DE10021468A1 - Use of PARP inhibitors in cosmetic preparations - Google Patents

Abstract

The invention relates to the use of PARP inhibitors in cosmetic preparations, especially in after-sun lotions. The invention further relates to cosmetic preparations that contain a PARP inhibitor and a UV absorber.

Description

The present invention relates to the use of PARP Inhibitors in cosmetic preparations, especially Ver Use in after-sun creams. The invention also relates to cosmetic preparations containing a PARP inhibitor and a UV absorber included.

The human skin is subject to certain aging processes that partly on intrinsic processes (chronoaging) and partly exogenous factors (environmental, e.g. photoaging) are to be fed. In addition, temporary or also occur permanent changes in the appearance of the skin, such as acne, oily or dry skin, keratosis, rosaceae, photosensitive, inflammatory Leaky, erythematous, allergic or autoimmune-reactive reac such as dermatoses, photodermatoses and others, their exact Causes and factors that influence them are often incomplete are constantly understood.

The exogenous factors include, in particular, sunlight or artificial radiation sources with a comparable spectrum, as well Compounds that can arise from the radiation, such as undefined reactive photo products, which are also radical or can be ionic. These factors also include harm Liche or reactive compounds such as ozone, free radicals for example the hydroxyl radical, singlet oxygen and others reactive oxygen or nitrogen compounds, cigarettes smoke, natural and synthetic toxins, and others that disrupt natural physiology or morphology of the skin. By among other things, the influence of these factors leads to direct Damage to the DNA of the skin cells as well as the collagen, elastin or glycosaminoglycan molecules of the extracellular matrix which are responsible for the firmness of the skin. Furthermore are influenced signal transduction chains, at the end of which the Activation of matrix-degrading enzymes is available. Important representatives of these enzymes are the matrix metalloproteinases (MMPs, e.g. Collagenases, gelatinases, stromelysins), whose activity is additional by TIMPs (tissue inhibitor of matrix metalloproteinases) be regulated.

Furthermore, the harmful influences cause damage to the Cells of the skin itself. As a result, for example, Skin regeneration ability reduced.  

As a further consequence, inflammatory reactions can occur, among others, immunoregulatory compounds such as Inter Leukine, prostaglandins and histamines released. Thereby among other things, immunocompetent cells are attracted and the inflammatory response intensified.

The consequences of aging are thinning of the skin, weaker ver Teething of epidermis and dermis, reduction of the number of cells as well of the supplying blood vessels. Due to the aging process it will form fine lines and wrinkles on the skin leathery, yellowish and drooping, there are pigment disorders on.

Cosmetic or dermatological care products with your own the processes described or comparable processes counteract or reduce or reduce their harmful consequences common, are often characterized by specific characteristics stem from; among other things, they are radical-catching, anti oxidative, anti-inflammatory or moisturizing; she prevent or reduce the activity of the matrix-degrading Enzymes or regulate the new synthesis of collagen, or elastin Proteoglycans. In addition, there are numerous others Mechanisms of action conceivable.

It is known that sun exposure to a variety of things desired effects in the skin: erythema, photosensitivity sation and immunological changes are examples of pre weighing acute reactions during photo-aging and Carcino Represent genesis long-term effects. The processes of photoaging are qualitatively and quantitatively independent of the intrinsic skin aging. It is also known that according to Be radiation of the skin matrix-degrading enzymes, such as collagenases or Stromelysine, and that this induction is induced by low molecular weight compounds, such as. B. retinoic acids, reduced can be. Another effect of UV radiation is that Appearance of sunburn cells in the skin. This is what it is about are special, "dyskeratotic" keratinocytes, which in the further course may become apoptotic. One through UV radiation or processes induced by it, massive cell damage also leads to non-apoptotic Cell death. These necrotic processes induce or intensify in turn, the inflammatory response, as a result of which it takes other to reinforce the damage already described oxidative processes. The use of connections, that would positively influence these processes would therefore be extremely possible partial and entirely in the sense of a cosmetic or dermato logical application.  

Beatrix-Farkas and Szekeres showed that pretreatment of mouse skin with O- (3-piperidino-2-hydroxy-1-propyl) -nicotinic acid amidoxime dihydrochloride and subsequent, acute UV radiation with 2-fold MED, clinical and histological signs of sunburn prevented (2 ^nd European Congress of Pharmacology; Budapest, Hungary, 3-July 7, 1999.).

Surprisingly, it was found that

• a) the use of a PARP inhibitor after UV Irradiation in the sense of an after-sun product, and that
• b) by timely application of a PARP inhibitor keeping, topically applied formulation the formation an "active substance depot" in the sense of preconditioning before expected UV radiation

is possible in such a way that the skin from radiation-related Damage is protected.

Furthermore, it was not evident whether other skin-damaging ones were "Principles" as described above through use can be positively influenced by PARP inhibitors.

The present invention relates to manufacture and use cosmetic and dermatological preparations with an effective seed of a PARP inhibitor.

In particular, the present invention relates to cosmetic and dermatological preparations which offer effective protection

• - caused by radiation or reactive compounds Processes,

damage caused directly or indirectly by such processes, such as B.

• - skin aging,
• - loss of skin moisture,
• - loss of skin elasticity,
• - the formation of folds or wrinkles or
• - pigmentation disorders or age spots.

The beneficial effect is due to the fact that that the active ingredients used as PARP inhibitors unwanted cell death and the associated also unwanted subsequent reactions, such as. B. the inflammatory Reactions, prevent or reduce.

