino Cχ_g alkoxysulphinylamino or Cχ_g alkoxysulphonylamino or ethenyl terminally substituted by Cχ_g alkylcarbonyl, nitro or cyano, or -C(Cχ_g alkyl)NOH or -C(Cχ_g alkyl)NNH2; or one of Rg and Rχo is nitro, cyano or C _3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two Cχ_g alkyl or by C2-.7 alkanoyl; or Rg is hydrogen and R o is Cχ_g alkyl or C3_β cycloalkyl; suitably R8NC R7 being trans to the R5 group when R5 is hydroxy, Cχ_g alkoxy or Cχ_ acyloxy.

Preferably X is oxygen.

Y is usually C-Rχo wherein R o is as defined in formula (I).

Cχ_g alkyl groups or alkyl containing moieties in R to Rχθ may be selected from methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Examples of Rχ/R2, R3/R4 also include C3, C4, C5, Cg or C7 polymethylene.

When R5 is Cχ_g alkoxy and Rg is hydrogen, preferred examples of R5 include methoxy and ethoxy, of which methoxy is more preferred. When R5 is Cχ_7 acyloxy and R is hydrogen, a preferred class of R5 is

unsubstituted carboxylic acyloxy, such as uns - tituted aliphatic acyloxy (formyloxy or C_;_7 alkanoyloxy) or benzoyloxy. However, it is preferred that R5 and Rg together are a bond, or R5 and Rg are both hydrogen, or, in particular, that R5 is hydroxy and Rg is hydrogen.

Favourably, R β , when R7 and R3 are not joined together, is hydrogen or methyl, most preferably hydrogen.

A sub-group of R7, when Cχ_g alkyl substituted by halogen is Cχ_g alkyl substituted by fluoro, chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by one, two or three fluoro, chloro or bromo.

Examples of R7, when Cχ_g alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.

A sub-group of R7, when Cχ_g alkyl substituted by Cχ_g alkoxy is Cχ_g alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.

A sub-group of R7, when Cχ_g alkyl substituted by Cχ_g alkoxycarbonyl is Cχ_g alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl.

Examples of R7, when Cχ_g alkyl substituted by carboxy include methyl or ethyl terminally substituted by carboxy.

Examples of R7 when alkyl substituted by amin , optionally substituted by one or two independent Cχ_g alkyl groups include a group (CH2)qNR a Rb where q is 1 to 6, and R a and Rfc are each independently hydrogen or Cχ_g alkyl or together are C4 or C5 polymethylene. Examples of q include 1 and 2, in particular 1. Preferably R a and Rfc are each independently selected from hydrogen and methyl.

Examples of R7, when C2_ alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists.

Examples of R7 when amino optionally substituted as hereinbefore defined include an amino optionally substituted by a methyl, ethyl, propyl, butyl, allyl or trichloroacetyl group or by a phenyl group optionally substituted by one methyl, methoxy or chloro group or atom, in particular amino, methylamino and phenylamino optionally substituted in the phenyl ring by one methyl, methoxy or chloro group or atom.

Examples of R7 aryl include phenyl and naphthyl of which phenyl is preferred.

A sub-class of R7 heteroaryl is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl of which 5- or 6-membered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one

02 heteroatom, are the same or different.

03

04 Examples of 5- or 6-membered monocyclic heteroaryl

05 containing one, two or three heteroatoms which are

06 selected from the class of oxygen, nitrogen and sulphur

07 include furanyl, thiophenyl, pyrrolyl, oxazolyl,

08 thiazolyl, imidazolyl and thiadiazolyl, and pyridinyl,

09 pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

10 Preferred examples of such groups include furanyl,

11 thiophenyl, pyrrolyl and pyridyl, in particular 2- and

12 3-furanyl, 2- and 3-pyrrolyl, 2- and 3-thiophenyl, and

13 2-, 3- and 4-pyridyl. 14

15 Examples of 9- or 10-membered bicyclic heteroaryl

16 containing one, two or three heteroatoms which are

17 selected from the class of oxygen, nitrogen and sulphur

18 include benzofuranyl, benzothiophenyl, indolyl and

19 indazolyl, quinolinyl and isoquinolinyl, and

20 quinazoninyl. Preferred examples of such groups

21 include 2- and 3-benzofuranyl, 2- and

22 3-benzothiophenyl, and 2- and 3-indolyl, and 2- and

23 3-quinolinyl. 24

25 Preferably, the number of groups or atoms for optional

26 substitution of aryl or heteroaryl is one, two, three

27 or four. 28

29 Preferred examples of the groups or atoms for optional

30 substitution of aryl or heteroaryl include methyl,

31 methoxy, hydroxy, bromo, chloro, fluoro, nitro or

32 cyano. 33

*34 R7 and Re, when together are -CH2-(CH2)n~ z ~(CH2) - as

35 defined, the resulting radical substituting the

-36 aryl-oxepine in the 5-position is preferably either

pyrrolidonyl or piperidonyl. Other examples o - 5-substituents when R7 and Re are joined together include those described in EP-A-107423.

When Z is other than CH2, m is often 0 or 1 and n is often 0 or 1. Suitable examples of R x when Z is xx include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl. Preferably Rxx is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably Rxx is hydrogen.

