Claims
- 1. A compound of formula I, ##STR22## in which R.sub.3 to R.sub.6 and R.sub.9 to R.sub.12, which may be the same or different, are each hydrogen, halogen, phenoxy, alkyl C.sub.1 to C.sub.6, fluoroalkyl C.sub.1 to C.sub.6, alkanoyl C.sub.1 to C.sub.6, benzoyl, RS(O).sub.n --, NO.sub.2, NR.sub.16 R.sub.17, NHCOR, --COOH or an ester derived from a C.sub.1 to C.sub.6 alcohol or an unsubstituted or a mono- or dialkyl C.sub.1 to C.sub.6 substituted amide thereof, or alkoxy C.sub.1 to C.sub.6 optionally substituted by phenyl,
- y is 0 or 1,
- p is 0 or 1,
- n is 0, 1, or 2,
- R.sub.18 is hydrogen, COR, COOR, or alkyl C.sub.1 to C.sub.6, said alkyl being optionally substituted by --OCOR or by phenyl,
- R, R.sub.16, and R.sub.17, which may be the same or different, are each hydrogen, phenyl or alkyl C.sub.1 to C.sub.6 optionally substituted by phenyl, the phenyl groups in turn optionally being substituted by alkyl C.sub.1 to C.sub.6,
- or a pharmaceutically acceptable salt thereof.
- 2. A compound according to claim 1 which p is 1.
- 3. A compound in accordance with claim 1 wherein y is 0.
- 4. A compound in accordance with claim 1 wherein R.sub.3 to R.sub.6 are selected from hydrogen, halogen, and alkoxy C.sub.1 to C.sub.6.
- 5. A compound in accordance with claim 1 wherein R.sub.9 to R.sub.12 are selected from hydrogen, alkyl C.sub.1 to C.sub.6 and alkoxy C.sub.1 to C.sub.6.
- 6. A compound in accordance with claim 1 selected from
- 2-[4-Dimethylamino-2-(4-methoxy-2-pyridinyl)phenyl thio]-1H-benzimidazole,
- 2-[4-Dimethylamino-2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methoxy-2-pyridinyl)phenylsulphinyl]-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridyl)-phenyl thio]-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridyl)-phenyl sulphinyl]-1H-benzimidazole,
- or a pharmaceutically acceptable salt thereof.
- 7. A compound in accordance with claim 1 selected from
- 2-[2-(2-Pyridyl)-phenylthio]-1H-benzimidazole,
- 2-[2-(2-Pyridyl)-phenylsulphinyl]-1H-benzimidazole,
- 5-Chloro-2-(2-(2-pyridyl)-phenylthio)-1H-benzimidazole,
- 5-Chloro-2-(2-(2-pyridyl)-phenylsulphinyl)-1H-benzimidazole,
- Methyl 2-(2-(2-pyridyl)-phenylthio)-1H-benzimidazole-5-carboxylate,
- Methyl 2-(2-(2-pyridyl)-phenylsulphinyl)-1H-benzimidazole-5-carboxylate,
- 4-Trifluoromethyl-2-[2-(2-pyridyl)-phenylthio]-1H-benzimidazole,
- 4-Trifluoromethyl-2-[2-(2-pyridyl)-phenylsuphinyl]-1H-benzimidazole,
- 2-[5-Chloro-2-(2-pyridyl)-phenylthio]-5-methoxy-1H-benzimidazole,
- 2-[5-Chloro-2-(2-pyridyl)-phenylsulphinyl]-5-methoxy-1H-benzimidazole,
- 5,6-Dimethyl-2-[2-(2-pyridyl)-phenylthio]-1H-benzimidazole,
- 5. 6-Dimethyl-2-[2-(2-pyridyl)-phenylsulphinyl]-1H-benzimidazole,
- 5-Methyl-2-[2-(2-pyridyl)-phenylthio]-1H-benzimidazole,
- 5-Methyl-2-[2-(2-pyridyl)-phenylsulphinyl]-1H-benzimidazole,
- 5-(4-Methylphenylsulphonyl)-2-[2-(2-pyridyl)-phenyl thio]-1H-benzimidazole,
- 5-(4-Methylphenylsulphonyl)-2-[2-(2-pyridyl)-phenyl sulphinyl]-1H-benzimidazole,
- N-[4-(4,7-Dimethoxy-1H-benzimidazol-2-yl thio)-3-(2-pyridyl)-phenyl]acetamide,
- N-[4-(4,7-Dimethoxy-1H-benzimidazol-2-yl sulphinyl)-3-(2-pyridyl)-phenyl]acetamide,
- 2-[2-(2-Pyridyl)-phenyl methylthio]-1H-benzimidazole,
- 2-[2-(2-Pyridyl)-phenyl methylsulphinyl]-1H-benzimidazole,
- 1-Methyl-2-[2-(2-pyridyl)-phenylsulphinyl]-1H-benzimidazole,
- 5,6-Diethoxy-2-[2-(2-pyridyl)-phenylthio]-1H-benzimidazole,
- 5,6-Diethoxy-2-[2-(2-pyridyl)-phenylsulphinyl]-1H-benzimidazole,
- Phenylmethyl 2-[2-(2-pyridyl)-phenylthio] benzimidazole-1-carboxylate,
- Phenyl [2-[2-(2-pyridyl)phenylthio]-1H-benzimidazol-5-yl]methanone,
- Phenyl [2-[2-(2-pyridyl)phenylsulphinyl]-1H-benzimidazol-5-yl] methanone,
- Phenylmethyl 2-[2-(2-pyridyl)-phenylsulphinyl] benzimidazole-1-carboxylate,
- 5-Methoxy-2-[2-(4-methoxy-2-pyridyl)phenylthio]-1H-benzimidazole,
- 5-Methoxy-2-[2-(4-methoxy-2-pyridyl)phenylsulphinyl]-1H-benzimidazole,
- 2-[2-(4-Ethyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(4-Ethyl-2-pyridinyl)phenylsulphinyl]-1H-benzimidazole,
- Methyl 2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole-5-carboxylate,
- Methyl 2-[2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole-5-carboxylate,
- 5-Methyl-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 5-Methyl-2-[2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methyl-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 5-Methoxy-2-[2-(4-methoxy-2-pyridinyl)-5-methoxy phenylthio]-1H-benzimidazole,
- 5-Methoxy-2-[2-(4-methoxy-2-pyridinyl)-5-methoxy phenylsulphinyl]-1H-benzimidazole,
- 2-[2-(1H-2-Benzimidazolylthio)phenyl]-N-methyl-N-phenyl-4-pyridinamine,
- 2-[2-(1H-2-Benzimidazolylsulphinyl)phenyl]-N-methyl-N-phenyl-4-pyridinamine
