JP2003510328A - Azepinoindole derivatives, their preparation and use - Google Patents

Abstract

(57) Abstract: The present invention relates to a compound of the formula I: [Where the symbols have the meanings described in the specification], tautomeric forms, possible enantiomeric and diastereomeric forms thereof, and prodrugs thereof, and their preparation and use.

Description

Detailed Description of the Invention

The present invention relates to a novel azepinoindole derivative, a method for producing the same, and an enzyme poly (ADP-ribose) polymerase or PARP (EC2.4.2.3) for producing a drug.
0) relates to its use as an inhibitor.

Poly (ADP-ribose) polymerase (PARP), also called poly (ADP-ribose) synthase (PARS), is a regulatory enzyme found in the cell nucleus (K. Ikai et al., J. Histochem. Cytochem. 1983). , 31, 1261-1264). PARP is thought to play an important role in repairing DNA damage (MS Satoh et al., Nat
ure 1992, 356, 356-358). DNA strand damage or breakage activates the enzyme PARP, which upon activation catalyzes the conversion of NAD to ADP-ribose (S.
Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). During this process, NAD releases nicotinamide. Utilizing the energy carrier ATP, nicotinamide is converted back to NAD by another enzyme. Excessive activation of PARP leads to non-physiological high consumption of ATP, which in extreme cases leads to cell damage and cell death.

It is known that free radicals such as superoxide anion, NO and hydrogen peroxide induce DNA damage in cells and activate PARP. A large amount of free radical formation was observed under various abnormal physiological conditions, which suggests that the accumulation of free radicals induces or causes damage to observed cells and tissues. For example, this includes tissue ischemia, such as stroke, myocardial infarction (
C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683) or renal ischemia, as well as reperfusion injury such as occurs after resolution of myocardial infarction (see above). : C. Thiemermann et al.). Therefore, inhibition of the enzyme PARP may mean at least partially preventing or alleviating such disorders. PARP inhibitors may represent new therapeutic tools for the treatment of many diseases.

The enzyme PARP influences the repair of DNA damage and, in combination with cytostatics, exerts a higher potency on tumor tissue and thus plays an important role in the treatment of cancerous diseases. (G. Chen et al., Cancer Chemo. Pharmacol.
1988, 22, 303). Examples of tumors are leukemia, glioblastoma, lymphoma, melanoma,
Breast cancer and cervical cancer, but not limited thereto.

Furthermore, it was found that PARP inhibitors show immunosuppressive action (D. Weltin
Int. J. Immunopharmacol. 1995, 17, 265-271).

It has been found that PARP is associated with immunodeficiency or diseases in which the immune system plays an important role, such as rheumatoid arthritis and septic shock, and PARP inhibitors positively influence the course of the disease. (H. Kroeger et al., Inflammation 1996, 20, 2
03-215; W. Ehrlich et al., Rheumatol. Int. 1995, 15, 171-172; C. Szabo et al., P.
roc. Natl. Acad. Sci. USA 1998, 95, 3867-3872; S. Cuzzocrea et al., Eur. J.
Pharmacol. 1998, 342, 67-76).

Within the meaning of the invention, PARP is understood to mean also an isoenzyme of the PARP enzyme.

Furthermore, the PARP inhibitor 3-aminobenzamide showed a protective effect in a model for circulatory shock (S. Cuzzocrea et al. Br. J. Pharmacol. 1997, 12).
1, 1065-1074).

Similarly, there are tentative suggestions that inhibitors of the enzyme PARP are useful as therapeutic agents for diabetes (V. Burkart et al., Nature Med. 1999, 5, 314-319).

[0012] WO0042040 describes azepinoindoles that inhibit the PARP enzyme. As activators, derivatives with a phenyl ring in the 2-position are described, which may be further substituted with simple substituents.

[0011]   The compounds of general formula I according to the invention have not hitherto been described and are therefore novel.

In the present invention, novel azepinoindole derivatives of general formula I which are potential PARP inhibitors are described.

