Piperizine-4-phenyl derivatives as inhibitors of the interaction between mdm2 and p 53 Number:6,770,627 from the United States Patent and Trademark Office (PTO) owispatent A compound of formula (1), wherein: R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl, C.sub.1-4 alkoxycarbonyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R7 is either a group or formula (2) or formula (3); and wherein L.sub.1, L.sub.2, L.sub.3, L.sub.4, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, A.sub.1, n, p, q, r and s are as defined herein. The compounds of formula (1) inhibit the interactions between MDM2 and p53 and may be useful in the treatment of cancers.<H interaction, derivatives, Piperizine, 4, ph, 6770627.html, Patent, pto, 6770627

Title: Piperizine-4-phenyl derivatives as inhibitors of the interaction between mdm2 and p 53

Abstract: A compound of formula (1), wherein: R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl, C.sub.1-4 alkoxycarbonyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R7 is either a group or formula (2) or formula (3); and wherein L.sub.1, L.sub.2, L.sub.3, L.sub.4, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, A.sub.1, n, p, q, r and s are as defined herein. The compounds of formula (1) inhibit the interactions between MDM2 and p53 and may be useful in the treatment of cancers.

Patent Number: 6,770,627 Issued on 08/03/2004 to Luke, et al.

Inventors: Luke; Richard Wa (Macclesfield, GB), Jewsbury; Philip J. (Macclesfield, GB), Cotton; Ronald (Macclesfield, GB)
Assignee: AstraZeneca AB (Sodertalje, SE)

Appl. No.: 09/786,702

Filed: March 7, 2001

PCT Filed: September 07, 1999

PCT No.: PCT/GB99/02957

PCT Pub. No.: WO00/15657

PCT Pub. Date: March 23, 2000

Foreign Application Priority Data


Sep 12, 1998 [GB]			9819860

Current U.S. Class: 514/18 ; 514/19; 514/252.13; 514/254.09; 514/255.01; 530/331; 544/359; 544/373; 544/386; 544/391

Current International Class: C07D 209/20 (20060101); C07D 295/185 (20060101); C07D 405/00 (20060101); C07D 401/12 (20060101); C07D 295/00 (20060101); C07D 401/00 (20060101); C07D 405/12 (20060101); C07D 209/00 (20060101); C07D 409/00 (20060101); C07K 5/09 (20060101); C07D 409/12 (20060101); C07D 417/12 (20060101); C07D 417/00 (20060101); C07K 5/00 (20060101)

Field of Search: 514/18,19,252.13,254.09,255.01 530/331 544/359,373,386,391

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Foreign Patent Documents


423858	Jun., 1994	DE
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WO 98/01467	Jan., 1998	WO
WO 98/25617	Jun., 1998	WO

Other References

Chemical Abstracts, vol. 116, No.13, Mar. 1992 Columbus, Ohio, US; abstract No. 128656Z, Furuta Takuya et al.: "Preparation of Indole Derivatives as Vasopressin Antagonists" p. 863; col. 1; XP002125251 abstract. .
Chemical Abstracts 13th Collective Index; Chemical Substances (Azau . . . -Benzamide, Tetrae . . . ), vol. 116-125, 1992-1996, p. 1647 XP002125250 Columbus, Ohio, US, col. 2, line 60-line 64 & JP 03 127732 A (Otsuka Pharmaceutical) May 30, 1991. .
Barakat, K.J. et al. Synthesis and Biological Activities of Pheayl Piperazinc-Based Peptidormimetic Growth Hormone Secretagogues. Bioorg. Med. Chem. Lett. 8, 1431-1436 (1998). .
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Primary Examiner: Russel; Jeffrey E.
Attorney, Agent or Firm: Ropes & Gray LLP

Parent Case Text

This application is the national phase of international application PCT/GB99/02957 filed Sep. 7, 1999 which designated the U.S.

Claims

What is claimed is:

1. A compound of formula (1): ##STR21##

wherein: L.sub.1 is hydrogen or methyl; R.sub.1 and R.sub.2 and R.sub.3 are each independently hydrogen, halo, nitro, cyano, carbamoyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl or C.sub.l-4 alkoxycarbonyl; R.sub.4 is indole, N-(C.sub.1-4 alkyl) indole, C.sub.5-7 carbocyclic ring or aryl, any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R.sub.7 is either a group of formula (2) or of formula (3): ##STR22##

wherein: L.sub.2, L.sub.3 and L.sub.4 are each independently hydrogen or methyl; R.sub.8 is amino, guanadino or, imidazolo, any of which can be mono or di-N-substituted with C.sub.1-4 alkyl; A.sub.1 is oxygen or a direct bond; R.sub.9 is a C.sub.5-8 membered mono-carbocyclic ring, a C.sub.6-10 membered bi-carbocyclic ring, C.sub.8-12 membered tri-carbocyclic ring, C.sub.5-7 alkyl or aryl, any of which can be optionally mono, bi or tri substituted by C.sub.1-4 alkyl; R.sub.10 is C.sub.1-6 alkyl or a C.sub.3-8 mono-carbocyclic ring; R.sub.11 is hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.12 is hydrogen or methyl or ethyl or R.sub.12 together with L.sub.2 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; R.sub.13 is hydrogen or methyl or ethyl or R.sub.13 together with L.sub.4 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; n is 0, 1 or 2; p is 0, 1 or 2; q is an integer from 1 to 6; r is 0, 1 or 2; s is 0, 1 or 2; provided that when R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl or NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl then R.sub.5 is other than R.sub.6 CH.sub.2 --; and when R.sub.1 to R.sub.3 are each hydrogen, L.sub.1 is hydrogen, n is 1, R.sub.4 is phenyl, R.sub.5 is R.sub.6 C(O)--, then R.sub.6 cannot be 2-methyl-4-amino-butyl, and excluding (S)-4-chloro-N-[1-(1H-indol-3-ylmethyl)-2-oxo-2-(4-phenyl-1-piperazinyl)et hyl]-N-methyl-benzamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

2. A compound according to claim 1 wherein R.sub.5 is hydrogen.

3. A compound according to claim 2 wherein R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; n is 1; R.sub.4 is indole, N-(C.sub.1-4 alkyl)indole, cyclohexyl or phenyl any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy, L.sub.1 is hydrogen and R.sub.5 is hydrogen.