Furthermore, the present invention relates to active substances and preparations containing such active substances for cosmetic and dermatological treatment or prevention of undesired changes in the skin appearance, such as

• - acne or oily skin
• - keratoses
• - Rosaceae
• - photosensitive, inflammatory, erythematous, allergic or autoimmune reactive reactions

and others that have a positive effect through use can be achieved by PARP inhibitors.

Possible PARP inhibitors in the sense of the invention are the following Groups that include a non-exhaustive list. As far as the connections are new, the expert can known method can be synthesized. In particular, is on Referred to WO 97/04771.

The first group of PARP inhibitors relates to substituted 2-phenylbenzimidazoles of the general formula I or II

wherein
R ^{1 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, where a C atom of the alkyl radical can also carry OR ¹¹ or a group R ⁵ , where
R ^{11 is} hydrogen or C ₁ -C ₄ alkyl, and
R ^{2 is} hydrogen, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NHCOR ²¹ , NR ²² R ²³ , OH, OC ₁ -C ₄ alkyl, OC ₁ -C ₄ alkylphenyl, NH ₂ , phenyl, wherein the phenyl rings can be substituted with a maximum of two radicals R ²⁴ , and R ²¹ and R ²² independently of one another are hydrogen or C ₁ -C ₄ alkyl and R ^{23 is} hydrogen, C ₁ -C ₄ alkyl or phenyl , and R ²⁴ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
x can be 0, 1 and 2 and
R ³ denotes -D- (F ¹ ) _p - (E) _q - (F ² ) _r -G, where p, q and r cannot simultaneously be 0, or -E- (D) _u - (F ² ) s _- (G) _v , where the radical E can still be substituted by one or two radicals A, or R ³ is B and
R ^{4 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ⁴¹ R ⁴² , NH-CO-R ⁴³ , OC ₁ -C ₄ -Alkyl, where
R ⁴¹ and R ^{42 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{43 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl phenyl or phenyl, and
DS and O,
E phenyl, imidazole, pyrrole, thiophene, pyridine, pyrimidine, piperazine, pyrazine, furan, thiazole, isoxazole, pyrrolidine, piperidine, trihydroazepine and F ^{1 is} a chain of 1 to 8 carbon atoms, one carbon atom of the chain being another OH or Can carry OC ₁ -C ₄ alkyl group and
F ^{2 is} a chain of 1 to 8 carbon atoms, where a carbon atom of the chain can also carry an OH or OC ₁ -C ₄ alkyl group and
p can mean 0 and 1 and
q can be 0 and 1 and
r can be 0 and 1 and
s can be 0 and 1 and
u can be 0 and 1 and
v can be 0 and 1,
G NR ⁵¹ R ⁵² and

can be and
R ^{51 is} hydrogen and branched and unbranched C ₁ -C ₆ alkyl, (CH ₂ ) _t -K and
R ^{52 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, phenyl,

-SO ₂ R ⁵³ , - (C = N) -R ⁵³ , -CO-NHR ⁵³ , - (C = N) -NHR ⁵³ ,
wherein
R ⁵³ branched or unbranched OC ₁ -C ₆ alkyl, phenyl, branched or unbranched C ₁ -C ₄ alkyl phenyl, where in R ⁵² and R ⁵³ independently of one another a hydrogen of the C ₁ -C ₆ alkyl radical by one of the following radicals can be substituted: OH, OC ₁ -C ₄ alkyl, cyclohexyl, cyclopentyl, tetrahydronaphthyl, cyclopropyl, cyclobutyl, cycloheptyl, naphthyl and phenyl, the carbocycles of the radicals R ⁵² and R ^{53 being} independent of one another can carry two of the following radicals: branched or unbranched C ₁ -C ₆ alkyl, ver branched or unbranched OC ₁ -C ₄ alkyl, OH, F, Cl, Br, J, CF ₃ , NO ₂ , NH ₂ , CN , COOH, COOC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl amino, CCl ₃ , C ₁ -C ₄ dialkylamino, SO ₂ -C ₁ -C ₄ alkyl, SO ₂ phenyl, CONH ₂ , CONH -C ₁ -C ₄ alkyl, CONHPhenyl, CONH-C ₁ -C ₄ alkylphenyl, NHSO ₂ -C ₁ -C ₄ alkyl, NHSO ₂ phenyl, SC ₁ -C ₄ alkyl,

CHO, CH ₂ -OC ₁ -C ₄ alkyl, -CH ₂ OC ₁ -C ₄ alkylphenyl, -CH ₂ OH, -SO-C ₁ -C ₄ alkyl, -SO-C ₁ -C ₄ -Alkyl-phenyl, -SO ₂ NH ₂ , -SO ₂ NH- C ₁ -C ₄ alkyl
and two residues form a bridge -O- (CH ₂ ) _1,2 -O-,
can mean

