CZ20012373A3 - Azepinoindole derivative, its use and pharmaceutical preparation in which the derivative is comprised - Google Patents

Abstract

The invention relates to compounds of formula (I) as well as to the tautomeric forms thereof, possible enantiomeric and diastereomeric forms and the prodrugs thereof, the production and use thereof, whereby the values have the meaning as given in the description.

Description

(57)

A compound of formula (I) wherein each symbol has a specific meaning, its diastereomeric forms and prodrugs, its preparation and its use in the treatment of neurodegenerative disorders and neuronal damage.

B (13) Type of document: A3 (51) Int. Cl. ⁷ ;

C07D 487/06

A61K 31/55

A61P 25/00

A61P 9/10

A61P 29/00 // (C07D 487/06, C07D 223: 00, C07D 209: 00)

♦ ♦ • · • • «· ♦ • 4 « 4 · * ·· • 99 • • • 9 ♦ • • • • «· • • • · « • • • • 4 · «· 9 · • · ·· ···

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Azepinindole derivative, its use and pharmaceutical composition containing it

Technical field

The invention relates to azepinindole derivatives, a process for their preparation and their use as inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2,4,2,30) for the preparation of medicaments.

BACKGROUND OF THE INVENTION

Poly (ADP-ribose) polymerase (PARP), also referred to as poly (ADP-ribose) synthase (PARS), is a regulatory enzyme found in the nucleus of cells (K. Ikai et al., J. Histochem. Cytochem 31, 1261) to 1264 (1983). It is believed that PARP is involved in DNA break repair (M.S. Satoh et al., Nature 356, pp. 356-358, 1992). Damage or breakage in DNA strains activates the enzyme

PARP, which upon activation catalyzes the transfer of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol. 11, pp. 1-6, 1984). In this process, nicotinamide is released from NAD. Nicotinamide is converted to NAD by other ATP carrier energy enzymes. Accordingly, excessive activation of PARP would lead to unphysiologically high consumption of ATP and, in an exceptional case, lead to cell damage or cell death.

It is known that free radicals such as superoxide and he, NO and hydrogen peroxide can lead to DNA damage in cells and thus activate PARP. The generation of large amounts of free radicals is observed in a number of pathophysiological conditions and it is believed that this accumulation of free radicals results in or contributes to the observed damage to cells or organs. This includes, for example, ischemic conditions of organs such as stroke, heart attack (C. Thiemermann et al. Proc. Natl. Acad. Sci. USA 94: 679-683, 1997), or renal ischemia, but also reperfusion injury. after lysing a heart attack (C. Thie-

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Φ φ Φ φ φ φ φ φ φ φ φφφφ φφ φφ φφ φφ φφφ

mermann et al., Proc. Nati. Acad. Sci. USA 94: 679-683 (1997). Inhibition of the PARP enzyme could therefore be a means of at least partially preventing or alleviating this damage. PARP inhibitors could therefore be a new therapeutic principle for the treatment of a number of diseases.

The PARP enzyme affects the repair of DNA disorders and could therefore be involved in the treatment of cancer as a higher anti-tumor tissue activity was observed in combination with cytostatically active substances (G. Chen et al. Cancer

Chemo. Pharmacol.

22, p.

303, 1988). Only examples of possible effects are leukemia, glioblastoma, lymphoma, melanoma, breast and cervical cancer.

In addition, PARP inhibitors have been found to have immune suppressive effects (D. Weltin et al., Int. J. Immunopharmacol 17: 265-271 (1995)).

PARP has been found to be involved in immunological disorders or diseases in which the immune system plays a significant role, such as rheumatoid arthritis and septic shock, and that PARP inhibitors may exert a beneficial effect during disease (H. Kroger et al., Inflammation 20). 1996, pp. 203-215; W. Ehrlich et al., Rheuraatol Int. 15, pp. 171-172, 1995; C. Szabo et al., Proc. Natl. Acad. Sci. USA 95, p. 3867-383, 1998, and S. Cuzzocrea et al., Eur. J. Pharmacol. 342: 67-76 (1998).

The abbreviation PARP is used herein to mean isoenzymes of the above-described PARP enzyme.

3-Aminobenzamide as a PARP inhibitor has shown protective effects in a circulatory shock model (S. Cuzzocrea et al., Br. J. Pharmacol. 121: 1065-1074, 1997). There are also similar experimental indications that PARP inhibitors would be >>

• ··

may be useful as a means to treat diabetes mellitus (V. Burkart et al., Nature Med. 5: 314-319, 1999).