4. A compound according to claim 1 wherein R.sub.5 is R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, wherein the aryl, heteroaryl or heterocyclyl rings can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from nitro, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy.

5. A compound according to claim 4 wherein R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; n is 1; L.sub.1 is hydrogen; and R.sub.6 is aryl or heteroaryl wherein the aryl or heteroaryl can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from nitro, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy.

6. A compound according to claim 1 wherein R.sub.6 is R.sub.7.

7. A compound according to claim 6 wherein R.sub.7 is of Formula (2).

8. A compound according to claim 7 wherein R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; n is 1; L.sub.1 is hydrogen; L.sub.2 is hydrogen or methyl; q is an integer between 2 and 4; R.sub.8 is amino; s is 1 and L.sub.3 is hydrogen or methyl.

9. A compound according to claim 6 wherein R.sub.7 is of Formula (3).

10. A compound according to claim 9 wherein R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; n is 1; s is 1 and L.sub.1 is hydrogen.

11. A compound selected from the following: 4,5-dimethoxy-2-nitrobenzoyl-Phe(4-Cl)-piperazine-4-nitrophenyl; 4,5-dimethoxy-2-nitrobenzoyl-NMe-Trp-piperazine-4-nitrophenyl; 4,5-dimethoxy-2-nitrobenzoyl-(D)(N.sup.in -Me)Trp-piperazine-4-nitrophenyl; Z-(D)(NMe)Dab-(NMe)(D)Phe-(D)Trp-piperazine-4-nitrophenyl; Z-NMe(D)Lys-NMe(D)Phe-(D)Phe(4-Cl)-piperazine-4-nitrophenyl; cyclohexyl-CO-(D)Lys-(D)NMe-Phe-Cha-piperazine-4-nitrophenyl; cyclohexyl-(D)Lys-(D)(NMe)Phe-(D)Phe(4-Cl)-piperazine-4-nitrophenyl; cyclohexyl-CH.sub.2 -(D,L)NMe-Phe{CH.sub.2 NH}(D)Trp-piperazine-4-nitrophenyl; and cyclohexyl-(D)Lys-(D)(NMe)Phe-(D)hPhe-piperazine-4-nitrophenyl;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

12. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.

13. A method of treating cancer, comprising administering to a warm-blooded animal an effective amount of a compound of formula (4): ##STR23##

wherein: L.sub.1 is hydrogen or methyl; R.sub.1 and R.sub.2 and R.sub.3 are each independently hydrogen, halo, nitro, cyano, carbamoyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl or C.sub.1-4 alkoxycarbonyl; R.sub.4 is indole, N-(C.sub.1-4 alkyl) indole, C.sub.5-7 carbocyclic ring or aryl, any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R.sub.7 is either a group of formula (5) or of formula (6): ##STR24##

wherein: L.sub.2, L.sub.3 and L.sub.4 are each independently hydrogen or methyl; R.sub.8 is amino, guanadino or imidazolo, any of which can be mono or di-N-substituted with C.sub.1-4 alkyl; A.sub.1 is oxygen or a direct bond; R.sub.9 is a C.sub.5-8 membered mono-carbocyclic ring, a C.sub.6-10 membered bi-carbocyclic ring, C.sub.8-12 membered tri-carbocyclic ring, C.sub.5-7 alkyl or aryl, any of which can be optionally mono, bi or tri substituted by C.sub.1-4 alkyl; R.sub.10 is C.sub.1-6 alkyl or a C.sub.3-8 mono-carbocyclic ring; R.sub.11 is hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.12 is hydrogen or methyl or ethyl or R.sub.12 together with L.sub.2 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; R.sub.13 is hydrogen or methyl or ethyl or R.sub.13 together with L.sub.4 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; n is 0, 1 or 2; p is 0, 1 or 2; q is an integer from 1 to 6, r is 0, 1 or 2; s is 0, 1 or 2; provided that when R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl or NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl then R.sub.5 is other than R.sub.6 CH.sub.2 ; or a pharmaceutically acceptable salt, prodrug or solvate thereof.