When one of Rg and Rχo is hydrogen, it is preferred that Rg is hydrogen and Rχo is selected from the class of Cχ_g alkyl, C3_β cycloalkyl, Cχ_g alkylcarbonyl, Cχ_g alkoxycarbonyl, nitro, trifluoromethyl or cyano. In particular, Rχo may be acetyl, nitro, cyano, methyl, ethyl, isopropyl or cyclopentyl.

When one of Rg and Rχo is nitro, cyano or Cχ_3 alkylcarbonyl the other is, preferably, amino optionally substituted by one or two Cχ_g alkyl or by C2-7 alkanoyl. In particular, when one of Rg and Rχo is nitro, cyano or Cχ_3 alkylcarbonyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably, one of Rg and Rχo is nitro or cyano, and the other is amino.

When one of Rg and Rχo is nitro, cyano or Cχ_3 alkylcarbonyl, it is preferred that Rχo is nitro, cyano or Cχ_3 alkylcarbonyl.

02 It is generally preferred, however, that Rg is-

03 hydrogen. 04

05 The alkyl groups or alkyl moieties of alkyl-containing

06 groups for Rg or Rχo are, preferably, methyl or ethyl. .07

08 When used herein the term ' 'halogen* refers to

09 fluorine, chlorine, bromine and iodine; preferably

10 fluorine. 11

12 Suitably alkyl groups, or alkyl groups forming part of

13 other groups such as in the alkoxy group, are Cχ_χ2

14 alkyl groups especially Cχ_g alkyl groups e.g. methyl,

15 ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or

16 tert-butyl groups, unless otherwise indicated. 17

18 Suitably alkenyl groups are C2-12 groups especially

19 C2-6 alkenyl groups. 20

21 Suitable alkynyl groups are C2_χ2 alkynyl groups

22 especially C2-6 alkynyl groups. 23

24 Suitable polymethylene groups include C3, C4, C5, Cg

25 and C7 polymethylene groups. 26

27 Suitable acyloxy groups include alkylcarbonyloxy groups

28 wherein the alkyl group is as defined above. 29

30 Suitable pharmaceutically acceptable salts of the

31 compounds of formula (I) include acid addition salts

32 and salts of carboxy groups. 33

" 34 Examples of pharmaceutically acceptable acid addition

35 salts of the compounds of formula (I) includes acid

'36 addition salts of optionally substituted amino groups,

such as the hydrochloride and hydrobromide salL . Such a salifiable group may form part of an R7 group. It will also be appreciated that when Y in the compound of formula (I) represents N, then the resulting pyridine moiety may yield acid addition salts, such as the hydrochloride or hydrobromide salts. Alternatively, internal salts such as the N-oxide may be formed by per-acid oxidation of the corresponding compound of formula (I) .

Examples of pharmaceutically acceptable salts of carboxy groups include metal salts, such as alkali metal salts, or optionally substituted ammonium salts.

Examples of esters of carboxy groups are pharmaceutically acceptable esters such as Cχ_g alkyl esters.

Examples of amides of carboxyl groups include pharmaceutically acceptable amides such as amides of formula -C0.NR s Rt wherein R s and R^ each independently represent hydrogen or Cχ_g alkyl.

The compounds of formula (I) may also exist in the form of solvates, preferably hydrates, and the invention extends to such solvates.

The compounds of formula (I), wherein Rx and R2 and/or R3 and 4 are different, or wherein R5 and Rg do not together form a bond, are asymmetric and, therefore, can exist in more than one stereoisomeric form. The invention extends to all isomers individually and to mixtures thereof, including racemates.

The invention also provides a process for the

2 preparation of a compound of formula (I) or a 3 pharmaceutically . acceptable salt thereof which 4 comprises the conversion of an intermediate of formula 5 (II): 6

3 (II) 4 5 wherein R 1 to R 4 and Z° are as defined hereinbefore, Y 1 6 and Rg 1 are Y and Rg respectively or groups or atoms 7 convertible thereto and the dotted line represents an 8 optionally present bond; to the required compound 9 formula (I) , according to the methods generally 0 described in the aforementioned European patent 1 publications for conversion of the corresponding 2 benzopyrans and pyranopyri ines to their 4-substituted 3 derivatives. 4 5 The present invention also provides a process for the 6 preparation of a compound of formula (I) or a 7 pharmaceutically acceptable salt thereof, which 8 comprises; 9 0 i) acylating a compound of formula (III): 1

8

wherein, Y 1 is ' Y or a group convertible thereto, Rg 1 is Rg or a group or atom convertible thereto, Rx to R4 and Z° are as hereinbefore defined, R5 1 is hydroxy, Cχ_g alkoxy or Cχ_7 acyloxy, and Re 1 is hydrogen or Cχ_g alkyl, the R8 1 NH group being trans to the R5 1 group,

a) with an acylating agent of formula (IV):

Rχ -C0-Lχ (IV)

wherein Lx is a leaving group, and Rχ2 is hydrogen; Cχ_g alkoxycarbonyl; Cχ_g alkyl optionally substituted by halogen, hydroxy, Cχ_g alkoxy, Cχ_g alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R7; C2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R7; or a group convertible to R7 as hereinbefore defined, and thereafter, when R3 is hydrogen and R 2 is (CH2)z L 2' where z is 3 or 4 and L2 is a leaving group, cyclising the resultant compound;

b) with a compound of formula (V):