can be and
A hydrogen, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, OH, OC ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl phenyl, NH ₂ , branched and unbranched C ₁ -C ₆ alkyl, CN, NH-CO-R ³³ , where R ³³ is hydrogen, C ₁ -C ₄ alkyl or phenyl, and can be
R ^{31 is} hydrogen, C ₁ -C ₆ alkyl, (CH ₂ ) _t -K and
R ^{32 is} hydrogen, C ₁ -C ₆ alkyl, -CO-R ⁸ , SO ₂ -R ⁸ , - (C = N) -R ⁸ , -CO-OR ⁸ , -CO-NHR ⁸ and - (C = N) -NHR ⁸ and
R ^{33 is} hydrogen and C ₁ -C ₄ alkyl and
t 0, 1, 2, 3, 4 and
K phenyl, which can carry a maximum of two radicals R, NR ^k1 R ^k2 (with R ^k1 or R ^k2 with the same meanings as R ⁴¹ or R ⁴² ), NH-C ₁ -C ₄ alkylphenyl, pyrrolidine , Piperidine, 1,2,5,6-tetrahydropyridine, morpholine, trihydroazepine, piperazine, which can still be substituted by an alkyl radical C ₁ -C ₆ -alkyl, and homopiperazine, which can still be substituted by an alkyl radical C ₁ - C ₆ alkyl may be substituted, and
R ^{5 is} hydrogen, C ₁ -C ₆ alkyl, NR ⁷ R ⁹ and

can mean and
R ^{7 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl, phenyl, where the ring can also be substituted by up to two radicals R ⁷¹ , and
R ⁷¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{8 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, C ₁ -C ₄ alkyl phenyl, where the ring can also be substituted by up to two radicals R ⁸¹ , and
R ⁸¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{9 is} hydrogen, COCH ₃ , CO-OC ₁ -C ₄ -alkyl, COCF ₃ , branched and unbranched C ₁ -C ₆ -alkyl, one or two hydrogens of the C ₁ -C ₆ -alkyl radical being replaced by one of the following radicals may be substituted: OH, OC ₁ -C ₄ alkyl and phenyl and the phenyl ring can also carry one or two of the following radicals: iodine, chlorine, bromine, fluorine, branched and unbranched C ₁ -C ₆ alkyl, nitro , Amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkyl amino, OH, OC ₁ -C ₄ alkyl, CN, CF ₃ , SO ₂ -C ₁ -C ₄ alkyl, and
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs and pharmacologically acceptable salts.

The compounds in which the radicals have the following meaning are preferred:
R ^{1 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, where a C atom of the alkyl radical can also carry OR ¹¹ or a group R ⁵ , where
R ^{11 is} hydrogen or C ₁ -C ₄ alkyl, and
R ^{2 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, nitro, CF ₃ , CN, NR ²¹ R ²² , NH-CO-R ²³ , OR ²¹ , where
R ²¹ and R ^{22 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{23 is} hydrogen, C ₁ -C ₄ alkyl or phenyl, and
R ³ -O- (CH ₂ ) _o - (CHR ³¹ ) _m - (CH ₂ ) _n -R ⁵ , where
R ^{31 is} hydrogen, C ₁ -C ₄ alkyl, OH and OC ₁ -C ₄ alkyl,
m, o independently of one another denotes 0, 1 or 2, and
n denotes 1, 2, 3 or 4, and
R ^{4 is} hydrogen, branched and unbranched C ₁ -C ₆ -alkyl, chlorine, bromine, fluorine, nitro, cyano, NR ⁴¹ R ⁴² , NH-CO-R ⁴³ , OR ⁴¹ , where R ⁴¹ and R ⁴² independently of one another are hydrogen or C ₁ -C ₄ alkyl and
R ^{43 is} C ₁ -C ₄ alkyl or phenyl, and
R ⁵ NR ⁵¹ R ⁵² or one of the following radicals

means where
R ^{51 is} hydrogen and branched and unbranched C ₁ -C ₆ alkyl and
R ^{52 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, phenyl,

-SO ₂ R ⁵³ , wherein
R ⁵³ branched or unbranched OC ₁ -C ₆ alkyl, phenyl, branched or unbranched C ₁ -C ₄ alkyl phenyl, where in R ⁵² and R ⁵³ independently of one another a hydrogen of the C ₁ -C ₆ alkyl radical through one of the the following radicals can be substituted: OH, OC ₁ -C ₄ alkyl, cyclohexyl, cyclopentyl, tetrahydronaphthyl, cyclopropyl, cyclobutyl, cycloheptyl, naphthyl and phenyl, the carbocycles of the radicals R ⁵² and R ⁵³ independently of one another or one of the can carry the following radicals: branched or unbranched C ₁ -C ₆ alkyl, branched or unbranched OC ₁ -C ₄ alkyl, OH, F, Cl, Br, J, CF ₃ , NO ₂ , NH ₂ , CN, COOH, COOC ₁ -C ₄ alkyl, C ₁ -C ₄ alkylamino, CCl ₃ , C ₁ -C ₄ dialkylamino, SO ₂ -C ₁ -C ₄ alkyl, SO ₂ phenyl, CONH ₂ , CONH-C ₁ - C ₄ alkyl, CONHPhenyl, CONH-C ₁ -C ₄ - alkyl-phenyl, NHSO ₂ -C ₁ -C ₄ alkyl, NHSO ₂ phenyl, SC ₁ -C ₄ alkyl,

CHO, CH ₂ -OC ₁ -C ₄ alkyl, -CH ₂ OC ₁ -C ₄ alkylphenyl, -CH ₂ OH, -SO-C ₁ -C ₄ alkyl, -SO-C ₁ -C ₄ -Alkyl-phenyl, -SO ₂ NH ₂ , -SO ₂ NH- C ₁ -C ₄ alkyl
and two radicals form a bridge -O- (CH ₂ ) _1,2 -O-.

Particularly preferred positions for the radical R ² in the general formula I or II are the 3-position and the 4-position relative to the benzimidazole ring. The 3-position or 4-position relative to the benzimidazole ring is also preferred for the radical R ³ .