[0013]   The present invention provides formula I:

[0014]

[Chemical 4]

[0015] [In the formula, A is C₁~_ThreeIt may be a chain, wherein each carbon atom additionally has the following substituent: C ₁ ~_Four-Alkyl, OH, OC₁~_Four-Alkyl, COOH, COO-C₁~ _Four -May have one or two alkyl and phenyl or a C atom
May also have a ═O group, X¹May be S, O or NH, X^TwoIs an additional C₁~_FourA carbon atom which may have a chain, and may be N
, X^ThreeIs N or C-R^TwoCan be here R^TwoIs hydrogen, branched or straight chain C₁~₆-Alkyl, C₁~_Four-Alkylfe
May be nil, phenyl, X^TwoAnd X^ThreeCannot be N at the same time, R¹Is hydrogen, chlorine, fluorine, bromine, iodine, branched or straight chain C₁~₆-Al
Kill, OH, nitro, CF_Three, CN, NR¹¹R¹², NH-CO-R^Thirteen, O
-C₁~_Four-Alkyl, where R¹¹And R¹²Are independent of each other
Then hydrogen or C₁~_Four-Alkyl, R^ThirteenIs hydrogen, C₁~_Four-Archi
Le, C₁~_Four-Alkylphenyl or phenyl, B is an unsaturated, saturated or partially unsaturated monocycle having up to 15 carbon atoms
, Bicyclic or tricyclic rings, up to 14 carbon atoms and 0 to 5 nitrogen atoms, acids
Unsaturated, saturated or partially having 0 to 2 elementary atoms and 0 to 2 sulfur atoms
It may be an unsaturated monocyclic, bicyclic or tricyclic ring, each of which is additionally 1
R^FourAnd different or identical up to 3 R⁵Substituted with a group,
Or one or two sulfur atoms and ═O groups, such as keto groups, sulfones or sulfur groups.
It may have one or two luphoxides, R^FourIs-(D)_p-(E)_s-(F¹)_q-G¹-(F^Two)_r-(G^Two) -G ^Three And here G¹, G^TwoAnd G^ThreeCannot simultaneously be hydrogen or a bond,
G if p = s = 0 and q or r = 1 or p, q and r = 0 ¹ , G^TwoAnd G^ThreeTwo groups of cannot simultaneously bond or become hydrogen, D is S, NR⁴³Or may be O, E is phenyl,

[0016]

[Chemical 5]

[0017] _{-SO 2 -, - SO 2 NH} -, - NHCO -, - CONH-, NHSO 2 -, -
NHCOCH ₂ X ⁴ , X ⁴ may be S, O or NH, and F ¹ is a straight or branched saturated or unsaturated carbon chain having 1 to 8 carbon atoms. well Te, F ² have the same meaning as that described from F ¹ independently vital F ^1, G ¹ is a bond or at most 15 having unsaturated carbon atoms, saturated or partially unsaturated Monocyclic, bicyclic or tricyclic rings of up to 14 carbon atoms and 0 nitrogen atoms
May be an unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having from 5 to 0, 2 to 0 oxygen atoms and 0 to 2 sulfur atoms, each of which is an addition Optionally substituted or identical with up to 3 R ⁵ groups and having 1 or 2 carbon or sulfur atoms and 1 or 2 ═O groups, G ² is NR ⁴¹ R ⁴² or

[0018]

[Chemical 6]