WO 00/42040 discloses azepinindoles which inhibit PARP. In particular, derivatives having a phenyl ring at the 2-position, which may be further substituted by simple substituents, are described as active.

The compounds of the formula I according to the invention have not been described so far and are therefore novel. Thus, novel azepinindole derivatives that are potent PARP inhibitors are described.

SUMMARY OF THE INVENTION

The present invention provides a substituted azepinindole derivative of the Formula I

(I) where is

A chain of 1 to 3 carbon atoms, each carbon atom optionally having one to two substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxyl, O-alkyl of 1 to 4 carbon atoms, COOH, COO-alkyl of 1 up to 4 carbon atoms and a phenyl or carbon atom may carry a group = O,

X ¹ is sulfur, oxygen or NH,

X ² is a carbon atom which additionally has a chain of 1 to 4 carbon atoms and a nitrogen atom,

X ³ is a nitrogen atom or a CR ² group where it is modified

R ² is hydrogen, branched or unbranched alkyl group having 1-6 carbon atoms, alkylphenyl having 1 to 4 carbon atoms in the alkyl or phenyl group, wherein

X ² and X ³ cannot simultaneously represent a nitrogen atom,

R ¹ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched alkyl having 1 to 6 carbon atoms, hydroxyl, nitro, trif1uormethy1ovou, cyano, NR ¹¹ R ^12, NH-COR ^13, and O-alkyl with 1 to 4 carbon atoms, wherein R ¹¹ and R ¹² are independently hydrogen or alkyl having 1 to 4 carbon atoms and R ¹³ independently are hydrogen, alkyl having 1 to 4 carbon atoms, alkylphenyl having 1 to 4 carbon atoms in an alkyl moiety or a phenyl group,

B a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 14 carbon atoms with 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 up to 2 sulfur atoms, all of which are optionally substituted by one R ⁴ and at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms as well as one or two = O, such as keto, sulfone or sulfoxide groups,

R ⁴ - (D) p- (E) s- (F ¹ ) q G ¹ - (F ² ) r - (G ² ) -G ³ , where G ¹ , G ² and G ³ cannot simultaneously represent a hydrogen atom or and if Ρ = s = 0 and q or r = 1 or p, qar = O, two of G ¹ , G ² and G ³ cannot simultaneously represent a bond or a hydrogen atom and where

D a sulfur atom, a NR ⁴³ group or an oxygen atom,

E is a phenyl group or a group of the formula

-SO ₂ -, -SO ₂ NH-, -NHCO-, -CONH-, NHSO ₂ -,

-NHCOCH ₂ X ⁴

X ⁴ is a sulfur, oxygen or NN atom,

F ^{1 is a} straight or branched, saturated or unsaturated chain of 1 to 8 carbon atoms,

F ² has the same meaning as F ¹ but independent of F ¹ ,

A G ¹ bond or a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having at most 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having at most 14 carbon atoms and having 0 to 5 nitrogen atoms, 0 to 2 atoms oxygen and 0 to 2 sulfur atoms, all of which are optionally additionally substituted by at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms and also one or two = O,

G ² is NR ⁴¹ R ⁴² or a group of formula

or a bond

G ^{3 a} saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having a maximum of 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms, all of which are optionally substituted by one R ⁴ and at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms as well as one or two = O or hydrogen, p 0 or 1, s 0 or 1, g 0 or 1, r 0 or 1,

R ⁴¹ is hydrogen, alkyl having 1 to 6 carbon atoms wherein each carbon atom can additionally carry up to two ^R groups, a phenyl group which may additionally carry up to two ^R groups and the group (CH) tK,

R ⁴² is hydrogen, alkyl having 1 to 6 carbon atoms, the group -C ^{0-R, C02-R,} SO2-NH2, ^S02-R, - (C = N) -R ^S

- (C = N) -NHR ^S ,

R ( ⁴³⁾ is hydrogen, (C1-C4) -alkyl, 1, 2, 3 or 4;

The group NR ¹¹ R ¹² , NR ¹¹ alkylphenyl of 1 to 4 carbon atoms in the alkyl moiety, pyrrolidine, piperidine,

1,2,5,6-tetrahydropyridine, morpholine, hoaopiperidine, piperasin, these groups being optionally additionally substituted with a (1-6C) alkyl group, and optionally additionally with a homopiperazine group (1-6C alkyl) group ,