- 2-[5-Methoxy-2-(2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[5-Methoxy-2-(2-pyridinyl)phenylsulphinyl-1H-benzimidazole,
- 5-Nitro-2-[4-nitro-2-(2-pyridyl)phenylthio]-1H-benzimidazole,
- 5-Nitro-2-[4-nitro-2-(2-pyridyl)phenylsulphinyl]-1H-benzimidazole,
- 4-Methoxy-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 4-Methoxy-2-[2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[2-(5-Methyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(5-Methyl-2-pyridinyl)phenylsulphinyl-1H-benzimidazole,
- 2-[2-(4-Methoxy-6-methyl-2Pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(4-Methoxy-6-methyl-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[2-(3-Methyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(3-Methyl-2-pyridinyl)phenylsulphinyl]-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridinyl)phenylthio]-4,5-dimethyl-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridinyl)phenylsulphinyl]-4,5-dimethyl-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridinyl)phenylthio]-5-nitro-1H-benzimidazole,
- 2-[2-(4-Methoxy-2-pyridinyl)phenylsulphinyl]-5-nitro-1H-benzimidazole,
- 5-Chloro-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 5-Chloro-2-[2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 5,6-Dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenyl thio]-1H-benzimidazole,
- 5,6-Dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- Ethyl 6-ethoxy-2-[2-(4-methoxy-2-pyridinyl) phenylthio]-1H-benzimidazole-5-carboxylate,
- Ethyl 6-ethoxy-2-[2-(4-methoxy-2-pyridinyl) phenylsulphinyl]-1H-benzimidazole-5-carboxylate,
- 4,7-Dimethoxy-2-[2-(4-methoxy-2-pyridinyl) phenyl thio]-1H-benzimidazole,
- 4,7-Dimethoxy-2-[2-(4-methoxy-2-pyridinyl) phenyl sulphinyl]-1H-benzimidazole,
- 2-[2-(4-Ethoxy-2-pyridinyl)phenylthio-1H-benzimidazole,
- 2-[2-(4-Ethoxy-2-pyridinyl)phenylsulphinyl-1H-benzimidazole,
- 2-[2-(4-(1-Methylethoxy)-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(4-(1-Methylethoxy)-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[2-(1H-Benzimidazol-2-yl thio)phenyl]-N,N-dimethyl-4-pyridinamine,
- 2-[2-(1H-Benzimidazol-2yl sulphinyl)phenyl]-N,N-dimethyl-4-pyridinamine,
- 2-[2-(4-Propyloxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(4-Propyloxy-2-pyridinyl)phenylsulphinyl]-1H-benzimidazole,
- 2-[5-Chloro-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[5-Chloro-2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[5-Methoxy-2-(4-methoxy-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- Methyl 2-(2-(4-methoxy-2-pyridinyl)phenylthio-6-methyl-1H-benzimidazole-5-carboxylate,
- Methyl 2-(2-(4-methoxy-2-pyridinyl)phenyl sulphinyl-6-methyl-1H-benzimidazole-5-carboxylate,
- 5,6-Dimethoxy-2-[5-methoxy-2-(2-pyridinyl) phenylthio]-1H-benzimidazole,
- 5,6-Dimethoxy-2-[5-methoxy-2-(2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- 2-[2-(4-Methyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 2-[2-(4-Methyl-2-pyridinyl)phenylsulphinyl]-1H-benzimidazole,
- 5-Methoxy-2-[2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole,
- 5-Methoxy-2-[2-(4-methyl-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole,
- Methyl 2-[2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole-5-carboxylate,
- Methyl 2-[2-(4-methyl-2-pyridinyl)phenyl sulphinyl]-1H-benzimidazole-5-carboxylate,
- 2-[2-(4-Methoxy-2-pyridinyl)-phenylsulphinyl]-1H-benzimidazole-5-amine,
- or a pharmaceutically acceptable salt thereof.
- 8. A pharmaceutical formulation for prophylaxis or treatment of inflammatory conditions or for prevention or inhibition of gastric acid secretion comprising an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
- 9. A method for the prophylaxis or treatment of inflammatory conditions, or for prevention or inhibition of gastric acid secretion, which comprises administration of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof to a patient suffering from such a condition.
Priority Claims (4)
| Number |
Date |
Country |
Kind |
| 8623299 |
Sep 1986 |
GBX |
|
| 8623301 |
Sep 1986 |
GBX |
|
| 8705017 |
Mar 1987 |
GBX |
|
| 8719644 |
Aug 1987 |
GBX |
|
Parent Case Info
This application is a continuation in part of U.S. patent application Ser. No. 918,832, filed Oct. 14, 1986.
This invention relates to new compounds, methods for their preparation and pharmaceutical formulations containing them.
A number of 2-(pyridylmethylsulphinyl) benzimidazoles are known for use as pharmaceuticals from European patent applications Nos. 5129 and 80602 and from British patent application No. 2,134,523. A number of 2-(heterocyclicmethylsulphinyl)benzimidazoles are known from West German OLS 2,548,340 and French Pat. No. 2,392,021.
We have now found a novel group of benzimidazoles, benzoxazoles and benzothiazoles which have pharmacological activity.