The particularly preferred meaning of R ¹ is hydrogen.

The particularly preferred meaning of R ² is hydrogen, branched or unbranched C ₁ -C ₆ alkyl, nitro, CN, NH ₂ , OC ₁ -C ₄ alkyl.

The particularly preferred meaning of R ³ is -O- (CH ₂ ) _p -R ⁵ where p is 2, 3 or 4.
R ⁵ preferably denotes a 6-membered ring, in particular piperazine,
R ⁵² preferably denotes an optionally substituted phenyl ring, in particular if R ⁵ denotes a 6-membered ring.

The particularly preferred meaning of R ⁴ is hydrogen.

The respective combinations of are very particularly preferred preferred meanings above.

Compounds with the following meanings for the substituents are also preferred:
R ^{1 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, where a C atom of the alkyl radical can also carry OR ¹¹ or a group R ⁵ , where
R ^{11 is} hydrogen or C ₁ -C ₄ alkyl, and
R ^{2 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, nitro, CF ₃ , CN, NR ²¹ R ²² , NH-CO-R ²³ , OR ²¹ , where
R ²¹ and R ^{22 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{23 is} hydrogen, C ₁ -C ₄ alkyl or phenyl, and
R ³

and
R ^{31 is} hydrogen, CHO and - (CH ₂ ) _o - (CHR ³² ) _m - (CH ₂ ) _n -R ⁵ , where
R ^{32 is} hydrogen, C ₁ -C ₄ alkyl, OH and OC ₁ -C ₄ alkyl,
m, o is independently 0, 1 or 2 and
n denotes 1, 2, 3 or 4, and
R ^{4 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, chlorine, bromine, fluorine, nitro, cyano, NR ⁴¹ R ⁴² , NH-CO-R ⁴³ , OR ⁴¹ , where
R ⁴¹ and R ^{42 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{43 is} C ₁ -C ₄ alkyl or phenyl, and
R ⁵ NR ⁵¹ R ⁵² or one of the following radicals

in which
R ^{51 is} hydrogen and branched and unbranched C ₁ -C ₆ alkyl and
R ^{52 is} hydrogen, COCH ₃ , CO-OC ₁ -C ₄ -alkyl, COCF ₃ , ver branched and unbranched C ₁ -C ₆ -alkyl, a hydrogen of the C ₁ -C ₆ -alkyl radical being substituted by one of the following radicals can: OH, OC ₁ -C ₄ alkyl and phenyl and the phenyl ring can also carry one or two of the following radicals: chlorine, bromine, fluorine, branched and unbranched C ₁ -C ₄ alkyl, nitro, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, OH, OC ₁ -C ₄ alkyl, CN, SO ₂ -C ₁ -C ₄ alkyl.

Particularly preferred positions for the radical R ² in the general formula I or II are the 3-position and the 4-position relative to the benzimidazole ring. The 3-position or 4-position relative to the benzimidazole ring is also preferred for the radical R ³ .

The particularly preferred meaning of R ¹ is hydrogen.

The particularly preferred meaning of R ² is hydrogen, branched or unbranched C ₁ -C ₆ alkyl, nitro, CN, NH ₂ , OC ₁ -C ₄ alkyl. R ² is particularly preferably hydrogen.

The same for R ³

is the particularly preferred meaning of R ^{31 is} hydrogen or - (CH ₂ ) _p -R ⁵ , where
p represents 1 or 2 and
R ^{52 is} hydrogen, branched and unbranched C ₁ -C ₆ -alkyl, where a hydrogen of the C ₁ -C ₆ -alkyl radical can be substituted by one of the following radicals: OH, OC ₁ -C ₄ -alkyl and phenyl and the phenyl- Ring can carry one or two of the following radicals: chlorine, bromine, fluorine, branched and unbranched C ₁ -C ₄ alkyl, nitro, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, OH, OC ₁ -C ₄ alkyl, CN, SO ₂ -C ₁ -C ₄ alkyl.

The same for R ³

is the particularly preferred meaning of R ^{31 is} hydrogen or - (CH ₂ ) _p -R ⁵ , where
p is 1 or 2 and R ^{52 is} hydrogen, branched and unbranched C ₁ -C ₆ -alkyl, where a hydrogen of the C ₁ -C ₆ -alkyl radical can be substituted by one of the following radicals: OH, OC ₁ -C ₄ -alkyl and phenyl and the phenyl ring can also carry one or two of the following radicals: chlorine, bromine, fluorine, branched and unbranched C ₁ -C ₄ -alkyl, nitro, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, OH, OC ₁ -C ₄ alkyl, CN, SO ₂ -C ₁ -C ₄ alkyl.

The same for R ³

is the most preferred meaning of
R ^{52 is} hydrogen, branched and unbranched C ₁ -C ₆ -alkyl, where a hydrogen of the C ₁ -C ₆ -alkyl radical can be substituted by one of the following radicals: OH, OC ₁ -C ₄ -alkyl and phenyl and the phenyl- Ring can carry one or two of the following radicals: chlorine, bromine, fluorine, branched and unbranched C ₁ -C ₄ alkyl, nitro, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, OH, OC ₁ -C ₄ alkyl, CN, SO ₂ -C ₁ -C ₄ alkyl.

The particularly preferred meaning of R ⁴ is hydrogen.

The respective combinations of are very particularly preferred preferred meanings above.