[0019] Or a join, G^ThreeIs an unsaturated, saturated or partially unsaturated monocycle having up to 15 carbon atoms
, Bicyclic or tricyclic rings, and up to 14 carbon atoms and 0 to 5 nitrogen atoms
Unsaturated, saturated or partially having 0-2 oxygen atoms or 0-2 sulfur atoms
May be an unsaturated monocyclic, bicyclic or tricyclic ring, each of which additionally
, Different or identical up to 3 R⁵Radicals and 1 of carbon or sulfur atoms
One or two may have one or two ═O groups or are hydrogen atoms
, p may be 0 or 1, s may be 0 or 1, q may be 0 or 1, r may be 0 or 1, R⁴¹Is hydrogen, R for each carbon atom in addition to 2⁶C which may have a group₁ ~₆-Alkyl, additionally the group R₆A phenyl which may have up to two, and
(CH_Two)_t-May be K, R⁴²Is hydrogen, C₁~₆-Alkyl, -CO-R⁸, CO_Two-R⁸, SO_TwoN
H_Two, SO_Two-R⁸,-(C = N) -R⁸And-(C = N) -NHR⁸And
Well, R⁴³Is hydrogen or C₁~_Four-May be alkyl, t can be 1, 2, 3 or 4; K is NR¹¹R¹², NR¹¹-C₁~_Four-Alkylphenyl, pyrrolidine,
Piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidi
, Piperazine, which additionally has an alkyl group C₁~₆-Substituted with alkyl
And optionally an alkyl group C₁~₆-An optionally substituted alkyl
May be mopiperazine, R⁵Is hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF_Three, CN, N
R¹¹R¹², NH-CO-R^Thirteen, C₁~_Four-Alkyl-CO-NH-R^Thirteen , COR⁸, C₀~_Four-Alkyl-O-CO-R^Thirteen, C₁~_Four-Alkylfe
Nyl, phenyl, CO_Two-C₁~_Four-Alkyl, and branched or straight chain C1-6
-Alkyl, O-C1-4-alkyl, S-C₁~_Four-May be alkyl,
Where each C atom in the alkyl chain has up to two radicals R⁶May have an alkyl chain
May be unsaturated, R⁶Is hydrogen, chlorine, fluorine, bromine, iodine, branched or straight chain C₁~₆-Al
Kill, OH, nitro, CF_Three, CN, NR¹¹R¹², NH-CO-R^Thirteen, O
-C₁~_Four-May be alkyl, R⁷Is hydrogen, C₁~₆-Alkyl, may be phenyl, where the ring is additional
Up to 2 radicals R⁷¹, And one amine NR¹¹R¹²Have been replaced with
Or additionally an alkyl group C₁~₆3-7 optionally substituted with alkyl
Membered cyclic saturated amine, and additionally alkyl group C₁~₆-Substituted by alkyl
Which may be homopiperazine, Where K, R⁵, R⁶And R⁷R in¹¹, R¹²And R^ThirteenMutually independent
Stand up R¹May have the same meaning as R⁷¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoMay be R⁸Is C₁~₆-Alkyl, CF_Three, Phenyl, C₁~_Four-Alkylphenyl
Where the ring is optionally up to two radicals R⁸¹May be replaced with
R⁸¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoMay be R⁹Is hydrogen, C₁~₆-Alkyl, C₁~_Four-Alkylphenyl, CO_Two-C ₁ ~_Four-Alkylphenyl, CO_Two-C₁~_Four-Alkyl, SO_Two-Phenyl,
COR⁸And phenyl, wherein the phenyl ring is additionally up to two radicals R^{9 1} May be replaced with R⁹¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoWhich may be
Mutant forms, possible enantiomeric and diastereomeric forms, and prods thereof
Regarding rag.

In preferred compounds of formula I, A is an optionally substituted C ₂ chain, X ¹ is O and R ¹ is hydrogen.

Preferred compounds of formula I are those mentioned above, in which B is an unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 15 carbon atoms. An unsaturated, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having up to 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. ^{May be a} formula ring, each additionally substituted with R ⁴ and up to 3 different or different R ⁵ groups, one or two carbon or sulfur atoms and one ═O group. Or have two.

Particularly preferred groups B are: phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrrole, pyrazole, thiophene, furan, oxazole, naphthalene, piperazine, quinoline, pyrazine, which are additional ^May be substituted with 1 R ⁴ or up to 2 R ⁵ .

Particularly preferred compounds of formula I are those in which R ⁴ is DF ^10, ₁ -G ² -G ³ , where G ³ is a hydrogen atom and D is O or NR ⁴³ There, wherein ^{R 43} is a hydrogen atom or _C 1 _{~ 3} - alkyl, ^{F 1} _is, C 2 _{~ 4} - alkyl.

The compounds of formula I can be used as racemates, enantiomerically pure compounds or diastereomers. If the enantiomerically pure compound is desired, it is obtained by classically resolving the compound of formula I or an intermediate thereof, for example using a suitable base or acid with optical rotation.

The alkyl chain may in each case be branched or straight-chain. Straight-chain alkyl is preferred.

[0026]   The present invention also relates to the mesomeric or tautomeric compounds of compounds of formula I.

The present invention further relates to physiologically tolerable salts of the compounds of formula I, which can be obtained by converting the compounds of formula I with a suitable acid or base. Suitable acids and bases are for example Fortscheitte der Arzneimittelforschung, 1996, Birkha.
Listed in euser Verlag, Vol. 10, 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid,
There are fumaric acid and the like, and sodium hydroxide, lithium hydroxide, potassium hydroxide and Tris.

A prodrug is understood to mean a compound which is metabolized in vivo to a compound of general formula I. Typical prodrugs are amino acid phosphates, carbamates, esters and others.

The azepinoindole derivative of the present invention can be produced by various methods as described in, for example, WO0042040.

The substituted azepinoindole derivative I obtained according to the present invention is a product of the enzyme poly (ADP
An inhibitor of ribose) polymerase or PARP (EC 2.4.2.30).