R ⁵ is hydrogen, chlorine, fluorine, bromine, iodine, hydroxyl, nitro, trifluoraethyovou, cyano, NR ^where R ^13, NH-COR ^13, alkyl-CO-NH-R ¹³ having 1 to 4 atoms of carbon to the the alkyl, COR ^s, alkyl-O-CO-NH-R ¹³ with up to 4 carbon atoms in the alkyl a1ky1f eny1ovou having 1 to carbon atoms in the alkyl moiety, phenyl,

C 1 -C 4 -alkyl of 1 to 4 carbon atoms in the alkyl moiety, branched or unbranched C 1 -C 6 -alkyl, O-C 1 -C 4 -alkyl, S-C 1 -C 4 -alkyl each bearing a carbon atom optionally up to two R ⁶ groups and alkyl chains are optionally unsaturated,

R ⁶ is hydrogen, chlorine, fluorine, bromine, iodine, branched agitated ⁷ Uhl I to group, or unbranched alkyl having 1 to 6 carbon hydroxyl, nitro, cyano trifluormethyovou, NR ¹¹ R ^13,

NH-COR ¹³ or

O-alkyl of up to 4 carbon atoms, hydrogen, alkyl of 1 to carbon atoms, phenyl, the ring being optionally substituted with up to two R ⁷ groups and one amino group

NR ¹¹ R ¹² _{or a} cyclic saturated amino group having 3 to 7 members optionally substituted by an alkyl group having 1 to 6 carbon atoms and a homopiperazine group optionally substituted by an alkyl group having 1 to 6 carbon atoms; R ¹³ and R ¹³ as portions of K, ^R, R ⁶ and R ⁷ each independently have the same meaning as R ¹ shares

R ( ⁷¹⁾ is hydroxy, (C1-C6) -alkyl, (C1-C4) -alkyl, chloro, bromo, iodo, fluoro, trifluoromethyl, nitro or amino,

^R is alkyl having 1 to 6 carbon atoms, trif1uormethylovou, phenyl, alkylfeny1ovou having 1 to 4 carbon atoms in the alkyl group, the ring being optionally additionally substituted by up to two radicals R ^s1,

R ¹ is hydroxy, C 1 -C 6 alkyl, C 1 -C 4 O-alkyl, chloro, bromo, iodo, fluoro, trifluoromethyl, nitro or amino,

R * ³ is hydrogen, alkyl of 1 to 6 carbon atoms, alkylphenyl of 1 to 4 carbon atoms in the alkyl moiety, CO2-alkylphenyl of 1 to 4 carbon atoms in the alkyl moiety, CO2-alkyl of 1 to 4 carbon atoms in the alkyl moiety SO 2 -phenyl, COR ^S, and phenyl, the phenyl ring optionally being optionally substituted with up to two R ⁹¹ groups,

R ⁹¹ is hydroxy, C 1 -C 6 alkyl, C 1 -C 4 O-alkyl, chloro, bromo, iodo, fluoro, trifluoromethyl, nitro or amino, and tautomeric forms thereof, possible enantiomeric and diastereomeric forms, and his prodrogs.

• · · · · · · · · · · · ·

Preferred are compounds of formula (I) wherein the two-carbon chain is optionally substituted, oxygen and

R ¹ is hydrogen.

Preferred are the aforementioned compounds of formula (I), wherein is

B a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 14 carbon atoms with 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms, all of which are optionally substituted by one R ⁴ and at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms as well as one or two = O.

It is particularly preferred

B is a phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, or pyrazine group optionally substituted by one R ⁴ group and at most two R ⁵ groups.

Particularly preferred are compounds of formula I, wherein

R ⁴ is DF ¹⁰ , iG ² -G ³ , where G ³ is a hydrogen atom,

D is O, NR ⁴³ where R ⁴³ is hydrogen or C 1 -C 3 alkyl,

F ^{1 is} C 2 -C 4 alkyl.

Compounds of formula I may be used as racemates, such as enantiomerically pure compounds or diastereomers. Enantiomerically pure compounds may be obtained, for example, by the known resolution of compounds of formula I or intermediates thereof using an optically active base or acid.

The alkyl chains may be branched or unbranched. More preferred are unbranched alkyl chains.

The invention also relates to compounds which are mesomeric or tautomeric compounds of formula I.