14. A compound of formula (1a): ##STR25##

wherein: L.sub.1 is hydrogen or methyl; R.sub.1 and R.sub.2 and R.sub.3 are each independently hydrogen, halo, nitro, cyano, carbamoyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl or C.sub.1-4 alkoxycarbonyl; R.sub.4 is indole, N-(C.sub.1-4 alkyl) indole, C.sub.5-7 carbocyclic ring or aryl, any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (C.sub.1-4 alkyl)sulfanyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R.sub.7 is either a group of formula (2) or of formula (3): ##STR26##

wherein: L.sub.2, L.sub.3 and L.sub.4 are each independently hydrogen or methyl; R.sub.8 is amino, guanadino or imidazolo, any of which can be mono or di-N-substituted with C.sub.1-4 alkyl; A.sub.1 is oxygen or a direct bond; R.sub.9 is a C.sub.5-8 membered mono-carbocyclic ring, a C.sub.6-10 membered bi-carbocyclic ring, C.sub.8-12 membered tri-carbocyclic ring, C.sub.5-7 alkyl or aryl, any of which can be optionally mono, bi or tri substituted by C.sub.1-4 alkyl; R.sub.10 is C.sub.1-6 alkyl or a C.sub.3-8 mono-carbocyclic ring; R.sub.11 is hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.12 is hydrogen or methyl or ethyl or R.sub.12 together with L.sub.2 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; R.sub.13 is hydrogen or methyl or ethyl or R.sub.13 together with L.sub.4 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; n is 0, 1 or 2; p is 0, 1 or 2; q is an integer from 1 to 6; r is 0, 1 or 2; s is 0, 1 or 2; provided that when R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl or NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl then R.sub.5 is other than R.sub.6 CH.sub.2 --; and when R.sub.1 to R.sub.3 are each hydrogen, L.sub.1 is hydrogen, n is 1, R.sub.4 is phenyl, R.sub.5 is R.sub.6 C(O)--, then R.sub.6 cannot be 2-methyl-4-amino-butyl,

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

15. A pharmaceutical composition comprising a compound of claim 1, or a compound of claim 14, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

Description

This invention relates to compounds which inhibit the interaction between MDM2 and the tumour suppressor protein, p53. This invention also relates to processes for the manufacture of MDM2/p53 interaction inhibitors and pharmaceutically acceptable salts, prodrugs or solvates thereof, to novel pharmaceutical compositions containing them and to the use of the compounds as probes of MDM2 and p53 function.

p53 is a transcription factor which plays a pivotal role in the regulation of the balance between cell proliferation and cell growth arrest/apoptosis. Under normal conditions the half life of p53 is very short and consequently the level of p53 in cells is low. However, in response to cellular DNA damage or cellular stress, levels of p53 increase. This increase in p53 levels leads to the activation of the transcription of a number of genes which induces the cell to either growth arrest or to undergo the processes of apoptosis. Thus the function of p53 is to prevent the proliferation of transformed cells and thus protect the organism from the development of cancer (for a review see Levine 1997, Cell 88, 323-331).

MDM2 is a key negative regulator of p53 function, which binds to the amino terminal transactivation domain of p53. MDM2 both inhibits the ability of p53 to activate transcription and targets p53 for proteolytic degradation, thus maintaining the low levels of p53 under normal conditions. MDM2 may also have separate functions in addition to inhibition of p53. For example, MDM2 also binds another tumour suppressor protein, the retinoblastoma gene product, and inhibits its ability to activate transcription. For reviews of MDM2 function see: Piette et al (1997) Oncogene 15, 1001-1010; Lane and Hall (1997) TIBS 22, 372-374; Lozano and de Oca Luna (1998) Biochim Biophys Acta 1377, M55-M59.

MDM2 is a cellular proto-oncogene. Overexpression of MDM2 has been observed in a range of cancers see Momand and Zambetti (1997) J. Cell. Biochem 64, 343-352. The mechanism by which MDM2 amplification promotes tumourigenesis is at least in part related to its interaction with p53. In cells over-expressing MDM2 the protective function of p53 is blocked and thus cells are unable to respond to DNA damage or cellular stress by increasing p53 levels, leading to cell growth arrest and/or apoptosis. Thus after DNA damage and/or cellular stress cells over-expressing MDM2 are free to continue to proliferate and assume a tumourigenic phenotype. Under these conditions disruption of the interaction of p53 and MDM2 would release the p53 and thus allow the normal signals of growth arrest and/or apoptosis to function. Thus disruption of the interaction of MDM2 and p53 offers an approach for therapeutic intervention in cancer.

A few patent applications have been published which describe peptide inhibitors of the interaction of p53 and MDM2, see: International Patent Application, WO9602642, University of Dundee; International Patent Application WO 9801467, Novartis & Cancer Research Campaign Technology Ltd.; and International Patent Application WO 9709343.

We have discovered a novel class of small molecule compounds which inhibit the interaction of MDM2 and p53. These compounds are useful as probes of MDM2 and p53 function and may be useful as agents for the treatment of cancer.

According to the invention there is provided a compound of formula (1): ##STR1##

wherein: L.sub.1 is hydrogen or methyl; R.sub.1 and R.sub.2 and R.sub.3 are each independently hydrogen, halo, nitro, cyano, carbamoyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl or C.sub.1-4 alkoxycarbonyl; R.sub.4 is indole, N-(C.sub.1-4 alkyl) indole, C.sub.5-7 carbocyclic ring or aryl, any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.5 is hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--; R.sub.6 is aryl, heteroaryl, heterocyclyl, aminoC.sub.3-6 alkyl, N(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7 ; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl, C.sub.1-4 alkoxycarbonyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl, N-(C.sub.1-4 alkyl)amino or NN-(diC.sub.1-4 alkyl)amino; wherein R.sub.7 is either a group of formula (2) of formula (3): ##STR2##