The inhibitory action of the substituted azepinoindole derivative I is measured using an enzyme test known in the literature, the measurement of the activity being determined by the K _i value. The azepinoindole derivative I was added to the enzyme poly (ADP-ribose) polymerase or PARP (EC2.
It was measured by the method for the inhibitory effect of 4.2.30).

Substituted azepinoindole derivatives of general formula I include poly (ADP-ribose) polymerase (PARP) (or poly (ADP-ribose) synthase (P
ARS)), and thus can be used in the treatment and prevention of diseases associated with increased enzymatic activity of these enzymes.

The compounds of formula I can be used for the manufacture of a medicament for the treatment of post-ischemic disorders and prophylaxis when ischemia is predicted in various tissues.

The azepinoindole derivatives of the general formula I according to the invention are therefore suitable for the treatment and prevention of ischemia, trauma (head trauma), massive bleeding, subarachnoid hemorrhage and neurodegenerative diseases after stroke, multi-infarct dementia. Neurodegenerative diseases such as (muotiple infarct dementia),
Treatment and prevention of Alzheimer's disease, Huntington's disease and epilepsy, especially systemic epileptic seizures, such as small and tonic-clonic seizures and focal epileptic seizures, such as temporal lobe epilepsy and complex partial seizures, as well as ischemic heart disease. It can be used for the treatment and prophylaxis of subsequent cardiac disorders and renal disorders after renal ischemia, such as acute renal insufficiency, acute renal failure or disorders occurring during and after renal transplantation. The compounds of the general formula I are furthermore suitable for the treatment of acute myocardial infarction and its disability during and after resolution by medication (for example by TPA, reteplase, streptokinase or by mechanical means with a laser or a rotablator). It can be used for heart valve replacement, aneurysm resection and treatment of microinfarction during and after heart transplantation. Similarly, the Azepinoindole Derivatives I of the present invention can be used in the treatment of severely stenotic coronary arteries, such as PTCA and bypass surgery, and in the revascularization of severely stenotic peripheral arteries, especially leg arteries. Furthermore, azepinoindole derivative I is used for the treatment of tumors and their metastases, the treatment of inflammation and rheumatic disorders such as rheumatoid arthritis and the treatment of diabetes, multiorgan failure.
), For example, treatment of septic shock, ARDS (acute respiratory distress syndrome, shock lung).

In addition to the customary pharmaceutical auxiliaries, the pharmaceutical products according to the invention contain a therapeutically effective amount of compound I.

For topical external application such as powders, ointments or sprays, the active compounds may be contained in conventional concentrations. In principle, the active compounds are contained in amounts of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.

For internal use, the product is administered in individual doses. The individual dose is 0.1 to 100 mg / kg body weight. The product is administered in one or more doses per day depending on the nature and severity of the disease.

Depending on the desired mode of administration, the medicaments of the invention contain conventional excipients and diluents in addition to the active compound. In the case of topical application topically, pharmaceutical aids such as ethanol,
Isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearic acid, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat can be used. For internal use, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.

Antioxidants such as tocopherols and butylated hydroxyanisole and butylated hydroxytoluene, seasoning additives, stabilizers, emulsifiers and lubricants may also be included.

The substances contained in the manufactured products in addition to the active compounds and the substances used in the production of pharmaceuticals are non-toxic and are suitable for each active compound. The manufacture of pharmaceutical products is carried out in the customary manner, for example by mixing the active compounds with a number of customary excipients and diluents.

The pharmaceutical agent can be administered by various administration methods such as oral administration, parenteral administration, for example, intravenous administration of infusion, subcutaneous administration, intraperitoneal administration and local administration. Thus, product forms are possible, such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays.

