PIPERIDINE AND PIPERAZINE DERIVATIVES

• US 20100222341A1
• Filed: 09/19/2008
• Published: 09/02/2010
• Est. Priority Date: 10/05/2007
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Schiemann, Kai, Schultz, Melanie, Kober, Ingo, Blaukat, Andree
• Granted Patent: US 8,791,111 B2
• Time in Patent Office: Days
• US Class Current: 514/233.800
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 235/26 Oxygen atoms
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07D 263/58 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 in position 2
• CPC Class Codes: C07D 277/68 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 in position 2
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

Compounds of the formula (I), in which R¹, R², R³, D, G, Q and W have the meanings indicated in claim (1), can and be employed for the treatment of tumours.

Claims

1. Compounds of the formula I

in which

R¹ denotes a bicyclic unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, NR₂, (CR₂)_nCN, OR⁵ and/or ═

O (carbonyl oxygen),

D denotes C or S,

G denotes N or C,

if G=N;

R² is absent,

if G=C;

R² denotes H or Ar¹ or also, together with the C atom to which R² is bonded and with E-W, denotes a spirocyclic radical selected from the group

Q denotes unbranched or branched alkylene having 1, 2, 3 or 4 C atoms, in which 1-5H atoms may be replaced by A, (CR₂)_n[X(CR₂)_n]_p—

Y, F and/or Cl,

R³ denotes H, A, Ar, OR, SR, NR₂, Hal, NO₂, CN or (CR₂)_n[X(CR₂)_n]_p—

Y,

X denotes O, NR or CR₂,

Y denotes OR or NR₂,

R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, in which 1-7H atoms may be replaced by F and/or Cl,

E denotes COO(CR₂)_n, COO(CRR⁴), CO(CR₂)_mO, CONH(CR₂)_n, C(═

S)NH(CR₂)_n, S(O)_qNH(CR₂)_n, S(O)_q(CR₂)_n, CO(CR₂)_n, (CR₂)_n, CO(CR₂)_mO(CR₂)_n, CO(CR₂)_mNH(CR₂)_n, CO(CH₂)_nCO, COCHR⁶CHR⁷, C(═

S)O(CR₂)_n, CO(CRR⁴)(CR₂)_n, COO(CRR⁴), (CRR⁴)(CR₂)_n, S(O)_qCR═

CR, COCR═

CR, (CR₂)_mCO, CONH(CR₂)_mCRR⁴ or (CR₂)_mCONR,

R⁴ denotes COOR⁵, Ar¹, NRCOOR⁸, (CR₂)_nNR₂ or NRCOOA,

R⁶, R⁷ together denote (CH₂)_1-4,

R⁸ denotes phenyl, naphtyl or fuorenyl,

R denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms,

W denotes Ar or Het,

Ar denotes phenyl, indanyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, (CR₂)_nOR, O(CR₂)_n, Ar¹, (CR₂)_nNR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_qA, CO-Het, (CR₂)_nHet, O(CR₂)_nNR₂, O(CR₂)_nHet, NHCOOA, NHCONR₂, NHCOO(CR₂)_nNR₂, NHCOO(CR₂)_nHet, CR⁵═

CR⁵Ar¹, SO₂Het, NHCONH(CR₂)_nNR₂, NHCONH(CR₂)_nHet, OCONH(CR₂)_nNR₂, OCONH(CR₂)_nHet, CONR(CR₂)_nNR₂, CONR(CR₂)_nHet and/or COA,

Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, (CR₂)_nAr¹, O(CR₂)_nAr¹, (CR₂)_nOR, (CR₂)_nNR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_qA, CO-Het¹, (CR₂)_nHet¹, O(CR₂)_nNR₂, O(CR₂)_nHet¹, NHCOOA, NHCONR₂, NHCOO(CR₂)_nNR₂, NHCOO(CR₂)_n−

Het¹, NHCONH(CR₂)_nNR₂, NHCONH(CR₂)_nHet¹, OCONH(CR₂)_nNR₂, OCONH(CR₂)_nHet¹, CO-Het¹, CHO, COA, ═

S, ═

NH, ═

NA and/or ═

O (carbonyl oxygen),

Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which may be mono- or disubstituted by A, OA, OH, Hal and/or ═

O (carbonyl oxygen),

Ar¹ denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, A and/or (CR₂)_nOR,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by OR, CN, NR₂, F and/or Cl and/or in which one or two non-adjacent CH₂ groups may be replaced by O, NH, S, SO, SO₂ and/or by CH═