wherein: L.sub.2, L.sub.3 and L.sub.4 are each independently hydrogen or methyl; R.sub.8 is amino, guanadino, imidazolo, any of which can be mono or di-N-substituted with C.sub.1-4 alkyl; A.sub.1 is oxygen or a direct bond; R.sub.9 is a C.sub.5-8 membered mono-carbocyclic ring, a C.sub.6-10 membered bi-carbocyclic ring, C.sub.8-12 membered tri-carbocyclic ring, C.sub.5-7 alkyl or aryl, any of which can be optionally mono, bi or tri substituted by C.sub.1-4 alkyl, R.sub.10 is C.sub.1-6 alkyl or a C.sub.3-8 mono-carbocyclic ring; R.sub.11 is hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sub.12 is hydrogen or methyl or ethyl or R.sub.12 together with L.sub.2 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; R.sub.13 is hydrogen or methyl ethyl or R.sub.13 together with L.sub.4 forms a C.sub.5-7 nitrogen-containing heterocyclic ring; n is 0, 1 or 2; p is 0, 1 or 2; q is an integer from 1 to 6 r is 0, 1 or 2; s is 0, 1 or 2; provided that when R.sub.6 is aryl, heteroaryl, heterocyclyl aminoC.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl or NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl then R.sub.6 is other than R.sub.6 CH.sub.2 --; and when R.sub.1 is hydrogen, R.sub.2 is hydrogen, R.sub.3 is hydrogen, L.sub.1 is hydrogen, n is 1, R.sub.4 is phenyl, R.sub.5 is R.sub.6 C(O)--, then R.sub.6 cannot be 2-methyl-4-amino-butyl,

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms.

The term "aryl" refers to phenyl or naphthyl.

The term "heteroaryl" refers to a 5-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur. Examples of 5- or 6-membered heteroaryl ring systems include imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, furan, pyrazole, 1,2,3-thiadiazole and thiophene. A 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, 4-oxo-4H-1-benzopyran and naphthyridine.

The term "heterocyclyl" refers to a 5-10 membered non-aromatic mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur. Examples of `heterocyclyl` include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl

The term "carbocyclic ring" refers to a totally saturated or partially saturated mono, bi or tri cyclic carbon ring. Examples of carbocyclic rings are cyclopentyl, cyclohexyl, cyclopentyl, bicyclo-octane or adamantyl.

The term "halo" refers to fluorine, chlorine, bromine or iodine.

The term carbamoyl refers to --C(O)NH.sub.2.

The term "warm-blooded animal" includes human.

Examples of C.sub.1-4 alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert-butyl; examples of C.sub.1-4 alkoxy include methoxy, ethoxy and propoxy; examples of C.sub.1-4 alkanoyl include formyl, acetyl and propionyl; examples of C.sub.1-4 alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of di-(C.sub.1-4 alkyl)amino include di-methylamino, di-ethylamino and N-ethyl-N-methylamino; examples of N-(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl include N-methyl-aminomethyl and N-ethyl-aminoethyl, and examples of NN-di(C.sub.1-4 alkyl)aminoC.sub.1-4 alkyl include: NN-dimethyl-aminomethyl and N-methyl-N-ethyl aminomethyl.

Examples of suitable values for R.sub.1, R.sub.2 or R.sub.3 include hydrogen, halo, nitro, carbamoyl, N-(C.sub.1-4 alkyl)carbamoyl, NN-(diC.sub.1-4 alkyl)carbamoyl or C.sub.1-4 alkoxycarbonyl. Preferably hydrogen, halo, nitro, carbamoyl, N-ethylcarbamoyl, NN-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methoxycarbonyl or ethoxycarbonyl. More preferably hydrogen, halo or nitro. More preferably hydrogen, chloro or nitro. Most preferably either R.sub.1 is halo, preferably chloro, R.sub.2 is halo, preferably chloro and R.sub.3 is hydrogen or R.sub.1 is hydrogen, R.sub.2 is nitro and R.sub.3 is hydrogen.

Examples of suitable values for R.sub.4 include indole, N-(C.sub.1-4 alkyl) indole, C.sub.5-7 carbocyclic ring or aryl, either of which can be optionally substituted by halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy. Preferably R.sub.4 is indole, N-methylindole, cyclopentyl, cyclohexyl, phenyl or naphthyl, optionally substituted as defined above. More preferably R.sub.4 is indole, N-methylindole, cyclohexyl, or phenyl, optionally substituted as defined above. More preferably R.sub.4 is indole, N-methylindole, or phenyl, optionally substituted as defined above. More preferably R.sub.4 is phenyl, optionally substituted as defined above. Most preferable R.sub.4 is phenyl substituted with halo, preferably chloro.

Examples of suitable values for R.sub.5 include hydrogen, C.sub.1-4 alkyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--. Preferably R.sub.5 is hydrogen, methyl, R.sub.6 CH.sub.2 -- or R.sub.6 C(O)--. Most preferably R.sub.5 is R.sub.6 C(O)--.

Examples of suitable values for R.sub.6 include aryl, heteroaryl, heterocyclyl, amino-C.sub.3-6 alkyl, N-(C.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, NN-(diC.sub.1-4 alkyl)aminoC.sub.3-6 alkyl, or R.sub.7. Preferably R.sub.6 is aryl, heteroaryl, heterocyclyl, (NN-dimethyl)aminopropyl or R.sub.7. More preferably R.sub.6 is aryl, heteroaryl, heterocyclyl or R.sub.7. More preferably R.sub.6 is aryl and heteroaryl. Most preferably R.sub.6 is aryl, preferably phenyl.

Examples of substituents on the aryl ring systems of R.sub.6 include nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, (C.sub.1-4 alkyl)sulfanyl. Preferably nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or methylsulfanyl. More preferably nitro or C.sub.1-4 alkoxy. Most preferably nitro or methoxy. More preferable substitution patterns on a phenyl group in R.sub.6 are 2-nitro-4,5-dimethoxy, 2-methyl-3-nitro, 2-methoxy, 2,4-dimethyl, 4,5-dimethoxy-2-nitro or 2-methylsulfanyl. Most preferred is 2-nitro-4,5-dimethoxy.