X=C=N.Rχ 3 (V)

wherein Rχ3 is hydrogen, Cχ_g alkyl, C2-g alkenyl, Cχ_g alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by Cχ_g alkyl, Cχ_g alkoxy or halogen; and X is oxygen or sulphur, and thereafter when Rχ3 is hydrogen, optionally converting Rχ3; or

ii) for compounds of formula (I) wherein R 7 and Re together represent a linking chain of formula -A!-A 2 as

02 defined above in relation to formula (I),

03 by reacting a compound of formula (VI): 04

II

12 wherein Rx, R2, R3, R4, Rg 1 , Y 1 and Z° are as

13 hereinbefore defined with a compound of formula (VII): 14

15 Rχ 5 NHCOR 1 (VII)

16

17 wherein χ4 and Rχ5 together represent a linking chain

18 -A 1 -A 2 -; or 19 0 iϋ) for compounds of formula (I) wherein A represents 1 a bond and R7 and R3 together with the nitrogen to 2 which they are attached form the above defined 3 unsaturated heterocyclic ring, by reacting a compound 4 of formula (VI) as defined above with an activated form 5 of a compound of formula (VIIA) : 6 7 R 8 NHR 7 (VIIA) 8 9 wherein R7 and R 8 are as defined above; 0 1 and thereafter if required, carrying out one or more of 2 the following optional steps: 3 -4 (i) converting a compound of formula (I) into a 5 further compound of formula (I); '6 (ii) converting Y 1 to Y;

(iϋ) converting Rg 1 to Rg; (iv) forming a pharmaceutically acceptable salt of the compound of formula (I); or (v) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Preferably in (VI), p * 2 when Z° is S(0) p .

In the process variant i) a) acylation of a compound of formula (III) with an acylating agent of formula (IV), the leaving group is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a group include C _4 alkanoyloxy, and halogen, such as chloro and bromo or hydroxy. When the leaving group Lx is either of these examples, the acylating agent of formula (IV) is either an acid anhydride or an acid halide. When it is an acid anhydride, it may be a mixed or simple anhydride. If it is a mixed anhydride, it may be prepared in situ from a carboxylic acid and an acid halide, although this is less preferred than using the halide itself. When Lx is hydroxy, conventional coupling methods using dicyclohexylcarbodiimide are suitable.

In process variant i) a), when R7 in the desired compound of formula (I) is an R7 optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that Rχ2 is a group convertible to the R7 substituted alkyl group as hereinbefore defined, in particular that it is Cχ_g alkyl substituted by halo, especially bromo. The Rχ2 halo substituent in the resultant compound of process variant i) a) may be converted to an R7 substituent which is amino optionally substituted as hereinbefore defined by a

02 conventional amination reaction with ammonia o_ -d

03 corresponding alkyl- or dialkylamine. when Rχ2 is

04 c l-6 alkoxycarbonyl, this may be converted to R7 is , 05 carboxy by conventional hydrolysis.

06

.07 Less favourably Rχ2 may be Cχ_g alkyl substituted by

08 protected amino, protected Cχ_g alkylamino or amino

09 substituted by two independent Cχ_g alkyl groups, it

10 being necessary to protect the Rχ2 amino function in

11 process variant i) a). 12

13 When the acylating agent of formula (IV) is an acid

14 anhydride, the acylation of the compound of formula

15 (III) may be carried out in the presence of an acid

16 acceptor, such as sodium acetate, optionally using the

17 anhydride as the solvent. 18

19 When the acylating agent of formula (IV) is an acid

20 halide, the acylation of the compound of formula (III)

21 is,- preferably, carried out in a non-aqueous medium,

22 such as dichloromethane, in the presence of an acid

23 acceptor, such as triethylamine, trimethylamine, or

24 calcium, potassium or sodium carbonate. 25

26 When the acylating agent of formula (IV) is an acid the

27 acylation of a compound of formula (III) is

28 conveniently performed in the presence of a dehydrating

29 agent, such as dicyclohexylcarbodiimide in an inert

30 solvent, such as dimethylformamide at a temperature of

31 0°C to ambient. 32

33 When R5 1 in a compound of formula (III) is hydroxy,

34 there is a risk of a side-reaction between the hydroxy

35 group and the acylating agent of formula (IV). '36 However, the reaction may be carried out under

controlled conditions such that only the amine; _s 1 NH- is acylated, for example, by using a C2- acyloxy group as the leaving group Lx, in the acylating agent of formula (IV) in the manner as previously described for an acid anhydride, and/or effecting the reaction at relatively low temperature, e.g. at below 10°C. Alternatively R5 1 may be Cχ_7 acyloxy in a compound of formula (III), although less preferably if R5 in the resultant compound of formula (I) is to be hydroxy, and, after reaction with the acylating agent of formula (IV), be converted into hydroxy, as described hereinafter.

When Rχ2 is (CH2) Z L2 where the variables are as hereinbefore defined, the leaving group L2 is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function. A preferred example is chloro.

The cyclisation reaction when Rχ2 is (CH2)z L 2 where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimethylformamide.

In process variant i) b) , when Rχ3 in a compound of formula (V) is Cχ_g alkyl, Cχ_g alkanoyl optionally substituted as hereinbefore defined, or phenyl optionally substituted as hereinbefore defined, the reaction between the compounds of formulae (III) and (V) is, preferably, carried out in a solvent, such as methylene chloride, at below room temperature, in particular below 10°C.