Pharmacological Examples The enzyme poly (ADP-ribose) polymerase or PARP (EC 2.4.2.3)
0) Inhibition of 96-well microtiter plates (Falcon) with histones (type II-AS;
SIGMA H7755). For this purpose, histones were added to carbonate buffer (0.
Dissolve it in 05M NaHCO ₃ ; pH 9.4) to a concentration of 50 μg / ml.
Add 100 μl of this histone solution to each well of a microtiter plate and incubate overnight. The histone solution is removed and 200 μl of a 1% strength BSA (bovine serum albumin) solution in carbonate buffer is added to each well and incubated at room temperature for 2 hours. Then wash buffer (0.05% in PBS
Wash the wells 3 times with Tween 10). The enzyme reaction was carried out by using an enzyme reaction solution (reaction buffer (1M trisHCl pH 8.0, 100 mM MgCl ₂ ,
0 mM DTT) 5 μl, PARP (c = 0.22 μg / μl) 0.5 μl, activated DNA (SIGMA D-4522, 1 mg / ml in water) 4 μl, H ₂ O 40.
5 μl) 50 μl are placed in each well and pre-incubated with 10 μl of inhibitor solution for 10 minutes per well. The enzyme reaction was carried out by adding 4 μl of substrate solution (reaction buffer (see above), 8 μl of NAD solution (100 μM in water), 28 μl of H ₂ O) 4
Start with the addition of 0 μl. The reaction time is 20 minutes at room temperature. The reaction is stopped by washing 3 times with wash buffer (see above). Specific anti-poly-
Add ADP-ribose antibody and incubate at room temperature for 1 hour. The antibody used was the monoclonal anti-poly- (ADP-ribose) antibody "10H" (
Kawamaitsu H et al. (1984) Monoclonal antibodies to poly (adenosine diphospha
te ribose) recognize different structures.Biochemistry 23, 3771-3777)
. Polyclonal antibodies may be used.

Antibodies are in antibody buffer (1% BSA in PBS; 0.05% Tween 20)
It was used by diluting it 1: 5000 in. After washing 3 times with the wash buffer, the cells are incubated with the secondary antibody for 1 hour at room temperature. Here, the monoclonal antibody is anti-mouse IgG bound to peroxidase (Boehringer Mannheim), and the rabbit antibody is anti-rabbit IgG bound to peroxidase (SIGMA).
A-6154), which was diluted 1: 10000 in the antibody buffer before use. After washing 3 times with the washing buffer, 100 μ / well of color reagent (SIGMA, TMB Readymix T8540) was used for about 15 minutes at room temperature to perform a color reaction (colo).
r reaction) was carried out. The color reaction is stopped by adding 100 μl of 2M H ₂ SO ₄ . Color was measured immediately (450 nm vs. 620 nm; ELI
SA plate reader "Easy Reader" EAR340
AT, SLTLabinstruments, Austria). The measured IC ₅₀ value of the inhibitor is indicated by the concentration of the inhibitor, and is the position at which half the maximum change in color density is shown.

The following compounds of the present invention can be prepared by analogy to the above methods: 1. 2- (4- (4-n-propylpiperazin-1-yl) phenyl) -1,3
, 4,5-Tetrahydro-6H-azepino [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-isopropylpiperazin-1-yl) phenyl) -1,3
, 4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 4.2- (4- (4-benzylpiperazin-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, d] indol-6-one 6.2- (4- (4-ethylpiperazin-1-yl) phenyl) -1,3,4 , 5
-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 7.2- (4- (2-N, N-dimethylaminoeth-1-yloxy) phenyl) -1,3 , 4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 8.2- (4- (2-pyrrolidinyleth-1-yloxy) phenyl) -1,3
, 4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 9.2- (4- (2-piperidin-1-yleth-1-yloxy) phenyl) -1 , 3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 10.2- (4- (2-piperazin-1-yleth-1-yloxy) phenyl) -1,3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 11.2- (4- (2- (4-methylpiperazin-1-yl)) Eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,5,3-
c, d] Indol-6-one 12.2- (4- (2- (4-propyl-piperazin-1-yl) eth-1-
Iloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,
3-c, d] indol-6-one 13.2- (4- (2- (4-ethyl-piperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro -6H-azepino [5,4,3
-C, d] Indol-6-one 14.2- (4- (2- (4-benzylpiperazin-1-yl) eth-1-yloxy) phenyl) -1,3,4,5-tetrahydro-6H -Azepino [5,4,3
-C, d] Indol-6-one 15. 2- (4- (2- (4- (4-acetamidopiperazin-1-yl) ethyl) eth-1
-Yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,
4,3-c, d] indol-6-one 16.2- (4- (2- (4-benzamidopiperazin-1-yl) eth-1
-Yloxy) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,
4,3-c, d] Indol-6-one 17.2- (4-Homopiperazin-1-ylphenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c , d] Indol-6-one 18.2- (4- (4-Methylhomopiperazin-1-yl) phenyl) -1,3
, 4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 19.2- (4- (4-benzylhomopiperazin-1-yl) phenyl) -1,
3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indole-6-
On 20. 2- (4- (4-n-butylhomopiperazin-1-yl) phenyl)-
1,3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indole-6
-One 21.2- (4- (4-ethylhomopiperazin-1-yl) phenyl) -1,3
, 4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indol-6-one 22.2-piperidin-4-yl-1,3,4,5-tetrahydro-6H-azepino [ 5,4,3-c, d] Indol-6-one 23.2- (1-methylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3- c, d] Indol-6-one 24.2- (1-n-propylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] Indole-6-one 25.2- (1-benzylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6-one 26 .2- (1-n-Butylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6 On 27.2- (1-isopropylpiperidin-4-yl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6-one 28.2- ( 2- (N, N-Dimethylamino) eth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6-one 29. 2- (2- (N, N-diethylamino) eth-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] indole-6-one 30. 2- (2-Piperidin-1-yleth-1-ylamino) phenyl)-
1,3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indole-6
-One 31.2- (2-pyrrolidin-1-yleth-1-ylamino) phenyl)-
1,3,4,5-Tetrahydro-6H-azepino [5,4,3-c, d] indole-6
-One 32.2- (3- (N, N-dimethylamino) prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] Indole-6-one 33.2- (3- (N, N-diethylamino) prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c, d] Indol-6-one 34.2- (3-piperidin-1-yl-prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3-c] , d] Indol-6-one 35.2- (3-pyrrolidin-1-yl-prop-1-ylamino) phenyl) -1,3,4,5-tetrahydro-6H-azepino [5,4,3- c, d] indole-6-on