Examples of suitable values for heteroaryl rings at R.sub.6 include: furan, thiophene, pyrrole, pyrazole, isoxazole, thiazole, thiadiazole, pyridine, pyridazine, benzofuran, 4-oxo 4H-1-benzopyran. Heteroaryl ring systems with one or two heteroatoms are preferred. Heteroaryl ring systems with one heteroatom are most preferred.

Examples of suitable values for substituents on ring carbon atoms in heterocyclic rings of R.sub.6 include, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo, hydroxy, oxo or C.sub.1-4 alkylcarbonyl.

Examples of suitable values for R.sub.8 include amino, guanadino and imidazolo, any of which can be mono or di-N-substituted with C.sub.1-4 alkyl. More preferably R.sub.8 is guanadino or amino, substituted as defined above. Preferably R.sub.8 is N-(C.sub.1-4 alkyl)amino or amino. Most preferably R.sub.8 is amino.

Examples of suitable values for R.sub.9 include C.sub.5-7 alkyl, a C.sub.5-10 membered carbocyclic ring and aryl, any of which can be optionally substituted with C.sub.1-4 alkyl. Preferably R.sub.9 is 3-propylbutyl, 2,2 dimethylpropyl, a C.sub.5-10 membered carbocyclic ring, or aryl. More preferably R.sub.9 is cyclohexyl, cycloheptyl, adamantyl or aryl. Even more preferably R.sub.9 is cyclohexyl or aryl. Yet more preferably R.sub.9 is aryl. Most preferably R.sub.9 is phenyl.

Examples of suitable values for R.sub.10 include C.sub.1-4 alkyl or a C.sub.3-7 carbocyclic ring. More preferably R.sub.10 is a C.sub.3-7 carbocyclic ring or a branched C.sub.1-4 alkyl chain. Even more preferably R.sub.10 is a C.sub.3-7 carbocyclic ring. Most preferably R.sub.10 is cyclohexyl.

Examples of suitable values for R.sub.11 include hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy. More preferably R.sub.11 is hydrogen or C.sub.1-4 alkyl. Most preferably R.sub.11 is hydrogen.

Examples of suitable values for R.sub.12 are hydrogen or methyl or when R.sub.12 is --CH.sub.2 --, L.sub.2 is hydrogen and s is 1, R.sub.12 together with L.sub.2 forms a six membered nitrogen containing ring Preferably R.sub.12 and L.sub.2 are both hydrogen.

Examples of suitable values for R.sub.13 are hydrogen or methyl or when R.sub.13 is --CH.sub.2 --, L.sub.4 is hydrogen and s is 1, R.sub.13 together with L.sub.4 forms a six membered nitrogen containing ring Preferably R.sub.13 and L.sub.4 are both hydrogen.

Preferably n is 1

Preferably p is 1

Preferably q is 2-4. Most preferable q is 4.

Preferably r is 1.

Preferably s is 1.

It is to be understood that, insofar as certain of the compounds of Formula (1) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting MDM2 interactions. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against MDM2 interactions may be evaluated using the standard laboratory techniques referred to hereinafter.

When R.sub.6 is other than R.sub.7 then the following stereo-chemistry is preferred, in the group --N(L.sub.1)CH((CH.sub.2).sub.n R.sub.4)CO--, in formula (1): ##STR3##

A particular group of compounds of the invention include for example, a compound of formula (1) wherein R.sub.5 is hydrogen or C.sub.1-4 alkyl, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein either: (a) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole, N-(C.sub.1-4 alkyl)indole or cyclohexyl; R.sub.5 is hydrogen or methyl; L.sub.1 is hydrogen and n is 1 or 2; and where the optical centre represented in the Formula (X) is in the S configuration; or (b) R.sub.1 is halo; R.sub.2 is halo; R.sub.3 is hydrogen; R.sub.4 is indole, N-(C.sub.1-4 alkyl)indole or cyclohexyl; R.sub.5 is hydrogen or methyl; L.sub.1 is hydrogen and n is 1 or 2; and where the optical centre represented in the Formula (X) is in the S configuration.

A further preferred group of compounds of the invention include, for example a compound of formula (1) wherein R.sub.5 is R.sub.6 C(O)-- or R.sub.6 CH.sub.2 --, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein either: (a) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole, halo-phenyl or cyclohexyl; R.sub.5 is R.sub.6 C(O)-- or R.sub.6 CH.sub.2 --; R.sub.6 is substituted phenyl; L.sub.1 is hydrogen or methyl and n is 1 or 2; and where the optical centre represented in the Formula (X) is in the S configuration; or (b) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; halo-phenyl or cyclohexyl, R.sub.5 is R.sub.6 C(O)-- or R.sub.6 CH.sub.2 --, R.sub.6 is a substituted heterocycle; L.sub.1 is hydrogen or methyl and n is 1 or 2; and wherein the optical centre represented in the Formula (X) is in the S configuration.