According to the invention we provide compounds of formula I, ##STR2##
in which A represents a 6 membered fully unsaturated carbocyclic ring, or a 5 or 6 membered nitrogen or sulphur containing saturated, partially unsaturated or fully unsaturated heterocyclic ring,
M is a carbon atom,
y is 0 or 1,
p is 0 or 1
W is --NR.sub.7 R.sub.8, --LNR.sub.7 R.sub.8 or is a 5 or 6 membered saturated or fully unsaturated heterocyclic ring containing a nitrogen atom positioned ortho or meta to the point of attachment to ring A, and which ring carries substituents selected from the values of R.sub.3 to R.sub.6,
L is a group containing 1 or 2 carbon atoms, optionally linked to the nitrogen atom by a double bond, in which case R.sub.7 has no significance,
R.sub.7 and R.sub.8, which may be the same or different, are each hydrogen, alkyl, phenyl or cycloalkyl, each of which is optionally substituted by phenyl, the phenyl groups in turn optionally being substituted by alkyl, or
R.sub.7 is as defined above and R.sub.8 is --OR.sub.13 or --NR.sub.14 R.sub.15, wherein
R.sub.13, R.sub.14 and R.sub.15, which may be the same or different, are each hydrogen, cycloalkyl, alkanoyl, pyridyl, phenyl or alkyl optionally substituted by halogen or by an oxo group, or
R.sub.7 and R.sub.8, together with the nitrogen atom to which they are attached, form a 4 to 8 inclusive membered ring which optionally contains 0, 1 or 2 further hetero atoms, which ring carries substituents selected from the values of R.sub.3 to R.sub.6, or
when W is NR.sub.7 R.sub.8 and R.sub.7 is as defined above, then R.sub.6 and --NR.sub.8 may, together with the carbon atoms of the ring to which --NR.sub.8 and R.sub.6 are attached, form a 4 to 8 inclusive membered saturated or unsaturated ring which may contain 0, 1 or 2 further hetero atoms, which ring carries substituents selected from the values of R.sub.3 to R.sub.6, save that when --NR.sub.8 forms parts of a double bond with an adjacent carbon atom, R.sub.7 has no significance,
R.sub.1 and R.sub.2, together with the ring carbon atoms to which they are attached, form a benzene ring, which ring carries substituents R.sub.9 to R.sub.12,
R.sub.3 to R.sub.6 and R.sub.9 to R.sub.12, which may be the same or different, are each hydrogen, halogen, phenoxy, alkyl, fluoroalkyl, alkanoyl, benzoyl, RS(O).sub.n --, --NO.sub.2, --NR.sub.16 R.sub.17, --NHCOR, --COOH or an ester or amide thereof, or alkoxy optionally substituted by phenyl,
and in addition, an adjacent pair of R.sub.3 to R.sub.6 carried on ring A or an adjacent pair of R.sub.9 to R.sub.12 may together form a chain --(CH.sub.2).sub.x -- or, together with the carbon atoms to which they are attached, form a 6 membered carbocylic or nitrogen heterocyclic ring,
n is 0, 1 or 2,
x is 3, 4 or 5,
X is S, O or NR.sub.18,
R.sub.18 is hydrogen, --COR, --COOR or alkyl which latter is optionally substituted by --OCOR or by phenyl,
R, R.sub.16 and R.sub.17, which may be the same or different, are each hydrogen, phenyl, or alkyl optionally substituted by phenyl, the phenyl groups in turn optionally being substituted by alkyl,
provided that
none of R.sub.3 to R.sub.6 nor R.sub.9 to R.sub.12 are selected from phenoxy, fluoroalkyl, alkanoyl, --NHCOR or alkoxy substituted by phenyl,
nor do an adjacent pair or R.sub.3 to R.sub.6 form a --(CH.sub.2).sub.x chain;
X is not NR.sub.18 where R.sub.18 is --COR, --COOR or alkyl substituted by phenyl,
R is not phenyl substituted by alkyl,
R.sub.16 and R.sub.17 are not phenyl substituted by alkyl nor alkyl substituted by phenyl,
n is 0, and
W is a 5 or 6 membered fully unsaturated heterocyclic ring containing a nitrogen atom ortho to the point of attachment of ring A, which ring carries substituents selected from the values of R.sub.3 to R.sub.6,
then in addition to the values given above, R.sub.1 and R.sub.2 may each be hydrogen, alkyl or may, together with the ring carbon atoms to which they are attached, form a pyridine ring, which ring carries substituents selected from the values of R.sub.9 to R.sub.12,
ring A may be a 5 membered fully unsaturated carbocyclic ring or a 5 or 6 membered fully unsaturated oxygen containing heterocyclic ring,
M may be an O, S or N atom,
R.sub.3 to R.sub.6 when carried on ring A or ring W may be alkoxy substituted by --OH, or by an optionally protected oxo group,
an adjacent pair of R.sub.3 to R.sub.6 when carried on ring A may, together with the ring carbon atoms to which they are attached, form a 5 membered fully unsaturated carbocyclic or nitrogen containing heterocyclic ring, or a 5 or 6 membered fully unsaturated O or S containing heterocyclic ring, each ring carrying substituents selected from the values of R.sub.3 to R.sub.6,
an adjacent pair of R.sub.3 to R.sub.6 carried on ring W may, together with the ring carbon atoms to which they are attached, form a 5 or 6 membered fully unsaturated carbocyclic or O, S or N containing heterocyclic ring carrying substituents selected from the values of R.sub.3 to R.sub.6,
an adjacent pair of R.sub.9 to R.sub.12, together with the ring carbon atoms to which they are attached, may form a 5 membered carbocyclic or nitrogen containing heterocyclic ring or a 5 or 6 membered O or S containing heterocyclic ring, and
R.sub.16 and R.sub.17 may, together with the nitrogen atom to which they are attached, form a 5 or 6 membered saturated ring which may contain a further heteroatom, and
pharmaceutically acceptable salts thereof.
According to the invention we also provide a process for the production of a compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises
(a) selective oxidation of a compound of formula I in which p is 0 to a corresponding compound of formula I in which p is 1,
(b) modification of a compound of formula I containing one or more groups convertible to a group, --NH.sub.2, --CH.sub.2 OH, or C.dbd.O, to a compound of formula I containing a group --NH.sub.2, --CH.sub.2 OH or C.dbd.O,
(c) reaction of a compound of formula I in which X is NR.sub.18 where R.sub.18 is hydrogen with a compound R.sub.19 Z in which R.sub.19 is as defined for R.sub.18 above, save that it cannot be hydrogen, and Z is a good leaving group,
(d) reaction of a compound of formula III, ##STR3## in which R.sub.1, R.sub.2 and X are as defined above, with a compound of formula IV, ##STR4##
in which R.sub.3, R.sub.4, R.sub.5, R.sub.6, y, W, M and A are as defined above, and
one of D and E is --SH or S.sup.- and the other is a good leaving group, or
(e) for the production of a compound of formula I, in which W is a fully unsaturated ring containing a nitrogen atom ortho to the point of attachment of ring A, reaction of a compound of formula V, ##STR5##
in which R.sub.1 to R.sub.6, p, y, M, X and A are as defined above with a compound of formula IIb, ##STR6##
in which B is a 5 or 6 membered fully unsaturated heterocyclic ring carrying substituents selected from the values of R.sub.3 to R.sub.6,
and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt thereof, or vice versa.
The selective oxidation of process (a) may be carried out in a solvent which is inert under the reaction conditions, e.g. ethyl acetate, dichloromethane, chloroform or a mixture thereof. The reaction is preferably carried out at less than room temperature, e.g. -20.degree. to +20.degree. C. Suitable oxidising agents for use in the reaction are hydrogen peroxide; peracids, e.g. m-Chloroperbenzoic acid; or t-butylhydroperoxide in the presence of a suitable catalyst, e.g. vanadyl acetyl acetonate, or periodates, e.g. sodium periodate in aqueous alcohol, e.g. methanol.