CH groups,

or

cyclic alkyl having 3-7 C atoms,

m denotes 1, 2, 3, 4, 5 or 6,

n denotes 0, 1, 2, 3, 4, 5, 6, 7 or 8,

p denotes 1, 2, 3, 4, 5 or 6,

q denotes 0, 1 or 2,

Hal denotes F, Cl, Br or I,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

2. Compounds according to claim 1 in which

R¹ denotes a bicyclic unsaturated or aromatic heterocycle selected from the group

which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, NR₂, (CR₂)_nCN, OR⁵ and/or ═ O (carbonyl oxygen),

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compounds according to claim 1 in which

R¹ denotes a bicyclic unsaturated or aromatic heterocycle selected from the group

which may additionally be mono- or disubstituted by A, Hal, NR₂, (CR₂)_nCN and/or OR⁵,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compounds according to claim 1 in which

if G=N:

R² is absent,

if G=C;

R² denotes H,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

5. Compounds according to claim 1 in which

R³ denotes H,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to claim 1 in which

Q denotes unbranched or branched methylene, ethylene, propylene or butylene,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

7. Compounds according to claim 1 in which

R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, in which 1-5H atoms may be replaced by F,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

8. Compounds according to claim 1 in which

R denotes H, methyl or ethyl,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

9. Compounds according to claim 1 in which

R denotes H,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

10. Compounds according to claim 1 in which

Ar denotes phenyl, indanyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, (CR₂)_nOR, O(CR₂)_nAr¹, (CR₂)_nNR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_qA, CO-Het, (CR₂)_nHet, O(CR₂)_nNR₂, CR⁵═

CR⁵Ar¹ and/or SO₂Het,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

11. Compounds according to claim 1 in which

Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 3 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by Hal, A, (CR₂)_nAr¹ and/or ═

O (carbonyl oxygen),

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

12. Compounds according to claim 1 in which

Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, 2,3-dihydrobenzo-1,4-dioxinyl, chromanyl, thiazolidinyl, isoindolyl, tetrahydrofuranyl, carbazolyl, benzo[b]thiophenyl or benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, (CR₂)_nAr¹ and/or ═

O (carbonyl oxygen),

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

13. Compounds according to claim 1 in which

A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

14. Compounds according to claim 1 in which

m denotes 1, 2, 3 or 4,

n denotes 0, 1, 2, 3 or 4,

p denotes 1, 2, 3 or 4,

q denotes 0, 1 or 2,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

15. Compounds according to claim 1 in which

R¹ denotes a bicyclic unsaturated or aromatic heterocycle selected from the group

which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, NR₂, (CR₂)_nCN, OR⁵ and/or ═

O (carbonyl oxygen),

D denotes C or S

G denotes N or C,

if G=N;

R² is absent,

if G=C;

R² denotes H or Ar¹ or also, together with the C atom to which R² is bonded and with E-W, denotes a spirocyclic radical selected from the group

Q denotes unbranched or branched methylene, ethylene, propylene or butylene,

R³ denotes H,

R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, in which 1-5H atoms may be replaced by F,

E denotes COO(CR₂)_n, COO(CRR⁴), CO(CR₂)_mO, CONH(CR₂)_n, S(O)_q(CR₂)_n, CO(CR₂), (CR₂)_n, CO(CR₂)_mO(CR₂)_p, CO(CR₂)_mNH(CR₂)_p, C(═

S)O(CR₂)_n, CO(CRR⁴)(CR₂)_n, COO(CRR⁴), (CRR⁴)(CR₂)_n, S(O)_qCR═

CR, COCR═

CR, (CR₂)_mCO or (CR₂)_mCONR,

R⁴ denotes COOR⁵, Ar¹, (CR₂)_nNR₂ or NRCOOA,

R denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms,

W denotes Ar or Het,

Ar denotes phenyl, indanyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, (CR₂)_nOR, O(CR₂)_nAr¹, (CR₂)_nNR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_qA, CO-Het, (CR₂)_nHet, O(CR₂)_nNR₂, CR⁵═

CR⁵Ar¹ and/or SO₂Het,

Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 3 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by Hal, A, (CR₂)_nAr¹ and/or ═

