WO2002057223A2

WO2002057223A2 - Compounds azepane, preparation method therefor and pharmaceutical compositions containing said compounds

Info

Publication number: WO2002057223A2
Application number: PCT/FR2002/000147
Authority: WO
Inventors: Patrick Casara; Thierry Le Diguarher; Gilbert Dorey; John Hickman; Alain Pierre; Gordon Tucker; Nicolas Guilbaud; Jean-Claude Ortuno; Jean-Luc Fauchere
Original assignee: Les Laboratoires Servier
Priority date: 2001-01-18
Filing date: 2002-01-16
Publication date: 2002-07-25
Also published as: FR2819511A1; WO2002057223A3; AR034287A1; AU2002231886A1

Abstract

A compound having formula (I), wherein X denotes an alkylene group or chain, CO, S(O)n, -S(O)n-A1-, -CO-A1-, -A1-S(O)n-A'1, or A1-CO-A'1-; Y denotes a substituted or non-substituted aryl, heteroaryl, cycloalkyl or heterocyclalkyl group; W denotes a CO or CH2 group; T denotes a N(R1)- or N(R1)CO- group; V denotes a hydrogen atom or a substituted or non-substituted aryl or heteroaryl group; A2 denotes a [C(R2)(R'2)]p group; R1 and R2 are as defined in the description. Medicaments.

Claims

- 68 - CLAIMS

1. Compounds of formula (I):

in which :

W represents a group CO or CH ₂

/ X represents a group chosen from alkylene, CO, S (O) _n , _* -S (O) _n -Aι-, _* -CO-Aι-,

-Aι-S (O) _n -A'ι-, and -Aι-CO-A'ι- (in which Ai and A'i, identical or different, represent an alkylene group and n is 0, 1 or 2) , the symbol " _* " representing the point of attachment of these groups to the 7-membered ring, and in this case W represents a group CO, or X represents a bond or a group chosen from alkylene, CO, S (O) _n , _* -S (O) _n -Aι-, _* -CO-Aι, -Aι-S (O) _n -A'ι-, and -Aι-CO-A'ι (in which Ai, A'i, and " _* " are defined as above), and in this case W represents a CH ₂ group,

Y represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of these groups being unsubstituted or substituted by one or more, identical or different, groups R ₄ ,

• / T represents a group -N (Rι) - or _* -N (Rι) CO- (where Ri represents a hydrogen atom or an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, each of these groups being unsubstituted or substituted by one or more, identical or different, groups R ₃ ), the symbol " _* " representing the point of attachment of this group to the 7-membered ring, - 69 -

y V represents a hydrogen atom or an aryl or heteroaryl group, each of these groups being unsubstituted or substituted by one or more, identical or different, groups R ₃ ,

> f A ₂ represents a group [C (R ₂ ) (R ')] _P where p is 0, 1, 2, 3 or 4 when T represents a group _* -N (Rι) CO- or p is 1, 2 , 3 or 4 when T represents a group -N (Rι) -, and R ₂ and R ' ₂ , identical or different, represent a hydrogen atom or an alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl group , optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl, R ₅ or alkyl substituted by a group R ₅ (where R ₅ represents a group -ORi, -N (Rι), -S (O) _m Rι, -CON (Rι) (R'ι), -N (Rι) COR'ι, -N (Rι) SO ₂ R'ι, -SO ₂ N (Rι) (R'ι), -N (Rι) COO (R'ι), m being equal to 0, 1, or 2, and R'i can take all the values of Ri),

/ R ₃ represents a halogen atom or an alkyl, alkoxy, hydroxy, mercapto, alkylthio, cyano, amino group (optionally substituted by one or two alkyl groups), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups), carbamoyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl,

J RΔ represents a halogen atom, or an oxo, hydroxy, cyano, nitro, carboxy, alkoxycarbonyl, perhaloalkyl group, or a group UI _t o, or A ₀ -UR ₄ o (in which AQ represents an alkylene group; U represents a bond, an oxygen atom, or a group -NH-, -S (O) _m -, -NHCO-, -CONH-, -SO ₂ NH- or -

NHSO ₂ -, m being 0, 1, or 2; and R ^ represents an alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group),

on the condition of : - 70 -

When W represents a CH ₂ group and simultaneously -XY represents an arylalkyl group, then NA ₂ -T cannot represent an optionally substituted phenylcarbonylamino group,