The modification of one group to another of process (b) may be selective reduction, e.g. --NO.sub.2 to --NH.sub.2 or HC.dbd.O to CH.sub.2 --OH, or selective hydrolysis, e.g. of a protected carbonyl group to C.dbd.O. The selective reduction of --NO.sub.2 to NH.sub.2 may, for example, be carried out chemically under basic conditions, e.g. using hydrazine and Raney nickel, but is preferably carried out using hydrogen and a catalyst, e.g. PtO.sub.2 in ethanol, as the reaction medium. The selection reduction of CH.dbd.O to CH.sub.2 OH may be carried out, for example using sodium borohydride. The selective hydrolysis is preferably carried out in an aqueous solution under acidic conditions.
In process (c) the good leaving group may be, for example, halogen (chlorine or iodine), and the reaction may be carried out in a solvent or solvent mixture which is inert under the reaction conditions, e.g. dimethyl formamide, in the presence of a base, e.g. potassium carbonate and at a temperature in the range 15.degree.-35.degree. C., e.g. at 20.degree.-25.degree. C.
For process (d) the good leaving group may be a sulphone, e.g. --SO.sub.2 Me, or a halogen, e.g. chlorine or bromine. The reaction may be carried out in any suitable solvent, e.g. N,N-dimethylformamide, N,N-dimethyl acetamide or methanol, at an optionally elevated temperature and may take place in the presence of a catalyst, e.g. Cu or an acid acceptor, e.g. potassium carbonate. We prefer D to be a good leaving group and E to be SH or S-.
The reaction of process (e) may be carried out in any suitable solvent, e.g. water, and at a temperature in the range 50.degree.-100.degree. C., e.g. at about 80.degree..
The compounds of formula III may be made from known compounds using conventional techniques known per se, for example, those compounds of formula III in which X is NR.sub.18, where R.sub.18 is H, and D is SH or S.sup.- may be made, for example, by reacting a compound of formula VII, ##STR7##
in which R.sub.1 and R.sub.2 are as defined above, with CS.sub.2. The reaction is preferably carried out under nitrogen and at a temperature in the range 50.degree.-80.degree. C. Those compounds of formula III in which D ia a sulphone, e.g. --SO.sub.2 Me, may be made from the corresponding thiol compound, e.g. by reaction first with methyl iodide and potassium carbonate in dimethyl formamide at a temperature in the range 0.degree.-50.degree. C. followed by treatment with Oxone (Registered Trade mark of the DuPont Co, peroxymonosulphate) in aqueous methanol at a temperature in the range 0.degree.-50.degree. C.
The compounds of formula IV may be made from known compounds using conventional techniques known per se, for example, those compounds of formula IV in which E is --SH or S.sup.-, y is O and W is a ring of formula IIb, may be made using the following route: ##STR8##
in which R.sub.3 to R.sub.6, M, A and B are as defined above.
The oxidation of step 1 may be carried out as described for process (a) above. Step 2 may be carried out, for example, with trifluoroacetic acid and triethylamine in methanol. Under oxidizing conditions (e.g. in the presence of air) a disulphide may be a bi-product of step 2. The disulphide may be converted to the corresponding sulphide by reduction. Suitable reagents for this reduction are sodium borohydride and sodium cyanoborohydride.
The compounds of formula VIII may be made by a coupling or cyclisation reaction reaction as shown below.
(a) Coupling
Reaction of a compound of formula IX ##STR9##
in which R.sub.3 to R.sub.6, M, and A are defined above and G is a metal ion (e.g. lithium) or a Grignard reagent (e.g. MgBr),
with a compound of formula IIa or its N-oxide or ortho halo (e.g. o-fluoro) derivative, ##STR10## in which B is as defined above.
(b) Cyclisation
Reaction of a compound of formula X ##STR11##
in which R.sub.3 to R.sub.6, M and A are as defined above, and Z is a good leaving group, e.g. chloro, with, for example,
(i) when ring B is pyridine, CH.sub.3 --C(O)--CH.dbd.CH--OMe, followed by NH.sub.3, or
(ii) when ring B is imidazole, NH.sub.2 C(R.sub.7).dbd.C(R.sub.21)NH.sub.2,
in which R.sub.20 and R.sub.21 are selected from the values of R.sub.3 to R.sub.6 above.
The compounds of formula V may be made by diazotisation of a compound of formula I, in which W is --NR.sub.7 R.sub.8 where R.sub.7 and R.sub.8 are both hydrogen.
The diazotisation may be carried out in any suitable solvent, e.g. water, in the presence of acid, e.g. hydrochloric acid, at a temperature in the range 0.degree.-15.degree. C., e.g. below 5.degree. C., and with an alkali metal nitrite, e.g. sodium nitrite.
The compounds of formulae IIb, IIa, VII, IX and X are either known or may be made by conventional processes known per se.
The compounds of formula I, and the intermediates therefor, may be isolated from their reaction mixtures using conventional techniques.
Certain of the compounds of formulae IV, VIII and VIIIa are novel and we provide these novel compounds for use as intermediates in the synthesis of compounds of formula I as defined above.
In particluar compounds of formula IVa, ##STR12##
in which E.sub.a is SH, S.sup.-, SMe or SOMe, ring A is a benzene or thiophen ring, M is a carbon or sulphur atom, R.sub.3 to R.sub.6 are as defined above and ring B is either a pyridine ring carrying substituents selected from the values of R.sub.3 to R.sub.6 as defined above, save that an adjacent pair of R.sub.3 to R.sub.6 cannot, together with the carbon atoms to which they are attached, form a ring or ring B and an adjacent pair of the substituents selected from the values of R.sub.3 to R.sub.6 which it carries form a 1-isoquinolinyl, 2-imidazo[1,2-a]pyridine or 2-N-alkylated-benzimidazoyl group, which group carries substituents selected from the values of R.sub.3 to R.sub.6, are novel and are provided for use as intermediates in the synthesis of compounds of formula I as defined above.
Pharmaceutically acceptable salts of the compounds of formula I include salts with suitable organic or inorganic acids, e.g. with a hydrohalic, sulphuric, alkanesulphonic, tartaric or citric acid. We also provide, when the compound of formula I carries a --COOH, or other acidic group, salts with suitable organic or inorganic bases, e.g. ammonium, alkali metal, alkaline earth metal, alkylamino, etc. salts. The benzimidazole nucleus itself is acidic and can form salts with appropriate bases as above.
