Gastrin and cholecystokinin receptor ligands(II)
AssigneeJames Black Foundation Limited
InventorsSarkis Barret Kalindjian, Ildiko Maria Buck, Katherine Isobel Mary Steel, Paul Trevor Wright, Matthew John Tozer, Michael John Pether, Caroline Minli Rachel Low
Life of this patent
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Abstract
Substituted imidazoles (1) are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure. Pharmaceutical compositions containing the novel imidazoles and pharmaceutical methods using them, alone and in conjunction with other drugs, especially diuretics and non-steroidal antiinflammatory drugs (NSAID's) are also described.
Claims39
A compound of formula (I)
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- wherein
- n is from 1 to 3;
- X and Y are independently ═N— or —N(R5)— (R5 being selected from H, Me, Et, Pr, Bn, —OH and —CH2COOR6, wherein R6 represents H, Me, Et, Pr or Bn);
- R1 is H or C1-Chydrocarbyl wherein up to three C atoms may optionally be replaced by N, O and/or S atoms, and up to three H atoms may optionally be replaced by halogen atoms;
- R2 is selected from H, Me, Et, Pr and OH, each R2 being independently selected from H, Me, Et, Pr and OH when n is greater than 1;
- R3 (when n is 1) is selected from H, Me, Et and Pr;
- or (when n is greater than 1) each R3 is independently selected from H, Me, Et and Pr, or two R3 groups on neighbouring carbon atoms are linked to form a C3 to C carbocylic ring, or two R3 groups are absent from neighbouring carbon atoms which are linked by a double bond;
- or R2 and R3 on the same carbon atom together represent an ═O group;
- R4 is H or C1-C hydrocarbyl wherein up to three C atoms may optionally be replaced by N, O and/or S atoms, and up to three H atoms may optionally be replaced by halogen atoms;
- Z is a diradical derived from an optionally substituted aromatic or non-aromatic C or Ccarbocycle, wherein 1, 2 or 3 C atoms are optionally replaced by N, O end/or S;
- Q is a 6-membered aromatic carbocycle substituted with 1 or 2 V groups and optionally substituted with 1, 2 or 3 T groups, wherein 1, 2 or 3 C atoms of the carbocycle are optionally replaced by N;
- V is —CO—NH—SO2—Ph, —SO2—NH—CO—Ph, —CH2OH, or a group of the formula —RU, (wherein U is —COOH, tetrazolyl, —CONHOH or —SO3H;
- and R7 is a bond;
- C1 to C hydrocarbylene, optionally substituted by hydroxy, amino or acetamido;
- —O—(C1 to C3 alkylene)—;
- —SO2NR —CHR9—;
- —CO—NR6—CHR9—, R and R being independently selected from H and methyl;
- or —NH—(CO)c—CH2—, c being 0 or 1);
- T is C1 to C6 hydrocarbyl, —NR10R11 (wherein R10 and R11 are independently selected from H, Me, Et, Pr or Bn), —OMe, —OH, CH2OH, halogen or trihalomethyl;
A compound according to any one of the preceding claims wherein R4 is C3 to C15 carbocyclic.
A compound according to any one of the preceding claims wherein R4 is adamantyl, cycloheptyl, cyclohexyl or phenyl.
A compound according to any one of the preceding claims wherein R4 is —NH—R12 or —OR12, wherein R12 is C3 to C12 carbocyclic.
A compound according to any preceding claim wherein R2 and R3 are H, and n is from 1 to 3.
A compound according to any one of the preceding claims wherein Z is a diradical derived from any one of cyclohexene, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazine, oxazine, cyclohexane, piperidine, piperazine, morpholine, thiomorpholine, thioxane, dioxane, pyran, dihydropyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyrrole, imidazole, pyrazole, thiophene, furan, oxazole, isoxazole, triazole, oxadiazole, thiazole, isothiazole, furazan, thiadiazole, thiophene, pyrrolidine, pyrroline, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, tetrahydrothiophene, oxathiolane, or oxazolidine.
A compound according to any one of the preceding claims wherein Z is
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A compound according to any one of the preceding claims wherein Q is selected from the group consisting of 3-carboxyphenyl, 5-carboxypyridin-2-yl, 4-carboxypyridin-2-yl and 6-carboxypyridin-2-yl.
A compound which is degraded in vivo to yield a compound according to any preceding claim.
A product containing as first active ingredient a compound of formula (I) and as second active ingredient a proton pump inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from gastrointestinal disorders.
Use of a proton pump inhibitor for the preparation of a medicament for the treatment of gastrointestinal disorders, said treatment comprising the simultaneous or sequential administration of said proton pump inhibitor and a compound of formula (I), wherein said proton pump inhibitor enhances the effect of the compound of formula (I) on gastrin-related disorders in patients suffering from gastrointestinal disorders.
Use of a compound of formula (I) for the preparation of a medicament for the treatment of gastrointestinal disorders, said treatment comprising the simultaneous or sequential administration of said proton pump inhibitor and a compound of formula (I), wherein said compound of formula (I) enhances the effect of the proton pump inhibitor on the reduction of acid secretion in patients suffering from gastrointestinal disorders.
Use of a compound of formula (I) for the preparation of a medicament for reducing adverse effects associated with administration of proton pump inhibitors in patients suffering from gastrointestinal disorders.
Use of a proton pump inhibitor for the preparation of a medicament for reducing adverse effects associated with administration of a compound of formula (I) in patients suffering from gastrointestinal disorders.
Dependencies are inferred from the claim text.