O (carbonyl oxygen),

Ar¹ denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, A and/or (CR₂)_nOR,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl,

m denotes 1, 2, 3 or 4,

n denotes 0, 1, 2, 3 or 4,

p denotes 1, 2, 3 or 4,

q denotes 0, 1 or 2,

Hal denotes F, Cl, Br or I,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

16. Compounds according to claim 1 in which

R¹ denotes a bicyclic unsaturated or aromatic heterocycle selected from the group

which may additionally be mono- or disubstituted by A, Hal, NR₂, (CR₂)_nCN and/or OR⁵,

D denotes C or S

G denotes N or C,

if G=N:

R² is absent,

if G=C;

R² denotes H or Ar¹ or also, together with the C atom to which R² is bonded and with E-W, a spirocyclic radical selected from the group

Q denotes methylene, ethylene, propylene or butylene,

R³ denotes H,

R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, in which 1-5H atoms may be replaced by F,

E denotes COO(CR₂)_n, COO(CRR⁴), CO(CR₂)_mO, CONH(CR₂)_n, S(O)_q(CR₂)_n, CO(CR₂), (CR₂)_n, CO(CR₂)_mO(CR₂)_p, CO(CR₂)_mNH(CR₂)_p, C(═

S)O(CR₂)_n, CO(CRR⁴)(CR₂)_n, COO(CRR⁴), (CRR⁴)(CR₂)_n, S(O)_qCR═

CR, COCR═

CR, (CR₂)_mCO or (CR₂)_mCONR,

R⁴ denotes COOR⁵, Ar¹, (CR₂)_nNR₂ or NRCOOA,

R denotes H, methyl or ethyl,

W denotes Ar or Het,

Ar denotes phenyl, indanyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, (CR₂)_nOR, O(CR₂)_nAr¹, (CR₂)_nNR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_qA, CO-Het, (CR₂)_nHet, O(CR₂)_nNR₂, CR⁵═

CR⁵Ar¹ and/or SO₂Het,

Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, 2,3-dihydrobenzo-1,4-dioxinyl, chromanyl, thiazolidinyl, isoindolyl, tetrahydrofuranyl, carbazolyl, benzo[b]thiophenyl or benzo-2,1,3-thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, (CR₂)_nAr¹ and/or ═

O (carbonyl oxygen),

Ar¹ denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, A and/or (CR₂)_nOR,

A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7H atoms may be replaced by F and/or Cl,

m denotes 1, 2, 3 or 4,

n denotes 0, 1, 2, 3 or 4,

P denotes 1, 2, 3 or 4,

q denotes 0, 1 or 2,

Hal denotes F, Cl, Br or I,

and pharmaceutically usable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

17. Compounds according to claim 1 selected from the group

No. Name and/or structure “

18. Compounds according to claim 1 selected from the group

Com- pound No. Name and/or structure “

19. Process for the preparation of compounds of the formula I and pharmaceutically usable salts, tautomers and stereoisomers thereof, characterised in that

a) a compound of the formula II

in which R², R³, G, E and W have the meanings indicated in claim 1,

is reacted with a compound of the formula III

in which

R¹, D and Q have the meanings indicated in claim 1, and

L denotes Cl, Br, I or a free or reactively functionally modified OH group,

or

b) a compound of the formula IV

in which

R¹, R², R³, D and Q have the meanings indicated in claim 1 and G=N

is reacted with a compound of the formula V

L-E-W 

 

V

in which

E and W have the meanings indicated in claim 1, and

L denotes Cl, Br, I or a free or reactively functionally modified OH group,

and/or a base or acid of the formula I is converted into one of its salts.

20. Medicaments comprising at least one compound of the formula I according to claim 1 and/or pharmaceutically usable, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

21. A method for the treatment of diseases in which the inhibition, regulation and/or modulation of the mitotic motor protein Eg5 plays a role, comprising administering compounds according to claim 1 and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

22. A method of claim 21 for the treatment and prophylaxis of cancer diseases.

23. A method according to claim 22, where the cancer diseases are associated with a tumour from the group of tumours of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the stomach, of the larynx and/or of the lung.

24. A method according to claim 23, where the tumour originates from the group monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma and colocarcinoma.

25. A method according to claim 24, where the disease to be treated is a tumour of the blood and immune system.

26. A method according to claim 25, where the tumour originates from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

27. A method for the treatment of tumours, comprising administering compounds of the formula I according to claim 1 and/or physiologically acceptable salts thereof where a therapeutically effective amount of a compound of the formula I is administered in combination with radiotherapy and a compound from the group 1) oestrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10) other angiogenesis inhibitors.