We also provide the compounds of formula I, without proviso (a) (i), and pharmaceutically acceptable salts thereof, for use as pharmaceuticals, e.g. for use as cytoprotective agents, in the treatment or prophylaxis of inflammatory conditions, as mucosa protectants, or in the prevention or inhibition of gastric acid secretion.
The compounds of formula I, and pharmaceutically acceptable salts thereof, are useful because they possess pharmacological activity in animals; in particular they are useful because they have cytoprotective properties, are useful in the treatment or prohylaxis of inflammatory situations and/or to prevent or inhibit gastric acid secretion, e.g. in the test set out in Am. J. Physiol., 1982, 243(6), G505-510. The compounds of formula I are also useful as intermediates in the synthesis of other chemicals.
The new compounds are thus indicated for use in the prevention or inhibition of gastric acid secretion, and/or conditions normally involving excess gastric acid secretion, e.g. peptic, duodenal, gastric, recurrent or stormal ulceration, dyspepsia, duodenitis, Zollinger-Ellison syndrome, reflux oesophagitis and the management of haemorrhage, e.g. from erosion of ulcers in the upper gastrointestinal tract, especially when a major blood vessel is not involved. The compounds may also be used to treat gastritis or dyspepsia associated with administration of non-steroidal anti-inflammatory drugs, in the prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill or burned patients, in the prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers, before general anaesthesia in patients at risk of acid aspiration syndrome (Mendelson's syndrome) and to reduce the chance of haemorrhage in patients with leukaemia, graft versus host disease or with severe hepatic failure. The above conditions may be treated whether or not they are associated with excess gastric acid secretion.
The compounds may also be used to treat cholera, paratyphus, tourist diarrhoea, toxin-induced diarrhoea and local gastric catarrh.
The new compounds are also indicated for use as cytoprotective agents, especially for the gastrointestinal tract, and can be utilized for the treatment or prevention of a non-gastric-acid-induced, non-traumatically-induced, non-neoplastic gastrointestinal inflammatory disease for example, Crohn's disease, inflammatory bowel disease, infectious enteritis, colitis, ulcerative colitis, pseudomembranous colitis, diverticulitis, and allergenic and radiological inflammatory diseases.
The compounds are also indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be specifically mentioned are: rheumatoid arthritis, gout, eczema, polyserositis and allergic alveolitis.
Patterns of therapeutic use which may be mentioned are:
(a) a high dose initially, for say 2-4 weeks, followed by lower-dose maintenance therapy after the condition has improved, e.g. the ulcer has healed,
(b) as in (a) above, but the maintenance therapy includes another cytoprotective agent, e.g. a PGE.sub.2 derivative,
(c) combination therapy, using a low dose of the compound of the invention in association with a low, well-tolerated dose of another cytoprotectant and/or antacid,
(d) intermittent dosing, e.g. every second day, may be appropriate as maintenance therapy.
For the above mentioned uses the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of from 10.sup.-6 M to 10.sup.-4 M in the test set out in Am. J. Physiol, 1982, 243 (6), G505-G510. For man the indicated total daily dosage is in the range of from about 1 mg to 3,000 mg, preferably 5 to 500 mg, and more preferably from about 10 mg to 200 mg, which may be administered in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for administration comprise from about 1.0 mg to 600 mg of the compound admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
The compounds of formula I, and pharmaceutically acceptable salts thereof, have one or more of the following advantages. They are more readily absorbed, have increased bioavailability, are more stable around neutral pH, are less irritant to the GI tract, are more specific in action, have less toxic side effects, are more rapidly activated by acid, e.g. gastric acid, are more stable to acid, e.g. gastric acid, produce more advantageous results, e.g. in the `Shay Rat Test` as described by H. Shay et al in Gastroenterology, 5 43-61 (1945), or have other advantageous properties when compared to known compounds of similar structure.
We prefer ring A to be fully unsaturated. When ring A is a heterocyclic ring we prefer it to contain one heteroatom. Specific groups ring A may represent include furan, pyrazole, pyrimidine, pyridine, benzene or thiophen. We prefer ring A to be a benzene or thiophen ring. When ring A is a pyridine ring it may be joined to the --S(O).sub.n group in the 4 position and to ring B in the 3 position, or it may be joined to the --S(O).sub.n group in the 3 position and to ring B in the 2 position. When ring A is a thiophen ring it may be joined to the --S(O).sub.n group at the 2 position and to the ring B at the 3 position or it may be joined to the --S(O).sub.n group at the 3 position and to the ring B at the 2 position.
When W is a 5 or 6 membered nitrogen containing heterocyclic ring, that ring may contain 1 or 2 further heteroatoms and preferably 1 or 2 further nitrogen atoms. We prefer that ring to be a ring of formula IIb. We particularly prefer that ring to be a pyridine or imidazole ring. When that ring is an imidazole ring it may be joined to ring A at its 2 or 4 position. When that ring is an imidazole ring it may be N-substituted, e.g. N-alkylated. When that ring is an imidazole ring joined to ring A at its 2 position we prefer it to be an N-methylated imidazole.
Specific groups R.sub.7 and R.sub.8 which may be mentioned include hydrogen, methyl and phenyl.
When R.sub.7 and R.sub.8, together with the nitrogen atom to which they are attached, form a ring, the ring may be saturated or unsaturated and may contain a further nitrogen, oxygen and/or sulphur atom, e.g. it may be a piperidino or morpholino ring.
When A is a benzene ring, and W is NR.sub.7 R.sub.8 where R.sub.7 and R.sub.8 are each hydrogen or alkyl C1 to C6, we prefer ring A to carry, in addition to the group NR.sub.7 R.sub.8, a substituent --NR.sub.16 R.sub.17 preferably positioned para to the NR.sub.7 R.sub.8 group. We prefer the group --NR.sub.16 R.sub.17 to be --NH.sub.2 or --N(CH.sub.3).sub.2.
When W is NR.sub.7 R.sub.8 and R.sub.6 and --NR.sub.8, together with the carbon atoms of the ring to which R.sub.6 and --NR.sub.8 are attached, form a ring, that ring may be an imidazole, pyridine, pyrrole or piperidino ring, e.g. an N-methyl piperidino ring, or preferably a pyridine ring. When R.sub.6 and --NR.sub.8 form a pyridine ring, as described above, we prefer ring A to be a benzene ring, y to be 0 and X to be NR.sub.18. When R.sub.6 and --NR.sub.8 form a pyridine ring as described above, we prefer that ring to have a substituent selected from the values of R.sub.3 to R.sub.6 other than hydrogen para to the nitrogen of the group --NR.sub.8. We prefer that substituent to be selected from alkoxy, phenoxy, benzyloxy, --NR.sub.16 R.sub.17, --RS(O).sub.n, where n is O, or alkyl C 1 to C6. We particularly prefer the substituent para to the ring nitrogen atom to be alkoxy, e.g. methoxy.