When Rχ3 is hydrogen, the reaction between the compounds of formulae (III) and (V) is, preferably,

02 carried out using a corresponding alkali metal, ^ yanate

03 or thiocyanate, for example that of sodium or

04 potassium, in an optionally methanolic aqueous medium , 05 acidified with a mineral acid, such as dilute

06 hydrochloric acid. A slightly elevated temperature

.07 such as 50 to 90°C is apt. 08

09 In the process variant ii), that is the reaction

10 between a compound of formula (VI) and a compound of

11 formula (VII), it is particularly preferred that the

12 reaction is carried out under basic conditions so as to

13 facilitate the formation of the anion of the compound

14 of formula (VII), for example, in the presence of an

15 alkali metal base such as potassium t-butoxide or

16 sodium hydride. 17

18 The reaction between the compounds of formula (VI) and

19 (VII) may be carried out in any suitable aprotic

20 solvent at a temperature that provides a convenient

21 rate of formation of the compound of formula (I), such

22 as at ambient temperature or at a slightly elevated

23 temperature, for example 40°C. 24

25 Conveniently, the compound of formula (VII) may itself

26 be used as the solvent for the reaction between

27 compounds of formulae (VI) and (VII). 28

29 In process variant iii), a suitable activated form of a

30 compound of formula (VIIA) is an ionic form. Thus in

31 the reaction between a compound of formula (VI) and a

32 compound of formula (VIIA) , it is preferred that the

33 reaction is carried out under basic conditions so as to '34 facilitate the formation of the anion of the compound 35 of formula (VIIA), for example, in the presence of an " 36 alkali metal base such as potassium t-butoxide or

sodium hydride .

The reaction between the compounds of formulae (VI) and (VIIA) may be carried out in any suitable aprotic solvent, for example dimethylsulphoxide, at a temperature that provides a convenient rate of formation of the compound of formula (I), such as at ambient temperature or at an elevated temperature, but conveniently at ambient temperature.

Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:

(i) converting R5 in the resulting compound of formula (I) into another R5; (ii) converting a compound of formula (I) wherein R5 and Rg represent hydroxy and hydrogen respectively to give another compound of formula (I), wherein R5 and Rg together represent a bond; (ϋi) reducing any compound of formula (I) wherein R5 and Rg together represent a bond; to give another compound of formula (I), wherein R5 and Rg each represent hydrogen; (iv) thiating the R8.N.CX.R7 group in the compound of formula (I), wherein X is oxygen, to give a compound wherein X is sulphur; (v) converting a compound of formula (I) wherein p represents zero to a compound of formula (I) wherein p represents 2; (vi) converting a compound of formula (I) wherein p represents 2 to a compound of formula (I) wherein p represents zero; or (vii) when R5 is other than hydrogen, interconverting the cis and trans mutual configuration of the variables R5 and Rg.

The reaction of the compounds of formulae (Iir;. -with (IV) or (V) results in a compound of formula (I) wherein R 5 is hydroxy, alkoxy or acyloxy, whereas the reaction of the compounds of formulae (VI), (VII) and (VIIA) results in a compound of formula (I) wherein R 5 is hydroxy. Examples of an optional conversion of R5 in a compound of formula (I) into another R5 are generally known in the art. For example, when R 5 is hydroxy, it may be alkylated using an alkyl iodide in an inert solvent, such as toluene, in the presence of a such as sodium hydride or potassium hydroxide, or it may be acylated using a carboxylic acid chloride or or an appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor, such as triethylamine. When R 5 is acyloxy or alkoxy, it may be converted into hydroxy by means of any conventional dealkylation method, such as by treatment with trimethylsilyliodide in an aprotic solvent. In addition when R 5 is acyloxy it may be converted into hydroxy by conventional hydrolysis using, for example, dilute mineral acid.

The optional conversion of a compound of formula (I), wherein R5 and Rg are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R 5 and Rg together are a bond, may be carried out by dehydration under conventional dehydration conditions, for example, by using a dehydrating agent, such as sodium hydride, in inert solvent, such as dry tetrahydrofuran, at reflux temperature; alternatively the hydroxy group represented by R 5 may be converted into a leaving group such as a mesyloxy or tosyloxy group and the resulting compound treated with a base such as sodium hydride to provide the compound of

formula (I) wherein R5 and Rg together repress..- a bond.

The reduction of a compound of formula (I), wherein R5 and Rg together are a bond, into another compound of formula (I), wherein R5 and Rg are each hydrogen, may be carried out by hydrogenation using a catalyst of palladium on charcoal.

The thiation of the R8.N.CX.R7 group in a compound of formula (I), wherein X is oxygen, to give another compound of formula (I), wherein X is sulphur, is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosphorus pentasulphide and Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer) . The use of hydrogen sulphide and phosphorus pentasulphide may lead to side-reactions and, therefore, the use of Lawesson's reagent is preferred.

The thiation reaction conditions are conventional for the thiation agent employed. For example, the use of hydrogen sulphide is, preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or ethanol. The preferred use of Lawesson's reagent is, preferably, carried out under reflux in a dry solvent, such as toluene or dichloromethane.

The interconversion of the cis and trans configuration of the variables R 5 and Rg is generally carried out by changing the configuration of variable R5, especially when R5 represents hydroxyl, by means of any convenient conventional procedure.

.Any conversion of γ to Y or Rg 1 to Rg may be -orried out using the appropriate conventional chemical procedure.