A further preferred group of compounds of the invention include, for example a compound of formula (1) wherein R.sub.5 is R.sub.6 C(O)-- and R.sub.6 is R.sub.7, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein either: (a) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; cyclohexyl or halo-phenyl; R.sub.5 is R.sub.6 C(O)--; R.sub.6 is R.sub.7 ; R.sub.7 is of formula (2); R.sub.8 is amino; R.sub.9 is an optionally substituted aryl group; R.sub.11 is hydrogen; A.sub.1 is oxygen or a bond; n is 1 or 2; p is 1; q is 2-4 and L.sub.1 and L.sub.2 and L.sub.3 are independently hydrogen or methyl; or (b) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; cyclohexyl or halo-phenyl; R.sub.5 is R.sub.6 C(O)--; R.sub.6 is R.sub.7 ; R.sub.7 is of formula (2); R.sub.8 is amino; R.sub.9 is an optionally substituted heterocyclic group; R.sub.11 is hydrogen; A.sub.1 is oxygen or a bond; n is 1 or 2; p is 1; q is 2-4 and L.sub.1 and L.sub.2 and L.sub.3 are independently hydrogen or methyl.

A further preferred group of compounds of the invention include, for example a compound of formula (1) wherein R.sub.5 is R.sub.6 CH.sub.2 -- and R.sub.6 is R.sub.7, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: (a) R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; cyclohexyl or halo-phenyl; R.sub.5 is R.sub.6 CH.sub.2 --; R.sub.6 is R.sub.7 ; R.sub.7 is of formula (3); R.sub.10 is either a C.sub.3-7 carbocyclic ring or a C.sub.1-4 alkyl chain; R.sub.11 is hydrogen; L.sub.4 is hydrogen or methyl and r is 1.

A more preferred compound of the invention is a compound of formula (1) wherein R.sub.5 is R.sub.6 C(O)-- and R.sub.6 is a substituted phenyl group, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein; R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; or 4-chloro-phenyl; R.sub.5 is R.sub.6 C(O)--; R.sub.6 is 4,5-dimethoxy-2-nitrophenyl; L.sub.1 is hydrogen or methyl; n is 1 and where the optical centre represented in the Formula (X) is in the S configuration.

A further more preferred compound of the invention is a compound of formula (1) wherein R.sub.5 is R.sub.6 C(O)-- and R.sub.6 is R.sub.7 and R.sub.7 is of formula (2), or a pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein: R.sub.1 is hydrogen; R.sub.2 is nitro; R.sub.3 is hydrogen; R.sub.4 is indole; N-(C.sub.1-4 alkyl)indole; phenyl; 4-chloro-phenyl or cyclohexyl; R.sub.5 is R.sub.6 C(O)--; R.sub.6 is R.sub.7 ; R.sub.7 is of formula (2); R.sub.8 is amino; A.sub.1 is oxygen or a bond, R.sub.9 is phenyl or cyclohexyl; R.sub.11 is hydrogen; L.sub.1, L.sub.2 and L.sub.3 are independently hydrogen or methyl; n is 1; q is 2-4 and p is 0-1.

Particular compounds of the invention are; 2-methyl-3-nitrobenzoyl-Trp-piperazine-4-nitrophenyl; 2,4-dimethyl-benzoyl-Trp-piperazine-4-nitrophenyl; 5-bromo-2-furoyl-Trp-piperazine-4-nitrophenyl; 2-methoxybenzoyl-Trp-piperazine-4-nitrophenyl; dimethoxynitrobenzoyl-Trp-piperazine-4-nitrophenyl; 2-methyl-3-furoyl-Trp-piperazine-4-nitrophenyl; tiophene-3-carboxyl-Trp-piperazine-4-nitrophenyl; 2-(methylthio)-nicotinoyl-Trp-piperazine-4-nitrophenyl; 3-chlorothiphene-2-carboxyl-Trp-piperazine-4-nitrophenyl; 2,5-dimethoxybenzoyl-Trp-piperazine-4-nitrophenyl; 2-benzofuroyl-Trp-piperazine-4-nitrophenyl; N-methylpyrrole-2-carboxyl-Trp-piperazine-4-nitrophenyl; 2-bromo-5-methoxybenzoyl-Trp-piperazine-4-nitrophenyl; thiophene-2-carboxyl-Trp-piperazine-4-nitrophenyl; 5-chlorothiophene-2-carboxyl-Trp-piperazine-4-nitrophenyl; 2-methoxy-4-nitrobenzoyl-Trp-piperazine-4-nitrophenyl; 2-furylcarbonyl-Trp-piperazine-4-nitrophenyl; 6-methylpicoliny-Trp-piperazine-4-nitrophenyl; 3-methoxy-2-nitrobenzoyl-Trp-piperazine-4-nitrophenyl; Dimethoxynitrobenzoyl-(D)Trp-piperazine-4-nitrophenyl; 4-oxo-4H-1-benzopyran-2-caboxyl-Trp-piperazine-4-nitrophenyl; 5-nitro-2-furoyl-Trp-piperazine-4-nitrophenyl; 1,2,3-thiadiazole-4-carboxyl-Trp-piperazine-4-nitrophenyl; Z-Lys-(NMe)Phe-Trp-piperazine-4-nitrophenyl; cyclohexylacetyl-(D)Lys-(D)NMe-Phe-(D)Trp-piperazine-4-nitrophenyl; adamantaneacetyl-(D)Lys-(D)NMe-Phe-(D)Trp-piperazine-4-nitrophenyl; cycloheptanoyl-(D)Lys-(D)NMe-Phe-(D)Trp-piperazine-4-nitrophenyl; 2-propylpentanoyl-(D)Lys-(D)NMe-Phe(D)Trp-piperazine-4-nitrophenyl; Z-(D)NMe-Lys-(D)NMe-Phe-(D)Trp-piperazine-4-nitrophenyl; Me.sub.2 CHCH.sub.2 (D,L)NME-Phe{CH.sub.2 NH}(D)Trp-piperazine-4-nitrophenyl; Z-LYS-(NMe)Phe-(D)Trp-piperazine-4-nitrophenyl; cyclohexyl-(D)Lys-(D)(NMe)Phe-(D)Trp-piperazine-4-nitrophenyl; T-butylacetyl-(D)Lys-(D)NMePhe-(D)Trp-piperazine-4-nitrophenyl; cyclohexyl-(D)Lys-(D)NMe-Phe-(D)Phe(4-Cl)-piperazine-dichlorophenyl;and cyclohexyl-(D)Lys-(D)NMePhe-(D)Tyr(Et)-piperazine-4-nitrophenyl;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Further particular compounds of the invention are: 4,5-dimethoxy-2-nitrobenzoyl-Phe(4-Cl)-piperazine-4-nitrophenyl; 4,5-dimethoxy-2-nitrobenzoyl-NMe-Trp-piperazine-4-nitrophenyl; 4,5-dimethoxy-2-nitrobenzoyl-(D)(N.sup.in -Me)Trp-piperazine-4-nitrophenyl; Z-(D)(NMe)Dab-(NMe)(D)Phe-(D)Trp-piperazine-4-nitrophenyl; Z-NMe(D)Lys-NMe(D)Phe-(D)Phe(4-Cl)-piperazine-4-nitrophenyl; cyclohexyl-CO-(D)Lys-(D)NMe-Phe-Cha-piperazine-4-nitrophenyl; cyclohexyl-(D)Lys-(D)(NMe)Phe-(D)Phe(4-Cl)-piperazine-4-nitrophenyl; cyclohexyl-CH.sub.2 -(D,L)NMe-Phe{CH.sub.2 NH}(D)Trp-piperazine-4-nitrophenyl; and cyclohexyl-(D)Lys-(D)(NMe)Phe-(D)hPhe-piperazine-4-nitrophenyl;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

