Pharmaceutical compositions comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands

• US 20030195240A1
• Filed: 04/14/2003
• Published: 10/16/2003
• Est. Priority Date: 05/08/2000
• Status: Abandoned Application

• Current Assignee: James Black Foundation Limited, Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Andries, Luc Joseph, Shankley, Nigel Paul, Black, James Whyte, Mesens, Jean Louis, Hull, Robert Anthony David, Kalindjian, Sarkis Barret
• Application Number:
  US10/275,624
• Publication Number:
  US 20030195240A1
• Time in Patent Office: Days
• US Class Current: 514/370
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

Pharmaceutical compositions comprising a proton pump inhibitor and a compound of the formula (I) or its pharmaceutically acceptable salts, are useful in treating gastrointestinal disorders. X and Y are independently ═N—, —N(R⁵)— (R⁵ being selected from H, Me, Et, Pr, Bn, —OH and —CH₂COOR⁶, wherein R⁶ represents H, Me, Et, Pr or Bn), ═CH—, S— or —O—; n is from 1 to 4; R¹ is H or C₁ to C₁₅ 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; 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 which are linked by a double bond; or R² and R³ on the same carbon atom are linked to form a C₃ to C₆ 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 C₁ to C₁₅ hydrocarbyl wherein up to two C atoms may optionally be replaced by N, O and/or S atoms and up to two H atoms may optionally be replaced by halogen atoms; Z is —(NR⁷)_a—CO—(NR⁸)_b— (wherein a is 0 or 1, b is 0 or 1, and R⁷ and R⁸ are independently selected from the groups recited above for R⁶), —CO—NR⁷—CH₂—CO—NR⁸—, —CO—O—, —CH₂—CH₂—, —CH═CH—, —CH₂—NR— or a bond; Q is —R⁹V, or (II) (wherein R⁹ is —CH₂—; —CH₂—CH₂—; or (III) R⁹ and R⁸, together with the nitrogen atom to which R⁸ is attached, form a piperidine or pyrrolidine ring which is substitued by V; V is —CO—NH—SO₂-Ph, SO₂—NH—CO-Ph, —CH₂OH, or a group of the formula —R¹⁰U, (wherein U is —COOH, tetrazolyl, —CONHOH— or —SO₃H; and R¹⁰ is a bond; C₁ to C₆ hydrocarbylene, optionally substituted by hydroxy, amino or acetamido; —O—(C₁ to C₃ alkylene)-; —SO₂NR¹¹—CHR¹²—; —CO—NR¹¹—CHR¹²—, R¹¹ and R¹² being independently selected from H and methyl; or —NH—(CO), —CH₂—, c being 0 or 1); T is C₁ to C₆ hydrocarbyl, —NR⁶R⁷ (wherein R⁶ and R⁷ are as defined above), —OMe, —OH, —CH₂OH, halogen or trihalomethyl; m is 1 or 2; p is from 0 to 3; and q is from 0 to 2, with the proviso that q is 1 or 2 when Z is a bond).

Claims

1. A pharmaceutical composition comprising a proton pump inhibitor and a compound of the formula (I)

2. A composition according to claim 1 wherein in formula (I) Q is

3. A composition according to claim 1 wherein in formula (I) Q is

4. A composition according to any preceding claim wherein in formula (I) X and Y are independently ═

N—

, ═

CH—

, —

NH—

, —

NOH—

or —

NMe-.

5. A composition according to claim 4 wherein in formula (I) X is —

NH— and

Y is ═

CH—

, or Y is

—

NH— and

X is —

CH—

.

6. A composition according to claim 4 wherein in formula (I) X is —

NH—

or —

NOH— and

Y is ═

N—

or wherein X is ═

N— and

Y is —

NH—

or —

NOH—

.

7. A composition according to any preceding claim wherein in formula (I) R¹ is C₁ to C₁₂ hydrocarbyl, wherein one C atom may optionally be replaced by N or O and up to three H atoms may optionally be replaced by F, Cl or Br.