The compounds of formula I can be used as racemates, as enantio pure compounds or as diastereomers. If enantiomerically pure compounds are desired, these can be used obtained, for example, by using a suitable optically active base or acid a classic resolution with the compounds of formula I or their intermediates performs.

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

The following individual connections are preferred:

example 1

2 (4 (2- (N, N-diethylamino) eth-1-yloxy) phenyl) benzimidazol-4- carboxamide

Example 2

2 (4 (2- (N, N-diethylamino) eth-1-yloxy) phenyl) benzimidazol-4- carboxamide × 2 hydrochloride

Example 3

2 (3 (2- (N, N-diethylamino) eth-1-yloxy) phenyl) benzimidazol-4- carboxamide

Example 4

2 (3 (2- (N, N-diethylamino) eth-1-yloxy) phenyl) benzimidazol-4- carboxamide × 2 hydrochloride

Example 5

2 (3 (2- (N, N-dimethylamino) eth-1-yloxy) phenyl) benzimidazol-4- carboxamide

Example 6

2 (3 (2- (N, N-Dimethylamino) eth-1-yloxy) -4-methoxyphenyl) benz imidazole-4-carboxamide  

Example 7

2 (3 (2- (N, N-Dimethylamino) eth-1-yloxy) -4-methoxyphenyl) benz imidazole-4-carboxamide × 2 HCl

Example 8

2 (2 (2- (N, N-dimethylamino) eth-1-yloxy) phenyl) benzimidazole-4- carboxamide × 2 HCl

Example 9

2 (3 (2- (N, N-dimethylamino) eth-1-yloxy) phenyl) benzimidazole-4- carboxamide × 2 hydrochloride

Example 10

2 (3 (3- (tert-Butoxycarbonylamino) prop-1-yloxy) phenyl) benz imidazole-4-carboxamide

Example 11

2 (3 (3- (tert-Butoxycarbonylamino) eth-1-yloxy) phenyl) benz imidazole-4-carboxamide

Example 12

2 (3 (3- (4 (3-chlorophenyl) piperazin-1-yl) prop-1-yloxy) phenyl) benz imidazole-4-carboxamide

Example 13

2 (3 (3- (N, N-diethylamino) prop-1-yloxy) phenyl) benzimidazole-4- carboxamide × 2 HCl

Example 14

2 (3 (3-aminoprop-1-yloxy) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 15

2 (3 (2-Aminoeth-1-yloxy) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 16

2 (4 (3- (N, N-diethylamino) prop-1-yloxy) phenyl) benzimidazole-4- carboxamide × 2 HCl

Example 17

1- (3 (N, N-diethylamino) prop-1-yl) -2 (4 (3- (N, N-diethylamino) prop- 1-yloxy) phenyl) benzimidazole-4-carboxamide × 2 HCl  

Example 18

2 (4 (2- (pyrrolidin-1-yl) eth-1-yloxy) phenyl) benzimidazole-4- carboxamide × 2 HCl

Example 19

1- (3 (Pyrrolidin-1-yl) -prop-1-yl) -2 (4 (2- (pyrrolidin-1-y1) -eth-1- yloxy) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 20

2 (4 (3 (N, N-benzylmethylamino) prop-1-yloxy) phenyl) benzimidazole 4-carboxamide × 2 HCl

Example 21

1 (3 (N, N-benzylmethylamino) prop-1-yl) -2 (4 (3 (N, N-benzylmethylam amino) prop-1-yloxy) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 22

2 (4 (3 (4-methylpiperazin-1-yl) prop-1-yloxy) phenyl) benzimidazole 4-carboxamide × 3 HCl

Example 23

2 (3 (2 (N, N-Benzylmethylamino) -eth-1-yloxy) -4-nitrophenyl) benz imidazole-4-carboxamide

Example 24

2 (4 (3-trifluoroacetamidomethyl-pyrrol-1-yl) phenyl) benzimidazole 4-carboxamide

Example 25

2 (4 (3-aminomethyl-pyrrol-1-yl) phenyl) benzimidazole-4-carboxylic acid reamid

Example 26

2 (4 (3-aminomethyl-pyrrol-1-yl) phenyl) benzimidazole-4-carboxylic acid reamid × 2 methanesulfonic acid

Example 27

2 (4 (1-imidazolyl) phenyl) benzimidazole-4-carboxamide

Example 28

2 (4 (1-imidazolyl) phenyl) benzimidazole-4-carboxamide × 2 methanesulfonic acid  

Example 29

2 (3 (3-trifluoroacetamidomethyl-pyrrol-1-yl) phenyl) benzimidazole 4-carboxamide

Example 30

2 (3 (3-aminomethyl-pyrrol-1-yl) phenyl) benzimidazole-4-carboxylic acid amid

Example 31

2 (4 (4-Methylpiperazin-1-yl) phenyl) benzimidazole-4-carboxamide

Example 32

2 (3 (2-trifluoroacetamidomethyl-pyrrol-1-yl) phenyl) benzimidazole 4-carboxamide

Example 33

2 (3 (3-formylpyrrol-1-yl) phenyl) benzimidazole-4-carboxamide

Example 34

2 (3 (3 (N, N-benzylmethylaminomethyl) pyrrol-1-yl) phenyl) benz imidazole-4-carboxamide × 2 HCl

Example 35

2 (3 (2-aminomethyl-pyrrol-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 36

2 (4 (4-Methylpiperazin-1-yl) phenyl) benzimidazole-4-carboxamide × 3 HCl

Example 37

2 (4 (4-tert-Butyloxypiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 38

2 (4 (piperazin-1-yl) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 39

2 (3 (2 (aminomethyl) pyrrol-1-yl) phenyl) benzimidazole-4-carbon acid amide × 2 HCl