The invention further relates to physiologically acceptable salts of the compounds of formula I, which are prepared by reacting the compounds of formula I with a suitable acid or base. Suitable acids and bases are disclosed, for example, in Fortschritte der Arzneimitteforschung 1966, Birkháuser Verlag, Vol. 10, pp. 224-265. Examples include hydrochloric, citric, tartaric, lactic, phosphoric, methanesulfonic, acetic, formic, maleic, fumaric or sodium hydroxide, lithium hydroxide, potassium hydroxide, and tris.

Prodrugs are compounds that are metabolized in vivo to compounds of formula I. Typical prodrugs are, for example, phosphates, amino acid catbamates, and esters.

The azepine indole derivatives of the formula I according to the invention can be prepared by the various processes described in WO 00/42040.

The substituted azepine indole derivatives of the formula I prepared according to the invention are inhibitors of the enzyme poly (ADP-ribose) polymerase or PARP (EC 2,4,2,30).

The inhibitory action of the substituted azepineindole derivatives of formula (I) can be demonstrated by a generally known enzyme assay, the measure of activity being the Ki value. The azepinoindole derivatives of the formula I are evaluated in this manner for their inhibitory action on the enzyme poly (ADP-ribose) polymerase or PARP (EC 2,4,2,30).

The substituted azepinindole derivatives of formula (I) are poly (ADP-ribose) polymerase (PARP) inhibitors, also known as poly (ADP-ribose) synthase (PARS), and can therefore be used for the treatment and prophylaxis of diseases associated with increased activity of these enzymes. .

The compounds of formula (I) may also be used for the manufacture of medicaments for treating damage following ischemia and for the prophylaxis in cases of expected ischemia of various organs.

The azepinoindole derivatives of formula I can be used for the treatment and prophylaxis of neurodegenerative diseases that may occur following ischemia, trauma (craniocerebral trauma), massive hemorrhage, subarachnoid haemorrhage and stroke, and neurodegenerative diseases such as multiple infarction dementia, Huntington's disease and episodes , especially in general epileptic seizures such as minor epileptic seizure and twitching seizure and partially epileptic seizures such as temporal lobe and complex / partial epileptic seizures, in addition to the treatment and prophylaxis of cardiac damage following cardiac ischemia and renal damage following renal ischemia such as acute renal insufficiency caused by medical treatment, as is the case with ciclosporin treatment, to treat acute renal failure or damage that occurs during and after the transplant of the kidney. In addition, compounds of Formula I may be used to treat acute myocardial infarction and injury that occurs during and after medical lysis (for example, using TPA, reteplases, our streptococci, or mechanically using laser or rotablator) and microinfarcts. resection of the aneurism and heart transplantation. Similarly, aaepinindole derivatives of formula (I) may be used to treat and revascularize critically narrowed coronary arteries, for example PCTA, and in bypass operations and critically narrowed pereral arteries, such as foot arteries. In addition, the azepinindole derivatives of formula (I) may be useful in the treatment of tumors and their metastases and in the treatment of inflammatory and rheumatic disorders such as rheumatoid arthritis as well as in the treatment of diabetes mellitus, multiorgan failure, septic rash and ARDS (acute respirators distress syndrome). , pulmonary shock).

In addition to conventional pharmaceutical excipients, the pharmaceutical compositions of the invention contain a therapeutically active amount of a compound of Formula I.

For topical application, for example in powders, ointments or sprays, the active compounds may be present in an amount of from 0.001 to 1% by weight, preferably from 0.001 to 0.1% by weight.

In the case of internal administration, the compositions are administered in individual doses. In an individual dose, 0.1 to 100 mg per kg of body weight is administered. The compositions may be administered daily in single or multiple doses depending on the nature and severity of the disease.

According to the route of administration, the pharmaceutical compositions according to the invention contain, in addition to the active ingredient, carriers and diluents known per se. For topical topical use, pharmaceutical excipients selected from the group consisting of ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petroleum gels and wool fat. For internal administration, for example, lactose, polyethylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.

The pharmaceutical compositions may further comprise antioxidants such as tocopherol and butylated hydroxyan salt as well as butylated hydroxytoluene, flavor enhancers, stabilizers, emulsifiers and lubricants.

The substances contained in the pharmaceutical compositions in addition to the active ingredient and the substance used in the manufacture of the pharmaceutical compositions are toxicologically harmless and compatible with the respective active ingredient. The pharmaceutical compositions are prepared in a manner known per se, for example by mixing the active ingredient with conventional carriers and diluents.

