Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-20
2004-03-16
Rotman, Alan L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S297000, C540S470000, C540S553000, C540S575000, C544S298000, C546S102000, C546S103000, C546S104000
Reexamination Certificate
active
06706722
ABSTRACT:
BACKGROUND
The invention relates to novel heteroaryl compounds, methods for their preparation, and to a therapeutic process for their use as medicaments, particularly for treating tumors.
DESCRIPTION OF THE INVENTION
According to one aspect of the invention, novel acridine derivatives are provided of the formula (1)
wherein
R, R
1
, R
2
, R
3
are attached to any of the acridine carbon atoms C
1-9
and are the same or different and independently of one another are hydrogen, hydroxyl, a straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, straight-chain or branched C
1-8
alkylcarbonyl, suitably acetyl, straight-chain or branched C
1-8
alkoxy, halogen, aryl-C
1-8
alkoxy, suitably benzyloxy or phenylethyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, C
1-8
alkoxycarbonylamino, C
1-6
alkoxycarbonylamino-C
1-8
alkyl, cyano, straight-chain or branched cyano-C
1-6
alkyl, carboxyl, C
1-8
alkoxycarbonyl, C
1-4
alkyl which is substituted by one or more fluorine atoms, suitably the trifluoromethyl group, carboxy-C
1-8
alkyl or C
1-8
alkoxycarbonyl-C
1-6
alkyl, C
1-6
alkenyl, suitably allyl, C
2-6
alkynyl, suitably ethynyl or propargyl, straight-chain or branched cyano-C
1-6
alkyl, suitably cyanomethyl, aryl, where the aryl radical is unsubstituted or mono- or polysubstituted by identical or different substituents from the group of halogen, straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, carboxyl, straight-chain or branched C
1-8
alkoxycarbonyl, suitably tert-butoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, cyano, straight-chain or branched cyano-C
1-6
alkyl,
Z is oxygen or sulfur, where the radical
substituted on the acridine heterocycle is attached to a C atom C
1-9
of the acridine ring skeleton;
P, Q independently of one another represent oxygen or in each case two hydrogen atoms (i.e. —CH
2
);
X is nitrogen or C—R
5
, where R
5
is hydrogen or C
1-6
alkyl;
n,m independently of one another denotes a cardinal number between 0 and 3, with the proviso that when n=0, X is a CR
5
R
6
group where R
5
and R
6
independently of one another represent hydrogen or C
1-6
alkyl and that the nitrogen atom adjacent to the C═Z group is substituted by a hydrogen atom or a C
1-6
alkyl group;
R
4
is a straight-chain or branched C
1-20
alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, —C═NH (NH
2
), C
1-6
alkoxycarbonylamino, C
1-6
alkoxy, amino, mono-C
1-4
alkylamino or di-C
1-4
alkylamino; carboxy, C
1-4
alkoxycarbonyl; a C
6-14
aryl radical, C
6-14
aryl-C
1-4
alkyl radical or a C
2-10
heteroaryl or C
2-10
heteroaryl-C
1-4
alkyl radical which contains one or more heteroatoms that are N, O or S, where the C
1-4
alkyl radical can be unsubstituted or mono- or polysubstituted with the same or different substituents from the group of C
1-6
alkyl, halogen or oxo (═O), and where the C
6-14
aryl or C
2-10
heteroaryl radical is unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, halogen, cyano, C
1-6
alkoxycarbonylamino, C
1-6
alkoxy, carboxyl, C
1-8
alkoxycarbonyl, straight-chain or branched C
1-6
alkyl which is substituted by one or more fluorine atoms, suitably trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, where adjacent oxygen atoms can also be linked by C
1-2
alkylene groups, suitably by a methylene group, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, aryl, which for its part can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, carboxyl, straight-chain or branched C
1-8
alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, cyano, straight-chain or branched cyano-C
1-6
alkyl;
and their structural isomers and stereoisomers, particularly tautomers, diastereomers and enantiomers, and their pharmaceutically acceptable salts, particularly acid addition salts.
Thus, for example, the compounds of the formula (1) of the present invention which have one or more centers of chirality and which are present as racemates and can be separated by methods known per se into their optical isomers, i.e. enantiomers or diastereomers. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent removal of the radical.
Furthermore, the acridine derivatives of the formula (1) of the present invention can be converted into their salts with inorganic or organic acids, especially for pharmaceutical use, into their pharmaceutically acceptable salts. Acids which are suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, malonic acid, embonic acid, trifluoroacetic acid maleic acid, methonesulfuric acid, or sulfo acetic acid.
Moreover, the compounds of the formula (1) of the invention if desired can be converted if they contain a sufficiently acidic group, such as a carboxyl group, into their salts with inorganic or organic bases, especially for pharmaceutical use, into their pharmaceutically acceptable salts. Bases which are suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
According to a further embodiment, acridine derivatives of the formula (1) are provided in which R, R
1
, R
2
, R
3
, X, Z, P, Q, n and m have the meanings given above and R
4
is phenyl which is unsubstituted or substituted by one or up to five the same or different C
1-6
alkoxy groups, in which adjacent oxygen atoms can also be linked by C
1-2
alkylene groups.
According to a further embodiment, acridine derivatives of the formula (1) are provided in which R, R
1
, R
2
, R
3
, X, Z, P, Q, n and m have the meanings given above and R
4
is 3,5-dimethoxyphenyl.
According to a further embodiment, acridine derivatives of the formula (1) are provided in which R
4
has the meanings given above, R, R
1
, R
2
, R
3
each are a hydrogen atom, Z is an oxygen atom, and X is a nitrogen atom, P and Q each are two hydrogen atoms (i.e. —CH2—), m is zero and n is the integer 2.
According to a further embodiment, acridine derivatives of the formula (1) are provided in which R, R
1
, R
2
and R
3
each are a hydrogen atom, Z is an oxygen atom, and X is a nitrogen atom, P and Q each are two hydrogen atoms (i.e. —CH2—), m is zero, n is 2, and R
4
is a 3,5-dimethoxyphenyl radical.
According to a yet further feature of the present invention, a process is provided for preparing acridine derivatives of formula (1) by reacting an acridine carboxylic acid of the formula (2) in which R, R1, R2, R3 have the meanings given above, Z is an oxygen or sulfur atom, and Y is a leaving group such as halogen, hydroxyl, C
1-6
alkoxy, suitably methoxy or ethoxy, —O-tosyl, —O-mesyl or imidazolyl,
with an amine of the formula (3) in which R4, P, Q, X, m and n are as defined above, in the optional presence of diluents and auxiliaries, to form the desired acridine derivatives.
Synthesis Route
The compounds of the formula 1 can be obtained according to reaction scheme 1:
The starting materials of formulae (2) and (3) are either commercially available or can be pre
Aue Beate
Baasner Silke
Bacher Gerhard
Beckers Thomas
Emig Peter
Goodwin & Procter LLP
Rotman Alan L.
Truong Tamthom
Zentaris AG
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