Example 40

2 (4 (3-formylpyrrol-1-yl) phenyl) benzimidazole-4-carboxamide  

Example 41

2 (4 (3- (N, N-Benzylmethylaminomethyl) pyrrol-1-yl) phenyl) benz imidazole-4-carboxamide × 2 HCl

Example 42

2 (4 (3- (N, N-diethylaminomethyl) pyrrol-1-yl) phenyl) benzimidazole - 4-carboxamide × 2 HCl

Example 43

2 (4 (3- (4-Methylpiperazin-1-ylmethyl) pyrrol-1-yl) phenyl) benz imidazole-4-carboxamide

Example 44

2 (4 (3- (4-Benzylpiperazin-1-ylmethyl) pyrrol-1-yl) phenyl) benz imidazole-4-carboxamide

Example 45

2 (4 (3- (piperidin-1-ylmethyl) pyrrole-1-yl) phenyl) benzimidazole 4-carboxamide

Example 46

2 (4 (4-Benzylpiperazin-1-yl) phenyl) benzimidazole-4-carboxamide 3 × HCl

Example 47

2 (4 (4-Cyclohexylpiperazin-2-yl) phenyl) benzimidazole-4-carbon acid amide

Example 48

2 (4 (4-Ethylpiperazin-1-yl) phenyl) benzimidazole-4-carboxamide

Example 49

2 (4 (4-n-Butylpiperazin-1-yl) phenyl) benzimidazole-4-carboxylic acid amid

Example 50

2 (4 (4-Diphenylmethylpiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 51

2 (2-methyl-4-piperazin-1-yl-phenyl) benzimidazole-4-carboxylic acid amide 3 × HCl

Example 52

2 (3-piperazin-1-yl-phenyl) benzimidazole-4-carboxamide 3 × HCl  

Example 53

2 (4 (4-isopropylpiperazin-1-yl) phenyl) benzimidazole-4-carboxylic acid amid

Example 54

2 (4 (4-tert-butyloxycarbonylhomopiperazin-1-yl) phenyl) benz imidazole-4-carboxamide

Example 55

2 (4 (Homopiperazin-1-yl) phenyl) benzimidazole-4-carboxamide

Example 56

2 (4 (4- (piperidin-1-yl) piperidin-1-yl) phenyl) benzimidazol-4- carboxamide

Example 57

2 (4 (3-Amino-pyrroldin-1-yl) phenyl) benzimidazole-4-carboxamide × 2 HCl

Example 58

2 (4 (4-Benzyl-homopiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 59

2 (4 (4-methyl-homopiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 60

2 (4 (4-ethyl-homopiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 61

2 (4 (4-isopropyl-homopiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 62

2 (4 (4-butyl-homopiperazin-1-yl) phenyl) benzimidazole-4-carbon acid amide

Example 63

Synthesis of 2-phenylbenzimidazole-4-carboxamide

Another group of PARP inhibitors relates to substituted benzodiazepine derivatives of the general formula I.

wherein
A is a chain C ₁ -C ₃ , where each carbon atom can also carry one or two of the following substituents: C ₁ -C ₄ alkyl, OH, OC ₁ -C ₄ alkyl, COOH, COO-C ₁ -C _4- alkyl and phenyl or a carbon atom can also carry an = O group and
X ^{1 can be} S, O and NH and
X ^{2 is} a carbon atom that can still carry a chain C ₁ -C ₄ , and N and
X ^{3 can be} N and CR ² , where
R ^{2 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl, phenyl and
R ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ - Alkyl, where R ¹¹ and R ¹² independently of one another are hydrogen or C ₁ -C ₄ alkyl and R ¹³ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl phenyl or phenyl, and
B is an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms such as phenyl, naphthalene, tetrahydronaphthalene, indane, carbazole, fluorene, cyclohexane, an unsaturated, saturated or partially unsaturated mono-, bi - or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms such as, for example, pyridine, thiophene, quinoline, quinoxaline, furan, imidazole, pyrrole, indole, benzimidazole, pyrimidine, pyrazine, Benzofuran, benzothiophene, thiophene, quinaxoline and isoxazole, can mean, which are each still substituted with an R ⁴ and a maximum of 3 different or identical R ⁵ radicals, and
R ^{4 is} hydrogen and - (D) _p - (E) _s - (F ¹ ) _q -G ¹ - (F ² ) _r -G ² , where
DS, NR ⁴³ and O,
E phenyl and

-SO ₂ NH-, -NHSO ₂ -, -CONH-, -NHCO-, -SO ₂ - and
F ^{1 can be} a straight-chain or branched, saturated or unsaturated (one or more -C = C- or -C∼C-containing) carbon chain of 1 to 8 carbon atoms and
F ^{2 has} the same meaning as F ¹ independently of F ¹ ,
G ^{1 represents} a bond or an unsaturated, saturated or partially unsaturated mono-, bi- or tri cyclic ring with a maximum of 15 carbon atoms such as, for example, phenyl, naphthalene, tetrahydronaphthalene, indane, carbazole, fluorene, cyclohexane, an unsaturated, saturated or partially unsaturated mono-, bi- or tri-cyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms such as, for example, pyridine, thiophene, quinoline, quinoxaline, furan, imidazole, pyrrole, indole, Benzimidazole, pyrimidine, pyrazine, benzofuran, benzothiophene, thiophene, quinaxoline and isoxazole, mean, which are each still substituted with a maximum of 3 different or identical radicals R ⁵ , means and
G ² NR ⁴¹ R ⁴² and