L may be, for example, --CH.sub.2 CH.sub.2 --, --CH.dbd., --CH.sub.2 CH.dbd. or preferably --CH.sub.2 --.
Specific groups --LNR.sub.9 R.sub.10 which may be mentioned include --CH.sub.2 N(CH.sub.3)Ph, --CH.dbd.N--NR.sub.22 R.sub.23, --CH.sub.2 NH--N(CH.sub.3).sub.2 and --CH.dbd.N--OR.sub.24,
in which R.sub.22, R.sub.23 and R.sub.24, which may be the same or different, are each hydrogen, alkyl C 1 to C6 or phenyl.
We prefer y to be 0.
We prefer X to be NR.sub.18.
R.sub.18 may be methyl, --CO.sub.2 CH.sub.2 Ph, or preferably hydrogen.
We prefer p to be 1.
When any of R.sub.3 to R.sub.6 or R.sub.9 to R.sub.12 is halogen, it may be chlorine or fluorine.
When any of R.sub.1 to R.sub.21 or R represent or contain a carbon containing group we prefer that group to contain up to and including 10, and preferably up to and including 6, carbon atoms.
When any of R.sub.3 to R.sub.6 or R.sub.9 to R.sub.12 represent an ester we prefer it to be derived from a C 1 to C6 alcohol, e.g. to be a methyl or ethyl ester.
When any of R.sub.3 to R.sub.6 or R.sub.9 or R.sub.12 represents an amide they may be, for example, an unsubstituted or a mono- or di-alkyl C1 to C6 substituted amide.
The number of substituents R.sub.3 to R.sub.6 or R.sub.9 to R.sub.12 clearly cannot be more than the number of positions available for substitution on the ring to which they are attached.
Specific groups R.sub.3, R.sub.4, R.sub.5 and R.sub.6 include hydrogen, methyl, ethyl, chloro, --NHCOCH.sub.3, --NO.sub.2, --NR.sub.20 R.sub.21, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted by OH, by an oxo group and by a protected oxo group, e.g. a ketal, in particular ethylene dioxy.
When an adjacent pair of R.sub.3 to R.sub.6, together with the ring carbon atoms to which they are attached, form a ring we prefer that ring to be a carbocyclic ring and more particularly to be a benzene ring. When an adjacent pair R.sub.3 to R.sub.6, which are carried on a ring W, form a ring as described above, we prefer ring W to be a pyridine or imidazole ring. We particularly prefer that when an adjacent pair R.sub.3 to R.sub.6, which are carried on a ring W, form a ring as described above, they form with ring W a 1-isoquinolinyl, 2-imidazo[1,2-a]pyridine or more particularly a 2-benzimidazolyl group, which groups carry substituents selected from the values of R.sub.3 to R.sub.6 above. Specific examples of such substituents include hydrogen, halogen (e.g. chloro) or alkoxy.
We prefer R.sub.1 and R.sub.2, together with the ring carbon atoms to which they are attached, to form a benzene ring.
Specific groups R.sub.9, R.sub.10, R.sub.11 and R.sub.12 include hydrogen, methyl, methoxy, ethoxy, chlorine, --NO.sub.2, CF.sub.3, p-toluenesulphonyl, --NR.sub.20 R.sub.21, benzoyl, methoxycarbonyl, ethoxycarbonyl and phenylcarbonyl.
When an adjacent pair or R.sub.9 to R.sub.12 form a 5 or 6 membered ring it may be saturated, partially unsaturated or fully unsaturated and may contain 0, 1 or 2 heteroatoms. We prefer that ring to be carbocyclic or to be an oxygen containing heterocyclic ring. We particularly prefer that ring to be a benzene or 1,3 dioxolan ring.
We prefer R.sub.9 to R.sub.12 to be selected from hydrogen, alkyl or alkoxy.
Specific groups R.sub.16 and R.sub.17 include hydrogen, methyl and phenyl.
When R.sub.16 and R.sub.17, together with the nitrogen atom to which they are attached, form a ring containing a further heteroatom, we prefer that heteroatom to be oxygen, When R.sub.16 and R.sub.17, together with the nitrogen atom to which they are attached, form a ring we prefer that ring to be a pyrrolidino or morpholino ring.
When R.sub.1 and R.sub.2 form a benzene ring, y is 0, A is a benzene ring and W is a pyridine ring, we prefer at least one of the substituents R.sub.3 to R.sub.6, carried on ring A, ring W or on a ring formed by an adjacent pair of substituents, to be selected from alkyl, RS(O).sub.n where n is 0, --NR.sub.16 R.sub.17 or alkoxy optionally subtituted by hydroxy or by an optionally protected oxo group. More specifically to be selected from methyl, ethyl, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted by OH, by an oxy group or by a protected oxo group, or --NR.sub.16 R.sub.17 where R.sub.16 and R.sub.17 represent methyl, phenyl or, together with the nitrogen atom to which they are attached, form a pyrrolidino or morpholino ring.
When ring A is a benzene ring attached to the --S(O).sub.n group in the 2 position and to ring W in the 1 position, we particularly prefer the substituent in the 4 position (i.e. para to the position of attachment of ring W) to be selected from alkyl, RS(O).sub.n where n is 0, --NR.sub.16 R.sub.17 or alkoxy optionally substituted by hydroxy or by an optionally protected oxo group.
When ring W is a pyridine ring attached to ring A in the 2 position, we prefer the substituent in the 4 position (i.e. para to the ring N atom) to be selected from alkyl, RS(O).sub.n where n is 0, --NR.sub.16 R.sub.17 or alkoxy optionally substituted by hydroxy or by an optionally protected oxo group.
We particularly prefer compounds of formula I in which R.sub.1 and R.sub.2, together with the ring carbon atoms to which they are attached, form a benzene ring which benzene ring carries substituents R.sub.9, R.sub.10, R.sub.11 and R.sub.12, X is NR.sub.18, R.sub.18 is hydrogen, y is 0, p is 1, A is a benzene ring and W is a ring of formula IIb in which ring B is a pyridine ring having a substituent para to the ring N atom selected from alkyl, RS(O).sub.n where n is 0, --NR.sub.16 R.sub.17 or alkoxy optionally substituted by hydroxy or by an optionally protected oxy group or for ring B to be an imidazole ring attached to ring A in the 2 position and in which the substituents in the 4 and 5 positions, together with the ring carbon atoms to which they are attached, form a benzene ring which benzene ring carries subtituents selected from the values of R.sub.3 to R.sub.6.