When W represents a CO group and simultaneously -XY represents an arylalkyl group then NA ₂ -T cannot represent an arylcarbonylamino, heterocyclocarbonylamino, arylalkylamino or arylalkylcarbonylamino group,

The compounds of formula (I) cannot represent N- (1-benzyl-3-azepanyl) acetamide,

Being heard that :

the term alkyl denotes a linear or branched group, containing from 1 to 6 carbon atoms,

the term alkylene denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms, the term cycloalkyl denotes a saturated cyclic group containing from 3 to 8 carbon atoms,

the term heterocycloalkyl designates a saturated or partially unsaturated cyclic group of 5 to 7 members containing from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur, the term aryl designates a phenyl or naphthyl group,

the term heteroaryl designates a mono or bicyclic group, aromatic or containing at least one aromatic ring, of 5 to 11 links, containing from 1 to 5 heteroatoms chosen from nitrogen, oxygen and sulfur,

- the substituted term assigned to the expressions aryl, heteroaryl, arylalkyl, and heteroarylalkyl, means that the cyclic part of these groups can be substituted by one or more groups, identical or different, chosen from cyano, alkylcarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups), or halogen atoms,

- the substituted term assigned to the expressions, cycloalkyle, heterocycloalkyle cycloalkylalkyle, and heterocycloalkylalkyle means that the cyclic part of these groups can be substituted by one or more groups, identical or - 71 -

different, chosen from oxo, cyano, alkylcarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups), or halogen atoms,

their enantiomers, diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

2. Compounds of formula (I) according to claim 1 for which T represents an —NH- group, their enantiomers, diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

3. Compounds of formula (I) according to claim 1 for which A ₂ represents a group -CH ₂ - or -CH ₂ -CH ₂ -, their enantiomers, diastereoisomers as well as their addition salts with an acid or with a pharmaceutically acceptable base.

4. Compounds of formula (I) according to claim 1 for which A ₂ represents a group (4-cyanophenyl) methylene, (4-chlorophenyl) methylene, (4-cyanobenzyl) methylene or (4-chlorobenzyl) methylene.

5. Compounds of formula (I) according to claim 1 for which V represents a heteroaryl group, optionally substituted with R ₃ , their enantiomers, diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

6. Compounds of formula (I) according to claim 1 for which V represents an imidazolyl group, optionally substituted with R ₃ , their enantiomers, diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

7. Compounds of formula (I) according to any one of claims 2, 3, 5 and 6 for which NA ₂ -T represents a group [(4-cyanobenzyl) -1H-imidazol-5-yljmethylamino, their enantiomers, diastereoisomers and their addition salts with a pharmaceutically acceptable acid or base.

8. Compounds of formula (T) according to claim 1 for which W represents a - 72 -

CO and XY group represents a benzyl group unsubstituted or substituted by _t , their enantiomers, diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

9. Compounds of formula (I) according to claim 1 for which W represents a CH ₂ group and XY represents a benzyl or benzene group unsubstituted or substituted by 1 ^, their enantiomers, diastereoisomers as well as their addition salts with a acid or a pharmaceutically acceptable base.

10. Compounds of formula (I) according to claim 1 which are (S) -4 - [(5 - {[(1-benzyl-2-oxo-3-azepanyl) amino] methyl} - 1H-imidazol- 1-yl) methyl] benzonitrile, (S) -4- {[5- ({[1 - (2-methylb enzyl) -2-oxo-3 -azepanyl] amino} methyl) - 1H-imidazol- 1 - ylmethyl} benzonitrile, (S) -4- {[5- ({[1 - (3-chlorobenzyl) -2-oxo-3-azepanyl] amino} methyl) - 1H- imidazol-1-yl] methyl} benzonitrile , (S) -4 - {[5 - ({[1- (2-chlorobenzyl) -2-oxo-3-azepanyl] amino} methyl) -lH-imidazol-1-yl] methyl} benzonitrile, ( S) -4 - {[5 - ({[1- (2-chlorobenzyl) -3-azepanyl] ammo} methyl) -lH-imidazol-1-yl] methyl} benzonitrile, (S) -4 - [( 5- {[(1-phenyl-3 -azepanyl) amino] methyl} -1H-imidazol-1 -yl) methyl] benzonitrile.