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 11/00 A61P 11/00 13/12 13/12 19/02 19/02 25/08 25/08 25 / 10 25/10 25/14 25/14 25/16 25/16 25/28 25/28 29/00 29/00 101 101 35/00 35/00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, A T, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE , GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US , UZ, VN, YU, ZA, ZW (72) Inventor Thomas Heger, Federal Republic of Germany Edingen-Neckerhausen Rathenaustraße 12 (72) Inventor Sabine Schult, Federal Republic of Germany Speyer Dr. Eduard-Ort Strasse 13 (72) Inventor Laurent Grundel Germany Dossenheim Birkenweg 49 (72) Inventor Reinhold Müller Germany Federal Republic Schifferstadt Othring 66 A F Term (reference) 4C050 AA02 BB04 CC10 EE02 FF05 GG03 HH04 4C086 AA01 AA02 AA03 CB11 MA01 NA14 ZA01 ZA02 ZA06 ZA16 ZA40 ZA60 ZA81 ZA96 ZB11 ZB15 ZB26 ZC35

Claims (22)

[Claims] 1. Formula I:     [Chemical 1] [In the formula, A is C₁~_ThreeIt may be a chain, wherein each carbon atom additionally has the following substituent: C ₁ ~_Four-Alkyl, OH, OC₁~_Four-Alkyl, COOH, COO-C₁~ _Four -May have one or two alkyl and phenyl or a C atom
May also have a ═O group, X¹May be S, O or NH, X^TwoIs an additional C₁~_FourA carbon atom which may have a chain, and may be N
, X^ThreeIs N or C-R^TwoCan be here R^TwoIs hydrogen, branched or straight chain C₁~₆-Alkyl, C₁~_Four-Alkylfe
May be nil, phenyl, X^TwoAnd X^ThreeCannot be N at the same time, R¹Is hydrogen, chlorine, fluorine, bromine, iodine, branched or straight chain C₁~₆-Al
Kill, OH, nitro, CF_Three, CN, NR¹¹R¹², NH-CO-R^Thirteen, O
-C₁~_Four-Alkyl, where R¹¹And R¹²Are independent of each other
Then hydrogen or C₁~_Four-Alkyl, R^ThirteenIs hydrogen, C₁~_Four-Archi
Le, C₁~_Four-Alkylphenyl or phenyl, B is an unsaturated, saturated or partially unsaturated monocycle having up to 15 carbon atoms
, Bicyclic or tricyclic rings, up to 14 carbon atoms and 0 to 5 nitrogen atoms, acids
Unsaturated, saturated or partially having 0 to 2 elementary atoms and 0 to 2 sulfur atoms
It may be an unsaturated monocyclic, bicyclic or tricyclic ring, each of which is additionally 1
R^FourAnd different or identical up to 3 R⁵Substituted with a group,
Or may have 1 or 2 sulfur atoms and 1 or 2 ═O groups,
R^FourIs-(D)_p-(E)_s-(F¹)_q-G¹-(F^Two)_r-(G^Two) -G ^Three And here G¹, G^TwoAnd G^ThreeCannot simultaneously be hydrogen or a bond,
G if p = s = 0 and q or r = 1 or p, q and r = 0 ¹ , G^TwoAnd G^ThreeTwo groups of cannot simultaneously bond or become hydrogen, D is S, NR⁴³Or may be O, E is phenyl,     [Chemical 2] -SO_Two-, -SO_TwoNH-, -NHCO-, -CONH-, NHSO_Two-,-
NHCOCH_TwoX^FourMay be X^FourMay be S, O or NH, F¹Is a linear or branched saturated or unsaturated carbon chain having 1 to 8 carbon atoms
May be F^TwoIs F¹Independent of and F¹May have the same meaning as described in G¹Is unsaturated, saturated or partially having up to 15 bonds or carbon atoms
Unsaturated mono-, bi- or tricyclic rings, up to 14 carbon atoms and 0 nitrogen atom
~ 5, 0-2 oxygen atoms and 0-2 sulfur atoms, unsaturated, saturated or
It may be a partially unsaturated mono-, bi- or tricyclic ring, which is
Up to 3 Rs that are additionally different or the same⁵Substituted with groups, carbon atoms or sulfur
It may have 1 or 2 atoms and 1 or 2 ═O groups, G^TwoIs NR⁴¹R⁴²Or     [Chemical 3] Or a join, G^ThreeIs an unsaturated, saturated or partially unsaturated monocyclic unit having up to 15 carbon atoms.