A suitable pharmaceutically-acceptable salt of a compound of the formula (1) is, for example, an acid-addition salt of a compound of the Formula (1) which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the Formula (1) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art, for example in-vivo hydrolysable esters.

In vivo hydrolysable derivatives include, in particular, pharmaceutically acceptable derivatives that may be oxidised or reduced in the human body to produce the parent compound or esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering for example, intravenously to the test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for hydroxy include acetyl and for carboxyl include, for example, alkyl esters, dialkylaminoalkoxy esters, esters of formula --C(O)--O--CH2C(O)NRa"Rb" where Ra" and Rb" are, for example, selected from hydrogen and C1-4 alkyl, and C1-6alkoxy methyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8 cycloalkoxycarbonyloxyC1-6alkyl esters for example 1-cylohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters for example 5-methyl-1,3-dioxolan-2-ylmethyl; and C1-6-alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl.

For examples of prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of inhibiting MDM2 interactions.

In another aspect the present invention provides a process for preparing a compound of the Formula (1) or a pharmaceutically acceptable salt, prodrug or ester thereof which process comprises deprotecting a compound of the Formula (7): ##STR4##

wherein n, L.sub.1 and R.sub.4 are as hereinabove defined and R.sub.1' is R.sub.1 or protected R.sub.1, R.sub.2' is R.sub.2 or protected R.sub.2, R.sub.3' is R.sub.3 or protected R.sub.3 and R.sub.5' is R.sub.5 or protected R.sub.5 ; wherein at least one protecting group is present; and thereafter if necessary: i) forming a pharmaceutically-acceptable salt, ii) forming a prodrug, and/or iii) forming a solvate.

Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.

Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chain C.sub.1-12 alkyl groups (for example isopropyl, t-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl group (for example 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); phenyl lower alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and C.sub.2-6 alkenyl groups (for example allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxy protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.

Example of hydroxy protecting groups include lower groups (for example t-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example t-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl group (for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for example trimethylsilyl, t-butyldimethylsilyl) and phenyl lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example t-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethyisilyl and t-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically.

The reader is referred to Advanced Organic Chemistry, 4.sup.th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis 2.sup.nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups.

Compounds of the formula (1) and (7) can be formed by: i) reacting a carboxylic acid of formula (8) or a reactive derivative thereof with a piperazine of formula (9) ##STR5##

wherein L.sub.1, n, R.sub.4, R.sub.1' -R.sub.3' and R.sub.5' are as hereinabove defined.

A suitable reactive derivative of an acid of the Formula III is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.

The reaction between compounds of the formulae (8) and (9) is carried out under conditions known for peptide bond formation. Typically the reaction is carried out in an organic solvent such as DMF or DMA. A small amount of THF and DMSO may be added as well. The reaction is usually carried out in the presence of an activating agent such as O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and a base, particularly an amine base, for example diisopropylethylamine. In addition 1-hydroxy-7-azabenzotriazole (HOAT) may be added as catalyst. The reaction is normally carried out in a temperature range of 0 to 80.degree. C., preferably at around ambient temperature. 2-(1H-Benzotriazol-1yl)-1,1,3,3-tetramethyluroniunhexafluorophosphate (HBTU), may be used instead of HATU in which case 1-hydroxy-benzotriazole (HOBt) is generally used as catalyst.

The compound of the formula (8) is conveniently prepared by solid phase organic synthesis on a polymer resin. The resin is preferably one that can be removed with mild acid such as chlorotritylchloride resin. For example of other suitable polystyrene resins see the Nova Biochem Combinatorial Chemistry Catalogue February 1997.