8. A composition according to any preceding claim wherein in formula (I) R¹ is C₃ to C₁₂ alicyclic;

phenyl (optionally substituted with OMe, NMe₂, CF₃, Me, F, Cl, Br or I);

or C₁ to C₈ alkyl.

9. A composition according to any preceding claim wherein in formula (I) Z is —

CO—

NH—

.

10. A composition according to any preceding claim wherein in formula (I) p is 0 or 1, and q is 0.

11. A compsition according to any preceding claim wherein in formula (I) T is C₁ to C₆ hydrocarbyl or halo.

12. A composition according to any preceding claim wherein in formula (I) V is —

CO₂H, —

CH₂CO₂H or tetrazolyl.

13. A composition according to any preceding claim wherein in formula (I) R² and R³ are H, and n is from 1 to 3.

14. A composition according to any of claims 1 to 12 wherein in formula (I) R² and R³ together form an ═

O group, and n is 1.

15. A composition according to claim 13 or claim 14 wherein in formula (I) R⁴ is C₃ to C₁₂ carbocyclic, preferably adamantyl, cycloheptyl, cyclohexyl or phenyl.

16. A composition according to claim 13 or claim 14 wherein in formula (I) R⁴ is —

NH—

R¹³ or —

OR¹³, in which R¹³ is C₃ to C₁₂ carbocyclic, preferably adamantyl, cycloheptyl, cyclohexyl or phenyl.

17. A composition according to claim 1 wherein in formula (I) R⁵ is selected from H, Me, Et, Pr and Bn;

Z is —

(NR⁷)_a—

C—

(NR⁸)_b—

, —

CO—

NH—

CH₂—

CO—

NH—

or a bond;

Q is

18. A composition according to claim 1 wherein in formula (I) R⁵ is selected from H, Me, Et, Pr and Bn;

Z is —

(NR⁷)_a—

CO(NR⁸)_b—

, Q is —

CH₂)_rCOOH, wherein r is from 1 to 3; and

T is C₁ to C₆ hydrocarbyl, —

NR⁶R⁷, —

OMe, —

OH, —

CH₂OH or halogen.

19. A composition according to claim 1 wherein in formula (I) R⁵ is selected from H, Me, Et, Pr and Bn;

-Z-Q is

20. A composition comprising a proton pump inhibitor and a compound which is degraded in vivo to yield a compound of formula (I) according to any preceding claim.

21. A composition according to any preceding claim wherein the proton pump inhibitor is selected from (RS)-rabeprazole, (RS)-omeprazole, lansoprazole, pantoprazole, (R)-omeprazole, (S)-omeprazole, perprazole, (R)-rabeprazole, (S)-rabeprazole, or the alkaline salts thereof.

22. A composition according to any preceding claim wherein the proton pump inhibitor and the compound of formula (I) are each in an amount producing a therapeutically beneficial effect in patients suffering from gastrointestinal disorders.

23. A composition according to claim 22 wherein said therapeutically beneficial effect is a synergistic effect on the reduction of acid secretion in patients suffering from gastrointestinal disorders, or the prevention of gastrointestinal disorders in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other active ingredients.

24. A composition according to any preceding claim wherein the amount of each of the active ingredients is equal to or less than that which is approved or indicated in monotherapy with said active ingredient.

25. A composition according to any preceding claim for use in medicine.

26. A composition according to any preceding claim for use in treating gastrointestinal disorders.

28. Use of a composition according to any one of claims 1 to 26 or a product according to claim 27 for the preparation of a medicament for the treatment of gastrointestinal disorders.

34. Use of a composition according to any one of claims 1 to 26 or a product according to claim 27 in the treatment of gastrointestinal disorders.

35. A method of making a pharmaceutical composition according to any one of claims 1 to 26, comprising mixing a compound of formula (I) and a proton pump inhibitor with a pharmaceutically acceptable diluent or carrier.

27. 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.

29. 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.

30. 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.

31. 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.

32. Use according to claim 31 wherein the adverse effect is hyperplasia.

33. 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.