The optional formation of a pharmaceutically acceptable salt, when the resulting compound of formula (I) contains a salifiable group, may be carried out conventionally. Similarly, pharmaceutically acceptable solvates, for example hydrates, may be prepared using any convenient conventional procedure.

A compound of formula (III) may be prepared by reacting a compound of formula (VI), as hereinbefore defined, with a compound of formula (VIII):

R8 1 NH (VIII)

wherein Rs 1 is as hereinbefore defined; and optionally converting R5 1 hydroxyl in the resulting compound of formula (II) into another R5 1 .

The reaction is normally carried out in a solvent, such as a C _4 alcohol, in particular methanol, ethanol or propanol at an ambient or an elevated temperature, for example 12 to 100°C. The reaction proceeds particularly smoothly if carried out in ethanol under reflux.

The resulting compound of formula (III) may be removed from the reaction mixture by removal of the solvent, for example, by evaporation under reduced pressure. Any epoxide impurity may be removed conventionally, for example by chromatography.

The optional conversion of the hydroxy group for R5 1 in

the resulting compound of formula (II) into a c l -6 alkoxy or Cχ_7 acyloxy group may be carried out as described hereinbefore in relation to the corresponding conversion of 5 in a compound of formula (I).

Compounds of the formula (VI) are preferably prepared by the reaction of the compound of formula (II) wherein the optional bond is present, with a per-acid, such as m-chloroperbenzoic acid; as described in Description 4 hereinafter.

Alternatively, the compound of formula (II) wherein the optional bond is present may be converted to the corresponding bromohydrin which is in turn converted to the epoxide as described in the aforementioned European Patent Publications.

Compounds of the formula (II) may be prepared according to the following general reaction scheme.

02 Scheme 1

27 28 ; the variables being as defined hereinbefore. 29 30 When Y is C-NO2 and Rg is hydrogen, the reaction steps 31 (a) and (b) are conveniently carried out with 32 intermediates wherein Y is C-H and Rg 1 is hydrogen, the 33 nitro group subsequently introduced by nitration with

' 34 concentrated/fuming HNO3 and steps (c) and (d) carried 35 out with intermediates wherein Y is C-NO2 and Rg 1 is

' 36 hydrogen. 37

It will be appreciated that, according to the ... ure of the groups Y and Rg, it may be necessary to introduce substituents Rg and/or Rχo at different stages in the synthesis, before or after the cyclisation step b) .

Alternatively it may be necessary to utilise a different synthesis from a corresponding chroman type by ring expansion techniques viz:

Scheme 2

1) Protect aryl-OH

2) bromination (eg PB PH 3 P/CBr 4 )

3) KCN/DMSO

4) deprotect

ate with R'-metal (eg Li or MgX)

= optional double bond according to nature of reducing agent.

; wherein R' represents R 1 or R 2 as required, the remaining variables being as defined hereinbefore.

Scheme 3

; the variables being as defined hereinbefore.

The intermediates of formulae (II), (III), and (VI) represent part of the present invention. The intermediates of formulae (IV), (V), (VII), (VIIA) and (VIII) are known and may be prepared in accordance with an appropriate known process . The starting compounds in schemes 1, 2 and 3 are also believed to be known or prepared by analogous processes to known compounds.

The compounds of formula (I) have been found to have bronchodilator activity and/or blood-pressure lowering activity. They are therefore useful in the treatment of respiratory tract disorders, such as reversible airways obstruction, diverticular disease and asthma and also hypertension. They may also be of potential use in the treatment of other disorders hereinbefore described.

The present invention accordingly provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral admin- istration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically

acceptable wetting agents such as sodium lauryC sulphate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in

water for injection and filter sterilized befc-___. filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions of this invention may also suitably be presented ' for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active

02 material, depending on the method of administration.

03

04 The present invention further provides a method of

05 treatment of respiratory tract disorders or

06 hypertension in mammals including man, which comprises , 07 administering to the suffering mammal an effective

08 amount of a compound of formula (I) or a

09 pharmaceutically acceptable salt thereof. 10

11 An effective amount will depend on the relative

12 efficacy of the compounds of the present invention, the

13 severity of the respiratory tract disorder or

14 hypertension being treated and the weight of the

15 sufferer. However, a unit dose form of a composition

16 of the invention may contain from 0.01 to lOOmg of a

17 compound of the invention (0.01 to lOmg via

18 inhalation) and more usually from 0.1 to 50mg, for

19 example 0.5 to 25mg such as 1, 2, 5, 10, 15 or 20mg.

20 Such compositions may be administered from 1 to 6 times

21 a day, more usually from 2 to 4 times a day, in a

22 manner such that the daily dose is from 0.02 to 200mg

23 for a 70 kg human adult and more particularly from 0.05

24 to lOOmg. 25

26 The present invention further provides a compound of

27 formula (I) or a pharmaceutically acceptable salt

28 thereof for use in the treatment of respiratory tract

29 disorders or hypertension. 30

31 The invention also provides the use of a compound of

32 formula (I), or a pharmaceutically acceptable salt

33 thereof, or a pharmaceutically acceptable solvate '34 thereof, for the manufacture of a medicament for the

35 treatment of respiratory tract disorders or

'36 hypertension. 37

In addition to respiratory tract disorders and-÷ - hypertension, the present invention also encompasses uses and methods of treatment comprising each of the indications and disorders mentioned hereinbefore. The abovementioned compositions, unit dose forms and effective amounts are also suitable for these last mentioned indications and disorders.