The pharmaceutical compositions of the invention may be administered in various ways, for example, orally, parenterally, such as by intravenous infusion, subcutaneously, intraperitoneally, and topically. The pharmaceutical compositions therefore take the form of tablets, emulsion solutions for infusion and injection, pastes, ointments, gels, creams, lotions, powders and sprays.

The pharmacological example illustrates the efficacy of the compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Inhibition enzyme oly (ADPribose) polymerase or1 i PARP (EC 2.4.2.30) Mi tame 96-well plate (Falcon) gets covered his- tonnes (typ II-AS; Sigma H7755). Histons are behind for this purpose roz-

in carbonate buffer (0.05M sodium bicarbonate, pH 9.4) to a concentration of 50 µg / ml. The individual wells of the microtiter plate are incubated overnight with 100 µl of each of these solutions. The histone solution is then removed

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9 • 99 ·· • 99

And incubate each well at room temperature for two hours with 200 µl of a 1% solution of BSA (bovine serum albumin) in carbonate buffer. The wells were washed three times with wash buffer (0.05% Tween 10 in PBS). For the enzyme reaction, 50 µl enzyme reaction solution (5 µl reaction buffer (1M tris HCl, pH 8.0, 100 mM magnesium chloride, 10 mM DTT), 0.5 µl PARP (c = 0.22 yg / yl) 4 µl of activated DNA (Sigma D-4522, 1 mg / ml in water) (40.5 µl of water) per well are preincubated for 10 minutes with 10 µl of inhibitor solution. The enzyme reaction is started by adding 40 µl of substrate solution (4 µl of reaction buffer, see above), 8 µl of NAD solution (100 µM in water), 28 µl of water). The reaction time is 20 minutes at room temperature. The reaction is terminated by washing three times with wash buffer (see above). Incubate for one hour at room temperature with specific anti-poly-ADP-ribose antibody. The antibody used is the monoclonal anti-poly- (ADP-ribose) antibody 10H (Kawamaitsu H. et al., Biochemistry 23, 3771-3777 1984). Monoclonal antibodies to poly (adenosine diphosphate base) recognize different structures. Polyclonal antibodies are also used.

Antibodies are used at a 1: 5000 dilution in antibody buffer (1% BSA in PBS; 0.5% Tveen 20). After washing three times with wash buffer, incubate for one hour at room temperature with the secondary antibody. Peroxidase-coupled anti-mouse IgG (Boehringer Mannheim) is used for monoclonal antibody and Peroxidase-coupled anti-rabbit IgG (Sigma A-6154) in each case at a dilution of 1 = 10,000 wash buffer. After washing three times with wash buffer, a color reaction is performed using 100 µl / well of color reagent (Sigma, TMB ready-mix T8540) for 15 minutes at room temperature. The color reaction was terminated by the addition of 100 µl of 2M sulfuric acid. Immediately measured (450 nm versus 620 nm; Easy Reader ELISA plate reader EAR340AT, SLT Labinstruments Austria). The Ki value is determined in a manner known per se from the inhibition curves for various substrate concentrations.

• ··· · - • φ Φ · Φ · 9 9 9 ·

9 9 9 9 9 9

99 99 99 99

The following compounds of the invention are prepared as described above:

1- 2- (4- (4-n-propylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

2. 2- (4-Piperazin-1-ylphenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one

3- 2- (4- (4-Isopropyl-piperazin-1-yl) -phenyl) -1,3,4,5-tetrahydro-6H-α2epino [5,4,3-c, d] indol-6-one

4. 2- (4- (4-Bezylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-

-azepino [5,4,3-c, d] indol-6-one

5. 2- (4- (4-n-Butylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-

-azepino [5,4,3-c, dl indol-6-one

6. 2- (4- (4-ethylpiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-

-azepieno [5,4,3-c, di-indol-6-one

7. 2- (4- (2-N, N-dimethylaminoeth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, indol-6-one; -on. 2- (4- (2-pyrrolidinyleth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, dlindol-6-one

9. 2- (4- (2-Piperidin-1-yl-ethyl-1-yloxy) -phenyl) -1,3,4,5-tetrahydro-6H-azepin-5,3,3-d] indol- 6-on

10. 2- (4- (2-Piperazin-1-yleth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepiamine 5,4,3-c, d] indol-6 -he