or hydrogen
means and
p can mean 0 and 1 and
s 0 and 1 and
q can be 0 and 1 and
r can be 0 and 1,
R ^{41 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, which can carry a maximum of two radicals R ⁶ , and (CH ₂ ) _t -K and
R ^{42 is} hydrogen, C ₁ -C ₆ alkyl, -CO-R ⁸ , SO ₂ -R ⁸ , - (C = N) -R ⁸ and - (C = N) -NHR ⁸ and
R ^{43 is} hydrogen and C ₁ -C ₄ alkyl and
t 1, 2, 3, 4 and
K NR ¹¹ R ¹² , NR ¹¹ -C ₁ -C ₄ alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, piperazine, which is still with an alkyl radical C ₁ -C ₆ alkyl can be substituted, and homopiperazine, which can also be substituted with an alkyl radical C ₁ -C ₆ alkyl, and
R ⁵ hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ - Alkyl, phenyl,
R ⁶ hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ - Alkyl,
R ^{7 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, where the ring can also be substituted by up to two radicals R ⁷¹ , and an amine NR ¹¹ R ¹² or a cyclic saturated amine having 3 to 7 members, such as pyrrolidine, Piperidine, 1,2,5,6-tetrahydro pyridine, morpholine, homopiperidine, piperazine, which may still be substituted by an alkyl radical C ₁ -C ₆ -alkyl, and homopiperazine, which may also be substituted by an alkyl radical C ₁ - C ₆ alkyl may be substituted, and
where K, R ⁵ , R ⁶ and R ⁷ the radicals R ¹¹ , R ¹² and R ^{13 can} independently assume the same meaning as in R ¹ , and
R ⁷¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{8 is} C ₁ -C ₆ alkyl, phenyl, C ₁ -C ₄ alkyl phenyl, where the ring can also be substituted by up to two radicals R ⁸¹ , and
R ⁸¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{9 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl and phenyl, where the phenyl rings can also be substituted by up to two radicals R ⁹¹ , and
R ^{91 can be} OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ ,
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

The compounds of formula I are preferred, wherein
A is a C ₂ chain, which may be substituted, and
X ¹ O represents and
X ² and X ³ each represent an N atom, and
R ^{1 is} hydrogen and
all other variables have the above meaning.

The compounds of the formula I are particularly preferred, where
A is a C ₂ chain, which may be substituted, and
X ¹ O represents and
X ² and X ³ each represent an N atom, and
R ^{1 is} hydrogen and
B can be phenyl, cyclohexyl, piperidine, pyridine, pyrimidine, pyrazine, naphthalene, piperazine and quinoline.

The use of compounds of the general formula I for the production of medicaments with PARP-inhibiting activity is also claimed, where R ¹ , X ¹ and A have the same meaning as above, X ² and X ³ each represent a nitrogen atom and B Can represent hydrogen and an alkyl chain C ₁ -C ₆ .

Examples of this group of compounds are

example 1

2- (4 (4-methyl-piperazin-1-yl) phenyl) -5,6-dihydro-imidazo- [4,5,1-jk] [1,4] benzodiazepin-7 (4H) -one

Example 2

2- (4-nitrophenyl) -5,6-dihydro-imidazo [4,5,1-jk] [1,4] benzodi azepin-7 (4H) -one

Example 3

2- (4- (2-N, N-Diethylaminoeth-1-yloxy) phenyl) -5,6-dihydro imidazo [4,5,1-jk] [1,4] benzodiazepin-7 (4H) -one

Example 4

2- (4- (2-piperidin-1-yl-eth-1-yloxy) phenyl) -5,6-dihydro-imidazo- [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one

Example 5

2- (4- (N, N- (2-N, N-diethylaminoeth-1-yl) methylamino) phenyl) - 5,6-dihydro-imidazo [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one

Example 6

2- (4 (4 (tert-butyloxycarbonyl) piperazin-1-yl) phenyl) -5,6-di hydro-imidazole [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one

Example 7

2- (4 (4 (tert-butyloxycarbonyl) homopiperazin-1-yl) phenyl) - 5,6-dihydro-imidazole [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one

Example 8

2- (4 (homopiperazin-1-yl) phenyl) -5,6-dihydro-imidazole [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one

Example 9

2- (4 (4 (tert-butyloxycarbonyl) homopiperazin-1-yl) phenyl-5,6- dihydro-imidazo [4,5,1-jk] - [1,4] benzodiazepin-7 (4H) -one Trihydrochloride

Another group of PARP inhibitors relates to heterocyclic compounds of the general formula I.