Rings, bicyclic or tricyclic rings, and up to 14 carbon atoms and 0 to 5 nitrogen atoms
, 0-2 oxygen atoms or 0-2 sulfur atoms, unsaturated, saturated or partial
May be an unsaturated mono-, bi- or tricyclic ring, each of which is an additional
And different or identical up to 3 R⁵Groups, and of carbon or sulfur atoms
1 or 2 may have 1 or 2 = O groups or are hydrogen atoms
, p may be 0 or 1, s may be 0 or 1, q may be 0 or 1, r may be 0 or 1, R⁴¹Is hydrogen, R for each carbon atom in addition to 2⁶C which may have a group₁ ~₆-Alkyl, additionally the group R₆A phenyl which may have up to two, and
(CH_Two)_t-May be K, R⁴²Is hydrogen, C₁~₆-Alkyl, -CO-R⁸, CO_Two-R⁸, SO_TwoN
H_Two, SO_Two-R⁸,-(C = N) -R⁸And-(C = N) -NHR⁸And
Well, R⁴³Is hydrogen or C₁~_Four-May be alkyl, t can be 1, 2, 3 or 4; K is NR¹¹R¹², NR¹¹-C₁~_Four-Alkylphenyl, pyrrolidine,
Piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidi
, Piperazine, which additionally has an alkyl group C₁~₆-Substituted with alkyl
And optionally an alkyl group C₁~₆-An optionally substituted alkyl
May be mopiperazine, R⁵Is hydrogen, chlorine, fluorine, bromine, iodine, OH, nitro, CF_Three, CN, N
R¹¹R¹², NH-CO-R^Thirteen, C₁~_Four-Alkyl-CO-NH-R^Thirteen , COR⁸, C₀~_Four-Alkyl-O-CO-R^Thirteen, C₁~_Four-Alkylfe
Nyl, phenyl, CO_Two-C₁~_Four-Alkyl, and branched or straight chain C1-6
-Alkyl, O-C1-4-alkyl, S-C₁~_Four-May be alkyl,
Where each C atom in the alkyl chain has up to two radicals R⁶May have an alkyl chain
May be unsaturated, R⁶Is hydrogen, chlorine, fluorine, bromine, iodine, branched or straight chain C₁~₆-Al
Kill, OH, nitro, CF_Three, CN, NR¹¹R¹², NH-CO-R^Thirteen, O
-C₁~_Four-May be alkyl, R⁷Is hydrogen, C₁~₆-Alkyl, may be phenyl, where the ring is additional
Up to 2 radicals R⁷¹, And one amine NR¹¹R¹²Have been replaced with
Or additionally an alkyl group C₁~₆3-7 optionally substituted with alkyl
Membered cyclic saturated amine, and additionally alkyl group C₁~₆-Substituted by alkyl
Which may be homopiperazine, Where K, R⁵, R⁶And R⁷R in¹¹, R¹²And R^ThirteenMutually independent
Stand up R¹May have the same meaning as R⁷¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoMay be R⁸Is C₁~₆-Alkyl, CF_Three, Phenyl, C₁~_Four-Alkylphenyl
Where the ring is optionally up to two radicals R⁸¹May be replaced with
R⁸¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoMay be R⁹Is hydrogen, C₁~₆-Alkyl, C₁~_Four-Alkylphenyl, CO_Two-C ₁ ~_Four-Alkylphenyl, CO_Two-C₁~_Four-Alkyl, SO_Two-Phenyl,
COR⁸And phenyl, wherein the phenyl ring is additionally up to two radicals R^{9 1} May be replaced with R⁹¹Is OH, C₁~₆-Alkyl, OC₁~_Four-Alkyl, chlorine, bromine,
Iodine, fluorine, CF_Three, Nitro, NH_TwoWhich may be
Mutant forms, possible enantiomeric and diastereomeric forms, and prods thereof
Rugg. 2. A compound of formula I according to claim 1, wherein A is an optionally substituted C ₂ chain, X ¹ is O and R ¹ is hydrogen. 3. B is an unsaturated, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring having at most 15 carbon atoms, at most 14 carbon atoms and 0 to nitrogen atoms. It may be an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring having 5, 0-2 oxygen atoms and 0-2 sulfur atoms, each of which is an additional Substituted with R ⁴ and up to 3 different or different R ⁵ groups,