11. 2- (4- (2- (4-Methylpiperazin-1-yl) eth-1-yloxy) phenyl) -

-1,3,4,5-tetrahydro-6H-azepidin 5,4,4-c, d] indol-6-one

12. 2- (4- (2- (4-Propylpiperazin-1-yl) eth-1-yloxy) phenyl) -

-1,3,4,5-tetrahydro-6H-azepinol 5,4,4-c, d] indol-6-one

13. 2- (4- (2- (4-ethylpiperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepinol-5,3,3-indole -6-on

14. 2- (4- (2- (4-Biphenylpiperidin-1-yl) eth-1-yl) oxy) phenyl) -

-1,3,4,5-telrahydro-6H-azepino [5,4,3-c, dlindol-6-one

15. 2- (4- (2- (4-acetamidopiperazin-1-yl) eth-1-yloxy) phenyl) -

-1,3,4,5-tetrahydro-6H-a2epinol5,4,3-c, d] indol-6-one

16. 2- (4- (2- (4-benamidamidopiperidin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, dl indol-6-one

17. 2- (4-Homopiperidin-1-ylphenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, dl indol-6-one. 2- (4- (4-Methyl-bipiperidin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one

19. 2- (4- (4-Bromo-homopiperidin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepidin 5,4,3-c] indol-6-one

20. 2- (4- (4-n-butylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepinol 5,4,3-c, d] indol-6-one

21. 2- (4- (4-ethylhomopiperazin-1-yl) phenyl) -1,3,4,5-tetrahydro-6H-azepiamine 5,4,3-c, dl indol-6-one

22. 2-Piperidin-4-yl-1,3,4,5-tetrahydro-6H-azepinol-5,4,3-indol-6-one. 2- (1-methylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-α2-epi-5,4,3-c, d] indol-6-one

24. 2- (1-n-Propyl-piperidin-4-yl) -1,3,4,5-tetrahydro-6H-α-epi-5,4,3-c, d] indol-6-one

25. 2- (1-benzylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

26. 2- (1-n-Butylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-a2epinol5,4,3-c, dl-indol-6-one · ························

27. 2- (1-Isopropylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepidin 5,4,3-c, d] indol-6-one

28. 2- (2- (N, N-dimethylamino) eth-1-ylamino) phenyl) -1,3,4,5-

-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

29. 2- (2- (N, N-diethylamino) eth-1-ylamino) phenyl) -1,3,4,5-

-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

30. 2- (2-Piperidin-1-yleth-1-ylamino) phenyl-1,3,4,5-tetrahydro-

6H-azepinol 5,4,3-o, d] indol-6-one

31. 2- (2-Pyrrolidin-1-yleth-1-ylamino) phenyl-1,3,4,5-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

32. 2- (3- (N, N-dimethylamino) prop-1-ylamino) phenyl-1,3,4,5-

-tetrahydro-6H-azepin 5,4,3-c, d] indol-6-one

33. 2- (3- (N, N-Diethylamino) prop-1-ylamino) phenyl-1,3,4,5-

-tetrahydro-6H-azepinol 5,4,3-c, d] indol-6-one

34. 2- (3-piperidin-1-ylprop-1-ylamino) phenyl-1,3,4,5-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

35. 2- (3-pyrrolidin-1-ylprop-1-ylamino) phenyl-1,3,4,5-

-tetrahydro-6H-azepinol-5,4,3-c, d] indol-6-one

Industrial applicability

Substituted azepinindole derivatives for the manufacture of a medicament for the treatment of disorders in which PARP activities increase pathologically as for the treatment of neurodegenerative disorders and neuronal damage and disorders caused by ischemia, trauma and massive bleeding.

JUDr. Petr Kalenský

Claims (22)