Specific groups of compounds of formula I include ##STR13## in which R.sub.3a, R.sub.4a, R.sub.5a, R.sub.6a, R.sub.9a, R.sub.10a, R.sub.11a and R.sub.12a, which may be the same or different, are each hydrogen, halogen, alkoxy, alkyl, fluoroalkyl, alkanoyl, RS(O).sub.n, --NO.sub.2, --NR.sub.16 R.sub.17, --NHCOR, or --COOH or an ester or amide thereof,
or an adjacent pair of R.sub.3a, R.sub.4a, R.sub.5a, R.sub.6a, R.sub.9a, R.sub.10a, R.sub.11a and R.sub.12a may, in addition to the values given above, together form a chain --(CH.sub.2).sub.x --or, together with the carbon atoms to which they are attached, form a 6 membered unsaturated carbocylic or nitrogen heterocyclic ring,
x, n, X, R.sub.16, R.sub.17 and R are as defined above,
R.sub.7a and R.sub.8a, which may be the same or different, are each hydrogen, alkyl, phenyl or cycloalkyl each of which may optionally be substituted by phenyl, the phenyl group in turn optionally being substituted by alkyl,
or one of R.sub.7a and R.sub.8a may be as defined above and the other may be --OR.sub.13 or --NR.sub.14 R.sub.15, or
R.sub.7a and R.sub.8a, together with the nitrogen atom to which they are attached, may form a saturated or unsaturated 4 to 8 inclusive membered ring which may contain 0, 1 or 2 further hetero atoms, which ring may carry one or more substituents R.sub.3a to R.sub.6a, and
R.sub.13, R.sub.14 and R.sub.15 are as defined above,
or R.sub.7a is as defined above save that it cannot form a ring with R.sub.8a, and R.sub.6a, and R.sub.8a, together with the nitrogen atom and the carbon atoms of the ring to which the nitrogen atom and R.sub.6a are attached, form a saturated 4 to 8 inclusive membered ring which may contain 0, 1, or 2 further hetero atoms, which ring may carry one or more substituents R.sub.3a to R.sub.a,
with the proviso (a) (ii) above, ##STR14## in which R.sub.4a to R.sub.6a, R.sub.7a and R.sub.8a, R.sub.9a to R.sub.12a and X are as defined above, and
A.sub.b represents a 5 or 6 membered nitrogen or sulphur containing heterocyclic ring which is connected to the rest of the molecule through a ring carbon atom, ##STR15##
in which R.sub.3a to R.sub.6a, R.sub.9a to R.sub.12a, y and X are as defined above,
W.sub.c is a group --L.sub.c NR.sub.7c R.sub.8c or is a 5 or 6 membered heterocyclic ring containing a nitrogen atom ortho or meta to the point of attachment to the rest of the molecule.
R.sub.7c and R.sub.8c, which may be the same or different, are each hydrogen, alkyl, phenyl or cycloalkyl each of which may optionally be substituted by phenyl, the phenyl groups in turn optionally being substituted by alkyl, or
one of R.sub.7c and R.sub.8c is as defined above and the other is --OR.sub.13 or --NR.sub.14 R.sub.15, or
R.sub.7c and R.sub.8c, together with the nitrogen atom to which they are attached, may form a saturated or unsaturated 4 to 8 inclusive membered ring which may contain 0, 1 or 2 further hetero atoms, which ring may carry one or more substitutents R.sub.3a to R.sub.6a, and
R.sub.13, R.sub.14 and R.sub.15 are as defined above,
L.sub.c is a group containing 1 or 2 carbon atoms inclusive, optionally linked to the nitrogen atom by a double bond in which case R.sub.7c has no significance, ##STR16##
in which R.sub.4a to R.sub.6a, R.sub.9a to R.sub.12a, W.sub.c, A.sub.b, X and y are as described above, ##STR17##
in which A, y and W are as defined above,
R.sub.3e to R.sub.6e and R.sub.9e to R.sub.12e, which may be the same or different, are each hydrogen, halogen, phenoxy, alkyl, fluoroalkyl, alkanoyl, RS(O).sub.n, --NO.sub.2, --NR.sub.16 R.sub.17, --NHCOR, --COOH or an ester or amide thereof, or alkoxy optionally substituted by phenyl,
and in addition, an adjacent pair of R.sub.3e to R.sub.6e or R.sub.9e to R.sub.12e may together form a chain --(CH.sub.2).sub.x --or, together with the carbon atoms to which they are attached, form a 6 membered carbocylic or nitrogen heterocyclic ring,
R, R.sub.16, R.sub.17, n and x are as defined above,
X is S, O or NR.sub.15,
R.sub.15 is hydrogen, --COR, --COOR or alkyl which latter is substituted by --COR,
with the provisos (a) (i), (a) (ii) and (b) above, ##STR18##
in which at least one of R.sub.3f, R.sub.4f, R.sub.5f, R.sub.6f, R.sub.22f, R.sub.23f, R.sub.24f and R.sub.25f is selected from alkyl, alkoxy, or --NR.sub.16f R.sub.17f,
and the remainder of R.sub.3f to R.sub.6f and R.sub.23f to R.sub.25f are each hydrogen, halogen, --NO.sub.2, or --COOH or an ester or amide thereof,
R.sub.9f, R.sub.10f, R.sub.11f and R.sub.12f, which may be the same or different, are each hydrogen, halogen, alkyl, alkoxy, --NO.sub.2, --NR.sub.f R.sub.26f or --COOH or an ester or amide thereof,
R.sub.18f is hydrogen or alkyl optionally substituted by --OCOR
R.sub.f and R.sub.26f, which may be the same or different, are each hydrogen, phenyl, or alkyl,
R.sub.16f and R.sub.17f, which may be same or different, are hydrogen, alkyl, phenyl or may, together with the nitrogen atom to which they are attached, form a 5 or 6 membered saturated ring, which ring may contain a further heteroatom, ##STR19##
in which A.sub.g represents a 5 or 6 membered nitrogen, oxygen or sulphur containing fully unsaturated heterocyclic ring which is connected to the --SO-- group through a ring carbon atom, and which may be fused to a benzene ring,
E.sub.g represents a 5 or 6 membered nitrogen containing fully unsaturated heterocyclic ring, which may be fused to a benzene ring,
R.sub.lg and R.sub.2g, which may be the same or different, are each hydrogen or alkyl,
or may, together with the carbon atoms to which they are attached, form a benzene or pyridine ring which in turn may be substituted by one or more substituents selected for the values of R.sub.9f to R.sub.12f defined above,
R.sub.18f is as defined above, ##STR20##
in which at least one adjacent pair of R.sub.22h, R.sub.23h, R.sub.24h and R.sub.25h, together with the ring atoms to which they are attached, form a 5 or 6 membered fully unsaturated carbocyclic or heterocyclic ring,