No toxicological effects are indicated at the aforementioned dosage ranges.

The following descriptions relate to the preparation of intermediates and the following examples relate to the preparation of compounds of formula (I) .

02 Description 1

03

04 7-Nitro-2 , 3 , 4 , 5-tetrahydro-l-benzoxepin-5-one

.05

06

,07 0

12

13

14 To a solution of 2,3,4,5-tetrahydro-l-benzoxepine-5-one

15 (2.15g, 13.3mmol) in concentrated HNO 3 (20ml) at -20°C

16 was added with stirring over 90 mins fuming HNO3 (18ml)

17 during which time the temperature rose to 0°C. The

18 solution was poured into H 2 O (200ml), the resulting

19 solid collected by filtration, washed with H 2 O (2 x

20 50ml) and dried to give the title compound (2.13g,

21 77%), m.p. 127°C; δ 2.34 (2H, quin, J=7Hz, 3,3'-H),

22 2.96 (2H,t, J=7Hz, 4,4'-H), 4.38 (2H,t, J=Hz, 2,2'-H),

23 7.19 (lH,d, J=9HZ, 9-H) , 8.26 (1H, d.d, J*9Hz, 3Hz,

24 8-H), 8.63 (lH,d, J - 3Hz, 6-H) ; υ max (nujol) 1685

25 (C=0) cm -1 .

26 Found: C, 57.89; H, 4.49; N, 6.73. CχøH Nθ 4 requires

27 C, 57.97; H, 4.38; N, 6.76%. 28

Description 2

5-Hvdroxy-7-nitro-2,3.4,5-tetrahvdro-l-benzoxepine

To 7-nitro-2,3,4,5-tetrahydro-l-benzoxepin-5-one (1.5g, 7.24mmol) suspended in EtOH (25ml) was added sodium borohydride (300mg, δmmol) and the mixture stirred for 2h at 5°C. The mixture was poured into H2O (300ml), extracted with CH2CI2 (3 x 75ml) and the combined extracts dried (MgSθ ). Concentration in vacuo of the organic phase afforded a solid (1.35g) which was purified by column chromatography on silica eluting with C2_2Cl2o The title compound was obtained as a white solid (1.2g, 81%), m.p. 78-80°C; δ 1.87-2.18 (4H,m, 3,3' ,4,4'-H) , 2.46 (lH,d, J=5.3Hz, exchangeable OH), 3.90 (lH,m, 2 or 2'-H), 4.30 (lH,m, 2 or 2'-H), 4.96 (lH,m, 5-H) , 7.07 (lH,d, J=8.8Hz, 9-H) , 8.06 (1H, d.d, J=8.8HZ, 2.75Hz, 8-H) , 8.37 (lH,d, J=2.75Hz, 6-H) . Found: C, 57.50; H, 5.37; N, 6.65. CχøHχχNθ4 requires C, 57.41; H, 5.30; N, 6.70%.

Description 3

2,3-Dihvdro-7-nitro-l-benzoxepine

5-Hydroxy-7-nitro-2,3,4,5-tetrahydro-l-benzoxepine (1.14g, 5.45mmol) and p-toluene sulphonic acid (250mg, 1.13mmol) were heated together in refluxing toluene (125ml) for 90 min under nitrogen. The solution was allowed to cool, filtered and the filtrate concentrated in vacuo to afford an off white solid (lg). Purification by column chromatography on silica eluting with CH2CI2 afforded the title compound as a white solid (990mg, 95%), m.p. 93-5°C; δ 2.73 (2H, d.d.t, J=4.7Hz, 1.5Hz, 3,3'-H), 4.32 (2H, t, J=4.7Hz, 2,2'-H), 6.15 (1H, d.t, J=11.7HZ, 4.6Hz, 4-H) , 6.37 (1H, d.t, J=11.7Hz, 1.6Hz, 5-H), 7.02 (1H, d, J=9Hz, 9-H) , 7.98 (1H, d.d, J=9HZ, 2.75Hz, 8-H) , 8.10 (lH,d, J=2.75HZ, 6-H) .

Found: C, 62.63; H, 4.85; N, 7.35. CχoHgNθ3 requires C, 62.82; H, 4.75; N, 7.33%.

Description 4

4,5-Epoxy-7-nitro-2,3,4,5-tetrahydro-l-benzoxepine

2,3-Dihydro-7-nitro-l-benzoxepine (925mg, 4.84mmol) and 3-chloroperbenzoic acid (l.lβg, 6.72mmol) were stirred together in CH2CI2 (50ml) at room temperature for 18h. The solution was washed with saturated aqueous sodium bicarbonate solution (50ml) and H2O (50ml), dried (MgSθ4) and concentrated in vacuo to afford a white solid (1.35g). Purification by column chromatography on silica eluting with CH2CI2 afforded the title compound as a white solid (922mg, 92%), m.p. 123-4°C; δ 2.50 (1H, m, 3-H or 3'-H), 2.70 (1H, m, 3-H or 3'-H), 3.74 (1H, m, 4-H), 3.91 (1H, d, J=4Hz, 5-H) , 4.08-4.22 (2H, m, 2,2'-H), 6.98 (1H, d, J=9Hz, 9-H) , 8.10 (1H, d.d, J=9Hz, 2.75Hz, 8-H) , 8.41 (1H, d, J=2.7 . 5Hz, 6-H) . Found: C, 57.79; H, 4.37; N, 6.68. CχoNgNU4 requires C, 57.97; H, 4.43; N, 6.76%.