PATENT CLAIMS • 9 9 99 9 9 9 9 9 9 99 99 99 A substituted azepinindole derivative of the Formula I (I) wherein is A chain of 1 to 3 carbon atoms, each carbon atom optionally having one to two substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, hydroxy, O-alkyl of 1 to 4 carbon atoms, COOH, COO-alkyl of 1 up to 4 carbon atoms and a phenyl or carbon atom may carry a group = O, X ¹ is sulfur, oxygen or NH, X ² is a carbon atom which additionally has a chain of 1 to 4 carbon atoms and a nitrogen atom, X ³ is a nitrogen atom or a CR ² group where it is exchanged R ² is hydrogen, branched or unbranched alkyl group having 1-6 carbon atoms, alkylphenyl having 1 to 4 carbon atoms in the alkyl or phenyl, and wherein BC X ² and X ³ cannot simultaneously represent a nitrogen atom, R ¹ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched alkyl having 1 to 6 carbon atoms, hydroxyl, nitro, trifluoromethyl, cyano, NR ¹¹ R ^12, NH-COR ^13, and 0-alkyl with 1 to 4 carbon atoms, wherein R ¹¹ and R ¹² are independently hydrogen or alkyl having 1 to 4 carbon uh19 * • · ·· ·· · · · »·>« • · · · · · · · • And R ^{13 is} independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkylphenyl; carbon in the alkali moiety or phenyl group, B a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic moiety of not more than 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic of up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms, all of which are optionally substituted by one R ⁴ and at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms as well as one or two = O, R ⁴ - (D) P- (E) s- (F ¹ ) q G ¹ - (F ² ) r - (G ² ) -G ³ , where G ¹ , G ² and G ³ cannot simultaneously represent a hydrogen atom or and if P = s = 0 and q or r = 1 or p, q and r = 0, two of G ¹ , G ² and G ³ cannot simultaneously represent a bond or a hydrogen atom and where D a sulfur atom, a NR ⁴³ group or an oxygen atom, E is a phenyl group or a group of the formula -SO2-, -SO2NH-, -NHCO-, -CONH-, NHSO2-, -NHCOCH2X ⁴ , X ⁴ is a sulfur, oxygen or NN atom, F ^{1 is a} straight or branched, saturated or unsaturated chain of 1 to 8 carbon atoms, F ² has the same meaning as F ¹ but independent of F ¹ , φφ ·· • »φ • 9 ·· • ·· * • ·· ΦΦΦΦ ·· A G ¹ bond or a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having at most 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having at most 14 carbon atoms and having 0 to 5 nitrogen atoms, 0 to 2 atoms oxygen and 0 to 2 sulfur atoms, all of which are optionally additionally substituted by at most three different or the same R ⁵ groups and may carry one or two carbon or sulfur atoms and also one or two = O, G ² is NR ⁴¹ R ⁴² or a group of formula or a bond G ^{3 a} saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having a maximum of 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group having a maximum of 14 carbon atoms and having 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, all of which are optionally substituted by one R ⁴ and at most three different or the same R ⁵ and may carry one or two carbon or sulfur atoms as well as one or two = O or hydrogen, p 0 or 1, • · · s with 0 or 1, q 0 or 1, r 0 or 1, R ⁴¹ is hydrogen, alkyl having 1 to 6 carbon atoms wherein each carbon atom can additionally carry up to two radicals R ^6, phenyl, which can additionally carry at most two radicals R ⁶ or (CH 2) t K R ⁴² is hydrogen, C 1 -C 6 alkyl, -CO-R ² , CO ₃ -R ⁵ , SO 2 -NH 2, SO 2 -R ⁵³ , - (CN) -R 5 ^, and - (C = N) -NHR ^S , R ( ⁴³⁾ is hydrogen, (C1-C4) -alkyl, 1, 2, 3 or 4; To the group NR ¹¹ R ¹² , NR ¹¹ C 1-4 alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, piperazine, these groups being optionally additionally substituted with an alkyl group C 1 -C 6, and a homopiperazine group optionally substituted with C 1 -C 6 alkyl, R ⁵ is hydrogen, chlorine, fluorine, bromine, iodine, hydroxyl, nitro, trif1uormethyovou, cyano, NR ¹¹ R ^12, NH-COR ^13, alky1 group -CO-NH-R ¹³ having 1 to 4 carbon atoms in the alkyl share, COR ^s, alkyl-O-CO-NH-R ¹³ O to 4 carbon atoms in the alkyl, alkylphenyl having 1 to 4 carbon atoms in the alkyl, phenyl, C02 ^_ alkyl having 1 to 4 carbon atoms in the alkyl , alkyl having up to 4 carbon atoms, branched or unbranched 6 carbon atoms, O-alkyl having 1 S-alkyl having 1 to 5 carbon atoms; 4 carbon atoms, each carbon atom optionally bearing up to two groups R ⁶ and a 1 truss chains are optionally unsaturated, R ⁶ is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched alkyl having 1 to 6 carbon atoms, hydroxy1ovou, nitro, trif1uormethyovou, cyano, NR ¹¹ R ^12, NH-COR ¹³ or O-alkyl having 1 up to 4 carbon atoms, R ( ⁷⁾ is hydrogen, (C1-C6) -alkyl; 6-carbon atoms, phenyl, the ring being