The synthesis of a compound of the formula (8) is normally started with an amino acid which has a --(CH.sub.2).sub.n R.sub.4 side chain. The amino acid functional groups not taking part in the reaction are protected by various functional groups. For example, the N-terminal and side chain amino groups may be protected by using 9-fluoroenylmethoxycarbonyl (Fmoc), t-butoxycarbonyl (Boc), biphenylisopropoxycarbonyl (Bpoc), 2-[3,5-dimethoxyphenyl]propyl-2-oxycarbonyl (Ddz), adamantyloxycarbonyl (Adoc), allyloxycarbonyl (Aloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl and various substituted benzyloxycarbonyl groups. These protected groups can be cleaved when required by the standard techniques (e.g. acid or base treatment, catalytic hydrogenolysis and Pd(0) treatment or zinc/acetic acid treatment). The choice of protecting group depends to a large extent on the type of resin used. When the resin is chlorotrityichoride the preferred amino protecting group is Fmoc.

The protected amino acid is then mixed with the resin so that its reacts with the resin through its carboxy group. When the resin is chlorotrityl resin, the reaction between amino acid and resin is conventionally carried out in an organic solvent such as DMF in the presence of a base such as DIPEA. The amino-protecting group is then removed so that the R.sup.5' can be introduced if it is other than hydrogen. The protecting group cleavage reactions can be performed at temperatures in the range of 4.degree. C. to 40.degree. C. (preferably at or about ambient temperature) and over a period of time in the range of 10 minutes to 24 hours.

The introduction of the R.sub.5' group when R.sub.5' is of the formula R.sub.6 C(O)-- is carried out using standard methods know for the formation of an amide bond, as shown for example in the presence of HBTU as described above.

When R.sub.6 is of the formula R.sub.7 the group R.sub.6 CO-- can gradually be built up with subsequent amide bond forming reactions. For example the group NH(L.sub.2)--CH(CH.sub.2 Ph)--CO-- may be introduced onto the amino acid attached to the resin by reacting a compound of the formula PN(L.sub.2)--CH(CH.sub.2 Ph)COOH (wherein P is an amino-protecting group), with the latter compound under amide bond-forming conditions. The amino-protecting group can then be removed and the resulting compound reacted with a compound of the formula PN(L.sub.3)CH((CH.sub.2).sub.n R.sub.8)COOH under similar conditions. Again the amino-protecting group can be removed and the resulting compound reacted with a compound of the formula R.sub.9 (CH.sub.2).sub.p A.sub.1 --COOH. Alternatively the group R.sub.7 COOH could be formed itself through subsequent amide-bond forming reactions and then introduced in one step onto the amino acid that is attached to the resin.

The resin is then removed, which in the case of chlorotrityl resin involves treating it with acetic acid and trifluoroethanol, to give a compound of the formula (8).

For further information on the formation of amide bonds see the procedures disclosed in "Solid Phase Peptide Synthesis: A practical approach" by Atherton and Sheppard (published by IRL press at Oxford University Press, 1989). "Solid Phase Peptide Synthesis" by Stewart and Young (published by the Pierce Chemical Company, Illinois, 1984), "Principles of Peptide Synthesis" (published by Springer-Verlag, Berlin, 1984), and a series of books "Amino Acids, Peptides and Proteins" (volumes 1-25; volume 25 published in 1994) (published by the Royal Society of Chemistry, Cambridge, UK).

Similar reaction conditions can be used to synthesise a compound of the (8) without using a resin support.

When R.sub.5' is of the formula R.sub.6 CH.sub.2 --, a compound of the formula (8) may be prepared by reacting together a compound of the formula R.sub.6 C(O)H and the appropriate amine under conditions known for the formation of a Schiff's base, followed by reduction of the Schiff's base to the methylamino group. The reaction is typically carried out in an organic solvent such as DMF or an alcohol such as methanol or ethanol. Suitable reducing agents include sodium trisacetoxyborohydride, sodium cyanoborohydride and sodium borohydride.

A compound of the formula (9) is conveniently prepared by reacting piperazine, in which one nitrogen is protected, with a group of the formula: ##STR6##

wherein L.sub.4 is a leaving group and R.sub.1' -R.sub.3' are as hereinabove defined. Preferably the leaving group is chloro. The reaction is generally carried out in an inert organic solvent such as toluene or methylformamide, in the presence of an organic base such as triethylamine or DBU, in a temperature range of 80-200.degree. C., preferably at reflux.

Optional substituents in a compound of the formula (1) or (7) or intermediates in their preparation may be converted into other optional substituents. For example an hydroxy group could be alkylated to a methoxy group.

Various substituents may be introduced into compounds of the formulae (1) or (7) and intermediates in this preparation, when appropriate, using standard methods known in the art. For example, an acyl group or alkyl group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a nitro group by nitration with concentrated nitric acid and concentrated sulphuric acid and bromination with bromine or tetra(n-butyl)ammonium tribromide.

It will be appreciated that, in certain steps in the reaction sequence to compounds of the formula (1), it will be necessary to protect certain functional groups in intermediates in order to prevent side reactions. Deprotection may be carried out at a convenient stage in the reaction sequence once protection is no longer required.,

In order to use a compound of the Formula (1), or a pharmaceutically-acceptable salt or in vivo cleavable ester thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

According to this aspect of the invention there is provided a pharmaceutical composition which comprises an amide derivative of the Formula (1), or a pharmaceutically-acceptable or in vivo cleavable ester thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by