Gastrin and cholecystokinin receptor ligands

• US 6,479,531 B1
• Filed: 08/02/2001
• Issued: 11/12/2002
• Est. Priority Date: 11/09/1998
• Status: Expired due to Fees

• Current Assignee: James Black Foundation Limited
• Original Assignee: James Black Foundation Limited
• Inventors: Vinter, Jeremy Gilbert, Watt, Gillian Fairfull, Griffin, Eric Peter, Gaffen, John David, Sykes, David Andrew, Wright, Laurence, Roberts, Sonia Patricia, Walker, Martin Keith, Hull, Robert Antony David, Lilley, Elliot James, Tozer, Matthew John, Linney, Ian Duncan, Pether, Michael John, Buck, Ildiko Maria, Harper, Elaine Anne, Low, Caroline Minli Rachel, Kalindjian, Sarkis Barret, McDonald, Iain Mair, Steel, Katherine Isobel Mary, Wright, Paul Trevor, Dunstone, David John, Shankley, Nigel Paul, Black, James Whyte
• Primary Examiner(s): Higel, Floyd D.
• Assistant Examiner(s): SAEED, KAMAL A
• Application Number:
  US09/831,385
• Time in Patent Office: 467 Days
• Field of Search: 548/326.5, 548/331.1, 548/335.1, 548/314.7, 514/397, 514/398, 514/399
• US Class Current: 514/397
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 263/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond

Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently ═N—, —N(R⁵)—═CH—, —S— or —O—. n is from 1 to 4; R¹ is H or C₁ to C₁₅ hydrocarbyl R² is selected from H, Me, Et, Pr and OH, R₃ 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 C₆ carbocylic ring, or R² and R³ on the same carbon atom together represent an ═O group; R⁴ is C₁ to C₁₅ hydrocarbyl Z is —(NR⁷)_a—CO—(NR⁸)_b— (wherein a is 0 or 1, b is 0 or 1, —CO—NR⁷—CH₂—CO—NR⁸—, —CO—O—, —CH₂—CH₂—, —CH═CH—, —CH₂—NR⁸— 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 substituted 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, —O—(C₁ to C₃ alkylene)—; —SO₂NR¹¹—CHR¹²—; —CO—NR¹¹—CHR¹²—, or —NH—(CO)_c—CH₂—, c being 0 or 1).

Claims

1. A compound of the formula (I)

wherein

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), 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 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 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 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—

NR⁸—

or a bond;

Q is —

R⁹V, or

(wherein R⁹ is —

CH₂—

;

—

CH₂—

CH₂—

;

or

 

or R⁹ and R⁸, together with the nitrogen atom to which R⁸ is attached, form a pyrrolidine ring which is substituted 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)_c—

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);

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Q is

3. A compound according to claim 2 wherein Q is

4. A compound according to claim 1 wherein R¹ is C₁ to C₁₂ independently ═

N—

, ═

CH—

, —

NH—

, —

NOH—

or —

NMe—

.

5. A compound according to claim 1 wherein X is —

NH— and

Y is ═

CH—

, or Y is —

NH— and

X is ═

CH—

.

6. A compound according to claim 1 wherein X is —

NH—

or —

NOH— and

Y is ═

N—

or wherein X is ═

N— and

Y is —

NH—

or —

NOH.

7. A compound according to claim 1 wherein 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, C1 or Br.

8. A compound according to claim 1 wherein R¹ is C₃ to C₁₂ alicyclic;

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

or C, to C₈ alkyl.

9. A compound according to claim 1 wherein Z is —

CO—

NH—

.

10. A compound according to claim 1 wherein p is 0 or 1, and q is 0.

11. A compound according to claim 1 wherein T is C₁ to C₆ hydrocarbyl or halo.

12. A compound according to claim 1 wherein V is —

CO₂H, —

CH₂CO₂H or tetrazolyl.

13. A compound according to claim 1 wherein R² and R³ are H, and n is from 1 to 3.

14. A compound according to claim 1 wherein R² and R³ together form an ═

O group, and n is 1.

15. A compound according to claim 13 wherein R⁴ is C₃ to C₁₂ carbocyclic.

16. A compound according to claim 13 wherein R⁴ is —

NH—

R¹³ or —

OR¹³, in which R¹³ is C₃ to C₁₂ carbocyclic.

17. A compound according to claim 1 wherein R⁵ is selected from H, Me, Et, Pr and Bn;

Z is —

(NR⁷)_a—

CO(NR⁸)_b—

, —

CO—

NH—

CH₂—

CO—

NH—

or a bond;

Q is

V is CO—

NH—

SO₂—

Ph, —

SO₂—

NH—

CO—

Ph, —

OCH₂COOH, tetrazolyl or CH₂)_sCOOH, wherein s is from 0 to 2; and

T is C₁ to C₆ hydrocarbyl, —

NR⁶R⁷, —

OMe, —

OH, —

CH₂OH or halogen.

18. A compound according to claim 1 wherein 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 compound according to claim 1 wherein R⁵ is selected from H, Me, Et, Pr and Bn;

—

Z—

Q is

k is 1 or 2; and

T is C₁ to C₆ hydrocarbyl, —

NR⁶R⁷, —

OMe, —

OH, —

CH₂OH or halogen.

20. A compound which is degraded in vivo to yield a compound according to claim 1.

21. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable diluent or carrier.

22. A compound according to claim 15 wherein R¹³ is adamantyl, cycloheptyl, cyclohexyl or phenyl.

23. A compound according to claim 16, wherein R¹³ is adamantyl, cycloheptyl, cyclohexyl or phenyl.