3. A compound of formula I according to claim 1 or 2 having 1 or 2 carbon or sulfur atoms and 1 or 2 = 0 groups. 4. B is phenyl, cyclohexyl, piperidine, pyridine,
4. A pyrimidine, a pyrrole, a pyrazole, a thiophene, a furan, an oxazole, a naphthalene, a piperazine, a quinoline, a pyrazine, which may be additionally substituted by 1 R ⁴ or at most 2 R ^5. A compound of formula I as described. 5. R ⁴ is DF ^10, ₁ -G ² -G ³ , wherein G ³ is a hydrogen atom, D is O or NR ⁴³ , and R ⁴³ is alkyl, ^{F 1} _is, C 2 _{~ 4} - - hydrogen atom or _C 1 _{~ 3} alkyl, claim 4 compounds of the formula I as claimed. 6. A medicament containing a compound of formula I according to any one of claims 1 to 5 in addition to conventional carriers and excipients. 7. Use of a compound of general formula I according to any one of claims 1 to 5 for the manufacture of a medicament having PARP inhibitory action. 8. A method for producing a therapeutic agent for neurodegenerative diseases and neurological disorders,
Use of a compound of formula I according to claim 7. 9. Use according to claim 7 for the treatment of neurodegenerative diseases and neurological disorders caused by ischemia, trauma or massive hemorrhage. 10. Use according to claim 7 for treating stroke and head trauma. 11. Use according to claim 7 for treating Alzheimer's disease, Parkinson's disease and Huntington's disease. 12. Use of a compound of formula I according to claim 7 for the manufacture of a medicament for treating or preventing disorders caused by ischemia. 13. A method for the treatment of epilepsy, in particular for the manufacture of a systemic epileptic seizure, for example of small seizures and tonic-clonic seizures and focal seizures, eg temporal lobe epilepsy and complex / partial seizures. Use of a compound of formula I according to claim 7. 14. A formula I of claim 7 for the manufacture of a renal disorder after renal ischemia, a disorder caused by drug treatment, for example during cyclosporine treatment, and for the manufacture of a therapeutic agent during and after renal transplantation. Use of compounds. 15. A method for producing a therapeutic agent for a disorder of the heart after ischemic heart disease,
Use of a compound of formula I according to claim 7. 16. Use of a compound of formula I according to claim 7 for the manufacture of a therapeutic agent for microinfarction during and after heart valve replacement, aneurysm resection and heart transplantation. 17. A method for producing a therapeutic agent for revascularization of a severely stenotic coronary artery, such as PTCA and bypass surgery or revascularization of a severely stenotic peripheral artery, especially a leg artery. Use of a compound of formula I 18. Use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of acute myocardial infarction and disorders thereof during or after its pharmacological or mechanical resolution. 19. A method for producing a therapeutic agent for tumor and metastasis thereof, claim 7.
Use of the described compound of formula I. 20. Use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of multitissue septicemia, eg septic shock and acute respiratory distress syndrome. 21. Use of a compound of formula I according to claim 7 for the manufacture of a medicament for the treatment of immunodeficiency, eg inflammation, rheumatic disorders, eg rheumatoid arthritis. 22. Use of a compound of formula I according to claim 7 for the manufacture of a therapeutic agent for diabetes.