02 Description 5

03

04 Trans 5-Azldo-4-hvdroxy-7-nitro-2,3,4,5-tetrahydro-l-

05 benzoxepine 06

12 13

14 A solution of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-l-

15 benzoxepine (182mg, 0.88mmol) and sodium azide (63mg,

16 0.97mmol) in dioxane (10ml) and water (2ml) was heated

17 under reflux for 5 hours, allowed to cool and diluted

18 with water (40ml). The mixture was extracted with

19 diethyl ether (2x30ml), the organic extract dried,

20 (MgSθ 4 ) and concentrated in vacuo to afford the title

21 compound as a solid (200mg, 91%), m.p. 86-88°C;

22 δ 1.90-2.60 (2H, m) , 3.10 (1H, br, exchangeable OH),

23 3.90-4.20 (2H, m) , 4.45 (1H, m) , 4.83 (1H, d, J=7Hz),

24 7.15 (1H, d, J=9Hz), 8.20 (1H, dd., J=9Hz, 2Hz) , 8.37

25 (1H, d, J=2Hz); υ max (KBr) 3440 (OH), 2120 (N 3 ) cm"- 1 . 26

Description 6

Trans 4-amino-5-hvdroxy-7-nitro-2,3,4,5-tetrahvdro-l- benzoxepine

Triphenylphosphine (183mg, 0.7mmol) was added to a solution of 4-azido-5-hydroxy-7-nitro-2,3,4,5- tetrahydro-1-benzoxepine (160mg, 0.69mmol) in dry tetrahydrofuran (25ml) at room temperature and the mixture stirred for 18 hours. The solution was diluted with water (100ml), extracted with chloroform (3x50ml) and the combined extracts dried (MgSO ). Concentration in vacuo of the organic phase afforded a solid (360mg) which was purified by column chromatography on silica eluting with CHCl3:MeOH (3:lv/v) to yield the title compound (lOOmg, 64%); δ 1.83 (IH, m) , 2.08 (2H, br s, exchangeable NH2), 2.20 (IH, m) , 3.58 (IH, m) , 3.99 (IH, d, J=7.7Hz), 4.03 (IH, m), 4.32 (IH, m) , 5.12 (IH, s, exchangeable OH), 7.09 (IH, d, J=8.8HZ), 8.04 (IH, dd., J=8.8HZ, 3HZ), 8.34 (IH, d, J=3Hz); υ max (KBr) 3370, 3290 (NH2)' 3100 (OH) cm" 1 .

Example 1

Trans 4-Hvdroxy-7-nitro-5-(2-oxopyrrolidin-l-yl) -2,3,4,5-tetrahydro-l-benzoxepine

2-Pyrrolidinone (370mg, 4.34mmole) in dry THF (10ml) at room temperature under nitrogen was treated with potassium bis(trimethylsilyl)amide (5.9ml of a 0.75M solution in toluene, 4.34mmol). The mixture was stirred for 90 mins and 4,5-epoxy-7-nitro-2,3,4,5 -tetrahydro-1-benzoxepine (450mg, 2.17mmol) in dry THF (15ml) added dropwise over 10 min. The solution was stirred overnight, poured into IN aq. HCl solution and extracted with ethyl acetate (3 x 50ml). The combined extracts were dried (MgS04), concentrated in vacuo and the resulting solid purified by column chromatography on silica eluting with CHCI3 to afford the title compound (143mg, 23%), m.p. 172-4°C; δ 2.09-2.34 (4H,m) 2.66-2.82 (2H,m, 3,3'-H), 3.44-3.58 (2H,m), 4.05-4.14 (IH, d.t, J=12Hz, 2.2Hz), 4.28-4.36 (IH, d.t, J=12Hz, 3.8Hz), 4.48 (IH, d.d, J=3.8Hz, 2.6Hz, 4-H) , 4.81 (IH, s, 5-H) , 5.66 (IH, br s, exchangeable OH), 7.19 (lH,d, J=8.6Hz, 9-H), 7.79 (lH,d, J=2.75Hz, 6-H) , 8.14 (IH, d.d, J=8.8Hz, 2.75Hz, 8-H) , 7.26 ( 0.2H,S, CHCI3); υ

max (nujol) 3270 (OH), 1655 (C=0 amide) cm -1 . Found: C, 55.32; H, 5.21; N, 8.70. Cχ4Hχ N2θ 5 .0.I5CHCI3 requires C, 54.79; H, 5.25; N, 9.03%.

02 Example 2

03

04 Trans 5-(4-fluorobenzoylamlno)-4-hydroxy-7-nitro-

05 2,3,4,5-tetrahvdro-l-benzoxepine 06

14 4-Fluorobenzoylchloride (0.05ml, 0.4mmol) was added to

15 a stirred solution of trans 5-amino-4-hydroxy-7-

16 nitro-2,3,4,5-tetrahydro-l-benzoxepine (83mg, 0.37mmol)

17 in dry dimethylformamide 95ml) and Et3N (0.2ml) under

18 nitrogen at room temperature. After 4 hours the mixture

19 was poured into water (50ml), extracted with chloroform

20 (3x25ml), the combined extracts dried (MgSθ4) and

21 concentrated in vacuo to an oil. Separation by column

22 chromatography on silica eluting with CH2CI2 followed

23 by recrystallisation (Et2θ/EtoAc/hexane) afforded the

24 title compound (40mg, 33%), m.p. 171-3°C; δ (DMSO) 1.90

25 (IH, m), 2.16 (IH, m) , 4.01 (IH, m) , 4.14 (IH, m) , 4.57

26 (IH, m), 5.30-5.36 (2H, m, 5H, exchangeable OH), 7.16

27 (IH, d, J=9.3Hz) 7.35 (2H, m, aromatic H) , 8.0 (2H, m,

28 8H, aromatic H) , 8.10 (2H, m, 6H, aromatic H) , 8.86

29 (IH, d, J=8Hz, exchangeable NH) , υ max (KBr) 3340,

30 3290, 1640 (C=0 amide).