and the remainder of R.sub.22h to R.sub.25h are as defined for R.sub.3f to R.sub.6f above,
B.sub.h is a 5 or 6 membered fully unsaturated nitrogen containing heterocyclic ring,
R.sub.18f, R.sub.9f, R.sub.10f, R.sub.11f and R.sub.12f are as defined above,
R.sub.3h, R.sub.4h, R.sub.5h and R.sub.6h have the significances given for R.sub.3f to R.sub.6f above and, in addition, an adjacent pair of R.sub.3h, R.sub.4h, R.sub.5h and R.sub.6h may, together with the ring atoms to which they are attached, form a 5 or 6 membered fully unsaturated carbocyclic or heterocyclic ring, ##STR21##
in which A.sub.i is a 5 or 6 membered, fully unsaturated, carbocyclic or heterocyclic ring,
B.sub.i is a 5 or 6 membered, fully unsaturated, nitrogen containing heterocyclic ring carrying substituents selected from the values of R.sub.3i to R.sub.6i,
X is NR.sub.18i, O or S,
R.sub.18i is hydrogen or alkyl optionally substituted by --OCOR,
p is 0 or 1,
R.sub.3i, R.sub.4i, R.sub.5i and R.sub.6i, R.sub.22i, R.sub.23i, R.sub.24i and R.sub.25i, which may be the same or different, are selected from hydrogen, alkyl, halogen, --SR.sub.i, benzoyl, --NO.sub.2, --NR.sub.16i R.sub.17i, --COOH or an ester or amide thereof, or alkoxy optionally substituted by hydroxy or by an optionally protected oxo group, or
in addition to the values above an adjacent pair of R.sub.3i to R.sub.6i or R.sub.22i to R.sub.25i may, together with the ring atoms to which they are attached, form a 5 or 6 membered, fully unsaturated, carbocyclic or heterocyclic ring which carries substituents R.sub.27i, R.sub.28i, R.sub.29i and R.sub.30i,
R.sub.27i, R.sub.28i, R.sub.29i and R.sub.30i, which may be same or different, are selected from hydrogen, alkyl, alkoxy, halogen, --SR.sub.i, benzoyl, --NO.sub.2, --NR.sub.16i R.sub.17i or --CO.sub.2 H or an ester or amide thereof,
save when ring A.sub.i, ring B.sub.i or the ring formed by an adjacent pair of R.sub.3i to R.sub.6i or R.sub.22i to R.sub.25i is 5 membered, then respectively R.sub.6i, R.sub.25i or R.sub.30i has no significance,
R.sub.1i and R.sub.2i, which may be the same or different, are selected from hydrogen or alkyl or may, together with the ring carbon atoms to which they are attached, form a benzene or pyridine ring, which ring carries subtituents R.sub.9i, R.sub.10i, R.sub.11i and R.sub.12i,
R.sub.9i, R.sub.10i, R.sub.11i and R.sub.12i, which may be the same or different, are selected from hydrogen, alkyl, halogen, --SR.sub.i, benzoyl, alkoxy, --NO.sub.2, --NR.sub.16i R.sub.17i or --CO.sub.2 H or an ester or amide thereof, or
in addition to the values above an adjacent pair of R.sub.9i, R.sub.10i, R.sub.11i and R.sub.12i may, together with the ring carbon atoms to which they are attached, form a 5 or 6 membered, carbocyclic or heterocyclic ring,
R.sub.16i and R.sub.17i, which may be the same or different, are selected from hydrogen, alkyl, phenyl or may, together with the nitrogen atom to which they are attached, form a 5 or 6 membered, saturated ring, which ring may contain a further heteroatom,
R.sub.i is hydrogen, phenyl or alkyl optionally substituted by phenyl,
provided that when R.sub.1i and R.sub.2i, together with the ring carbon atoms to which they are attached, form a benzene ring, A.sub.i is a benzene ring and B.sub.i is a pyridine ring, then at least one or R.sub.3i to R.sub.6i, R.sub.22i to R.sub.25i and R.sub.27i to R.sub.30i is selected from alkyl, --SR.sub.i, --NR.sub.16i R.sub.17i or alkoxy optionally substituted by hydroxy or by an optionally protected oxo group.
According to our invention we also provide a pharmaceutical composition comprising (preferably a minor proportion of) a compound of formula I, or a pharmaceutically acceptable salt thereof, as active ingredient, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets and dragees; lactose, starch, talc or stearic acid; for capsules, tartaric acid or lactose; for suppositories, natural or hardened oils or wax; and for injections (i.m. or i.v.) or enemas water, surfactants and preservatives. The compounds may also be administered transdermally, e.g. in an ointment base. The compound of formula I, or the pharmaceutically acceptable salt thereof, preferably has a mass median diameter of from 0.01 to 10 microns. The compound of such particle size may be made by grinding or milling followed if necessary by particle size classification using, for example, a sieve. The compositions may also contain suitable preserving, stabilising, and wetting agents, solubilizers, sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form.
The compounds may, if desired, be co-administered, with (e.g. as a mixture with) an antacid buffer.
We prefer compositions which are designed to be taken by ingestion or rectally and to release their contents in the intestine. We particularly prefer compositions which will pass through the acidic parts of the gastrointestinal tract unaffected, e.g. enteric coated formulations.
Some of the compounds of formula I are optically active and may be resolved into their optical isomers using conventional techniques known per se. The invention therefore provides the compounds as their optical isomers, or as mixtures, e.g. racemic mixtures, thereof.
The compounds of formula I may exist in tautomeric forms and these tautomeric forms are included in the definition of the compounds of formula I. In particular when X is R.sub.18 and R.sub.18 is hydrogen the imidazole nucleus may exist in tautomeric forms.
The invention is illustrated, but in no way limited, by the following Examples in which temperatures are in degrees centigrade.
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 2161160 |
Jan 1986 |
GB2 |
| 0171372 |
Dec 1986 |
EPX |
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
918832 |
Oct 1986 |
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Patent Grant
4900751