11. A process for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is used as starting material:

which is cyclized in the presence of hexamethyldisilazane and trimethylsilane chloride to yield the compound of formula (III):

which is subjected, in basic medium, to the action of a compound of formula Ηal-XY in which X and Y are as defined in formula (I) and Ηal represents a halogen atom, to lead to the compound of formula (IN): - 73 -

in which X and Y are as defined above,

or which is subjected to an iodine treatment to lead to the compound of formula (V):

in which X and Y are as defined above,

> which is subjected to the action of an aromatic amine to yield the compound of formula (La), special case of the compounds of formula (I):

in which X, Y and V are as defined above,

which can be successively subjected to the action of a thionating agent such as the Lawesson reagent, to the Meerwein reagent and then to a reducing agent such as NaBH ₄ to obtain the compound of formula (I / b), special case of the compounds of formula (I):

in which X, Y and V are as defined above,

or which is subjected to the action of sodium azide, followed by a reduction in the presence of triphenylphosphine to yield the amine of formula (VI): - 74 -

in which X and Y are as defined above,

whose amino function is protected by a protective group such as tertbutoxycarbonyl to lead to the compound of formula (VII):

in which X and Y are defined as above and P represents a protective group,

[compound of formula (Vil) which can be advantageously obtained, in particular with the aim of obtaining enantiomerically pure compounds, from the compound of formula (II '):

which is cyclized in the presence of hexamethyldisilazane and trimethylsilane chloride to yield the compound of formula (III '):

which is protected by a protective group such as tertbutoxycarbonyl to yield the compound of formula (IV '): 75 -

in which P represents a protective group,

on which we condense a compound of formula Hal-X-Y as defined above to obtain the compound of formula (V):

in which P represents a protective group and X and Y are as defined above],

compound of formula (VII) which can be successively subjected to the action of a thionating agent such as the Lawesson reagent, to the Meerwein reagent then to a reducing agent such as NaBH ₄ to obtain the compound of formula (VIII):

in which P represents a protective group and X and Y are as defined above

the compounds of formulas (VII) and (VIII) forming the compound of formula (IX):

in which P represents a protective group, W is as defined in formula (I), and X and Y are as defined above, - 76 -

which we deprotect the amino function on which we then condense:

^ a compound of formula (X):

V- [C (R ₂ ) (R ' ₂ )] _p - CR " _{2 (X} ) O in which V is as defined above, R ₂ and R' ₂ are as defined in formula (I), R " ₂ represents the same groups or atoms as those defined by R ₂ or R ' ₂ , and p is equal to 1, 2, 3 or 4,

to lead, after reduction, to the compound of formula (Le), special case of the compounds of formula (I):

in which R ₂ , R ' ₂ , R " ₂ , X, Y, V, W and p are defined as above,

^ or a compound of formula (XI):

V— A ₇ - C - Z (XI) ² II ^J

O in which V and A ₂ are as defined above, and Z represents a halogen atom or a hydroxy group,

to obtain the compound of formula (Ld), special case of the compounds of formula (I):

in which X, Y, V, W and A ₂ are defined as above, - 77 -

the compounds of formula (La), (I / b), (Le) and (Ld) which can be subjected to an alkylating agent Hal-R "ι in which Hal represents a halogen atom and R" ι can take all the values of Ri with the exception of the hydrogen atom to yield the compound of formula (Le), special case of the compounds of formula (I):

in which X, Y, V, W and A ₂ are as defined above, and T 'represents a group -N ^{- or} - C— N ^- where R " _j is as defined above,

R " _j OR 'the set of compounds of formula (La) to (Le) forming the set of compounds of formula (I), - which can be, if necessary, purified according to a conventional purification technique,

- from which the isomers are separated, where appropriate, according to a conventional separation technique,

- which is converted, if desired, into their addition to a pharmaceutically acceptable acid or base.

12. Pharmaceutical compositions containing as active ingredient at least one compound according to any one of claims 1 to 10, alone or in combination with one or more excipients or inert, non-toxic, pharmaceutically acceptable vehicles.

13. Pharmaceutical compositions according to claim 12 containing at least one active principle according to any one of claims 1 to 10 useful for the manufacture of medicaments useful in the treatment of cancer diseases.

14. Pharmaceutical compositions according to claim 12 containing at least one active principle according to any one of claims 1 to 10 useful for the manufacture of medicaments useful in the treatment of restenosis after angioplasty or vascular surgery, and of neurofibromatosis type I .