31 Found: C, 58.79; H, 4.42; N, 8.02. CX7HX5 N2O5

32 Requires C, 58.96; H, 4.37; N, 8.02%. 33

Pharmacological Data

1. Bronchodilator Activity

(a) Bronchodilation in vitro; guinea pig tracheal spiral preparations.

Male guinea pigs (300-600g) were stunned by a blow to the head and bled from the carotid artery. The trachea was exposed, dissected free of connective tissue, and transferred to oxygenated krebs solution at 37°C. Next, spirals (2 per trachea) were prepared by cutting the whole trachea spirally along its longitudinal axis and then dividing this spiral lengthwise. Each preparation was mounted, using silk thread, in a 10ml organ bath filled with krebs solution at 37°C and bubbled with 5% CO2 with O2. The resting tension of the preparations was set at 2g and changes in muscle tension were monitored isometrically by means of a UFI (2oz) force and displacement transducer (Ormed Ltd) connected to a Linseis pen recorder. All preparations were allowed to equilibrate for 60 minutes. During this equilibration period the preparations were washed by upward displacement at 15 minute intervals and, if necessary, the resting tension was readjusted to 2g using a mechanical micromanipulator system.

Once a steady resting tension had been obtained, the preparations were dosed simultaneously with the test compound (10 ~8 -2xlO~ 5 M) , and finally a maximum relaxation achieved by addition of 10 ~3 M isoprenaline. The fall in tension evoked by the test compound -was expressed as a percentage of the total relaxation evoked in the presence of 10 ~3 M isoprenaline. Appropriate concentration-relaxation curves were then

constructed and values for potency (IC50) were obtained.

The composition of Krebs solution is: sodium chloride 118.07mM, sodium hydrogen carbonate 26.19mM, potassium chloride 4.68mM, potassium orthophosphate 1.18mM, magnesium sulphate septahydrate l.δmM and calcium chloride 2.52mM;pH ca. 7.45.

(b) Bronchodilation in vivo by the Konzett Rossler method.

Animals were prepared according to the methodology described by Konzett and Rossler (1). Guinea pigs were anaesthetized by an intraperitoneal injection of Urethane (1500mg/kg) and then prepared with tracheal, arterial and venous cannulae. The animals were connected to a respiratory pump which was adjusted to deliver a volume of 1ml per lOOg body weight to the guinea pig. The back pressure of the Ugo Basile 7020 overflow sensor was then adjusted to give a constant, resting overflow volume. The animals were then allowed to equilibrate for 10 minutes before experimentation began.

Arterial blood pressure was recorded with a pressure transducer (Bell and Howell 4-422-0001) connected via a Devices 3552 pressure pre-amplifier to a Devices pen recorder. Changes in overflow volume - an index of total pulmonary resistance - were expressed as a percentage of the maximum bronchoconstriction obtained by total occlusion of the tracheal cannula. In all determinations of bronchoconstrictor activity, peak overflow volumes were used.

In experiments in which non-immunized animals w_re used, bronchoconstriction was produced by a bolus injection of a submaximal dose of 5-hydroxytryptamine (5-HT) into the jugular vein. The bronchodilator activity of the test compound was assessed by its ability to inhibit a subsequent 5-HT-induced bronchoconstriction. In other experiments, the ability of compounds to inhibit anaphylactic bronchoconstriction in actively sensitized animals was determined.

1. H. Konzett and R. Rossler (1940) Arch. Exp. Path. Pharmak (Naunyn Schmiedeberg) 195, 71-74.

In test (a) in vitro, the compound of Example 1 had an C50 of 1 * 41 x 10~ 5 M, and in test (b), in vivo, at a dose of img/kg i.v., the compound of Example 1 gave 30 ± 10% protection from the effects of 5-HT.

2. Antihvpertensive Activity

Blood Pressure Lowering Activity

Systolic blood pressures were recorded by a modification of the tail cuff method described by I.M. Claxton, M.G. Palfreyman, R.H. Poyser, R.L. Whiting, European Journal of Pharmacology, 3J7, 179 (1976). A W+W BP recorder, model 8005 was used to display pulses.Prior to all measurements rats were placed in a heated environment (33.5 ± 0.5°C) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings. Spontaneously hypertensive rats (ages 12-18 weeks) with systolic blood pressures >180 mmHg were considered hypertensive.

Compound of Time Post % Change in. -Gy≤tolic Example 1 Dose, Hours Blood Pressure

6 rats 1 -26 ± 3

Dose 3mg/kg, p.o. 2 -22 ± 3

Initial Blood 4 -22 ± 3

Pressure 6 -11 ± 3

289 ± 0.49 mmHg