optionally substituted by up to two R ⁷ groups and one amino group NR 11 R 6 _{or a} cyclic saturated amino group having from 3 to 7 members optionally substituted by C 1-6 alkyl and homopiperazine optionally substituted by C 1-6 alkyl wherein R ¹¹ , R ¹³ , and R ¹³ as the moieties of group K, R ⁵ , R ⁶ and R ⁷ independently of one another have the same meaning as the moieties of group R ¹ R ⁷¹ is hydroxy, C 1 -C 6 alkyl, C 1 -C 4 O-alkyl, chloro, bromo, iodo, fluoro, trifluoromethyl, nitro or amino, ^R is alkyl having 1 to 6 carbon atoms, trifluoromethyl, phenyl, alkylfeny1ovou having 1 to 4 carbon atoms in the alkyl group, the ring being optionally additionally substituted by up to two radicals R ^s1, R @ ¹ is hydroxy, C1 -C6 alkyl; (C 1 -C 4) -alkyl, ston of chlorine, bromine, iodine, fluorine, trifluoromethyl, nitro or amino, R @ ⁹ is hydrogen, C1 -C6 -alkyl, C1 -C4 -alkylphenyl, C1 -C4 -alkyl-C1 -C4 -alkyl, C1 -C4 -alkyl-C1 -C4 -alkyl; alkyl, SO 2 -phenyl, COR ^3, and phenyl, the phenyl ring optionally being optionally substituted with up to two R ⁹¹ groups, R ⁹ is hydroxy, C 1 -C 6 alkyl, C 1 -C 4 O-alkyl, chloro, bromo, iodo, fluoro, trifluoromethyl, nitro or amino, and its tautomeric forms, possible enantiomeric and diastereomeric forms and its prodrogs. 2. A compound according to claim 1, wherein is A chain with two carbon atoms optionally substituted, X ¹ oxygen atom and R ¹ is hydrogen. 3. A compound of claim 1, wherein the compound is a compound B a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 15 carbon atoms, a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic group of not more than 14 carbon atoms with 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and O All these groups are optionally substituted by one R ⁴ group and at most three different or the same R ⁵ groups and may carry one or two carbon or sulfur atoms as well as one or two = O groups. 4. A compound according to claim 3, wherein: is a compound B is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, or pyrazine, optionally substituted with one R ⁴ group and at most two R ⁵ groups. 5. A compound according to claim 4, wherein the compound is a compound R ⁴ is DF ^x o, i-G ² -G ³ , where G ³ is a hydrogen atom, D is O, NR ⁴³ where R ⁴³ is hydrogen or C 1 -C 3 alkyl, F ^{1 is} C 2 -C 4 alkyl. 6. A pharmaceutical composition comprising the compounds of formula (I) as claimed in claims 1 to 5 and carriers and excipients. Use of compounds of the formula I according to claims 1 to 5 for the production of pharmaceutical compositions having PARP inhibitory action. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of neurodegenerative disorders and neuronal damage. Use according to claim 7 of compounds of formula I for the treatment of neurodegenerative disorders and neuronal damage caused by ischemia, trauma or massive bleeding. Use according to claim 7 of compounds of formula I for the treatment of stroke and craniocerebral trauma. Use according to claim 7 of compounds of formula I for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment and prophylaxis of disorders caused by ischemia. Use according to claim 7 of the compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of epilepsy, in particular generated epileptic seizure, e.g. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of damage following renal ischemia, damage caused by medical therapy, for example cyclosporine therapy, and for treatment in and after renal transplantation. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of cardiac damage following cardiac ischemia. The use according to claim 7 of the compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of infarct steps during and after cardiac valve replacement, aneurysm resection and cardiac transplantation. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment associated with revascularization of critically narrowed coronary arteries as in PTCA and bypass surgery or for the treatment of critically narrowed peripheral arteries, in particular leg arteries. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of acute myocardial infarction during or after lysis thereof, medicinal or mechanical. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of tumors and their metastases. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of multi-organ sepsis, for example in septic shock and acute respiratory stress syndrome. Use according to claim 7 of compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of immunological diseases such as inflammation and rheumatic disorders such as rheumatoid arthritis. Use according to claim 7 of compounds of formula I for the manufacture of a medicament for the treatment of diabetes mellitus.