wherein
either A ¹ or A ^{2 is} CONH ₂ and the other radical A ² or A ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ alkyl, and
X ^{1 can be} N and CR ² and
X ^{2 can be} independent of X ¹ , N and CR ² and
R ^{2 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl, phenyl and
R ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ alkyl, where R ¹¹ and R ¹² independently of one another are hydrogen or C1-C ₄ -alkyl and R ^{13 are} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl-phenyl or phenyl, and
B an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 15 carbon atoms, such as, for example, phenyl, naphthalene, tetrahydronaphthalene, indane, carbazole, fluorene, cyclohexane, an unsaturated, saturated or partially unsaturated mono-, bi- or tricyclic ring with a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms or 0 to 2 sulfur atoms such as pyridine, thiophene, quinoline, quinoxaline, furan, imidazole, pyrrole, indole, benzimidazole, pyrimidine, pyrazine , Benzofuran, benzothiophene, thiophene, quinaxoline and isoxazole, which can each be substituted by an R ⁴ and a maximum of 3 identical or different radicals R ⁵ , and
R ⁴ denotes hydrogen and - (D) _p - (E) _s - (F) _q -G, where
DS, NR ⁴³ and O,
E phenyl and
s 0 and 1 and
G NR ⁴¹ R ⁴² and

means and
p can mean 0 and 1 and
F can be a C ₁ -C ₈ alkyl chain and
q can be 0 and 1 and
R ^{41 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-phenyl, phenyl, where the rings can carry a maximum of two radicals R ⁶ , and (CH ₂ ) _r -H and
R ^{42 is} hydrogen, C ₁ -C ₆ alkyl, -CO-R ⁸ , SO ₂ -R ⁸ , - (C = N) -R ⁸ and - (C = N) -NHR ⁸ and
R ^{43 is} hydrogen and C ₁ -C ₄ alkyl and
r 1, 2, 3, 4 and H NR ¹¹ R ¹² , NR ¹¹ -C ₁ -C ₄ alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, morpholine, homopiperidine, homopiperazine, piperazine , which can still be substituted with a C ₁ -C ₆ alkyl radical or with a C ₁ -C ₆ alkyl phenyl radical and the phenyl ring can also be substituted with a maximum of two R ⁸¹ , and
R ^{5 is} hydrogen, chlorine, fluorine, bromine, iodine, C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ alkyl,
R ^{6 is} hydrogen, chlorine, fluorine, bromine, iodine, C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ alkyl,
R ^{7 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, where the ring can also be substituted with up to two identical or different radicals R ⁷¹ , and an amine NR ¹¹ R ¹² or a cyclic saturated amine having 3 to 7 members, such as pyrrolidine, piperidine, etc., and
R ⁷¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{8 is} C ₁ -C ₆ alkyl, phenyl, C ₁ -C ₄ alkyl phenyl, where the ring can also be substituted by up to two radicals R ⁸¹ , and
R ⁸¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{9 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl and phenyl, where the phenyl rings can also be substituted by up to two identical or different radicals R ⁹¹ , and
R ^{91 can be} OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro and NH ₂ ,
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

The radicals R ¹¹ , R ¹² and R ¹³ can assume the different meanings independently of one another and irrespective of the respective meaning in the case of another radical (for example A ¹ , R ¹ , R ⁵ etc.).

C _x -C _y alkyl is always understood to mean, as far as possible, branched and unbranched C _x -C _y alkyl.

The compounds of formula I are preferred, wherein
X ^{1 represents} an N atom and
X ^{2 represents} CH and
R ^{1 is} hydrogen and
A ^{1 represents} CONH ₂ and
A ^{2 represents} hydrogen and
all other variables have the above meaning.

The compounds of the formula I are particularly preferred, where
X ^{1 represents} an N atom and
X ^{2 represents} CH and
R ^{1 is} hydrogen and
A ^{1 represents} CONH ₂ and
A ^{2 represents} hydrogen and
B represents phenyl, pyridine or piperidine, each of which may also be substituted by a radical R ⁴ and R ⁵ and
all other variables have the above meaning.

Examples of this group are:

example 1

2-phenyl-imidazo [1,2-a] pyridine-8-carboxamide

Example 2

2- (4-Nitrophenyl-imidazo [1,2-a] pyridine-8-carboxamide

Example 3

2- (4-aminophenyl) imidazo [1,2-a] pyridine-8-carboxamide

Example 4

2- (2-benzothienyl) imidazo [1,2-a] pyridine-8-carboxamide

Another group of PARP inhibitors are substituted phthalazines of the general formula I.

wherein
R ^{1 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ Alkyl, where R ¹¹ and R ¹² independently of one another are hydrogen or C ₁ -C ₄ alkyl and R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylphenyl or phenyl, and
A ^{1 is} a straight-chain or branched C ₀ -C ₆ alkyl radical and
A ² NR ² , NR ² -C ₁ -C ₆ alkyl-, O and S and
R ^{2 is} hydrogen and C ₁ -C ₆ alkyl and
A ^{3 is} an aromatic or heteroaromatic one or two-membered ring, each with 5 or 6 ring atoms and up to 3 heteroatoms, selected from N, O, S, such as, for example, phenyl, thiophene, pyridine, pyrimidine, naphthalene, indole, imidazole, the can be substituted with R ⁴ and one or two R ³ , where R ^{3 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , SO ₂ NR ¹¹ R ¹² , SO ₂ -C ₁ -C ₄ alkyl, SC ₁ -C ₄ alkyl, O-Ph, O-CF ₃ , NH-CO-R ¹³ , OC ₁ -C ₄ alkyl , where R ¹¹ and R ¹² independently of one another are hydrogen or C ₁ -C ₄ alkyl and R ^{13 can} be hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylphenyl or phenyl,
R ^{4 is} hydrogen, (X) _0.1 -C ₁ -C ₄ alkyl-NR ⁴¹ R ⁴² , where X = O, S and NR ⁴³ and R ⁴¹ and R ^{42 are} independently hydrogen, C ₁ -C ₆ alkyl Can be C ₁ -C ₄ alkylphenyl and a cyclic amine of 3 to 7 members and R ^{43 can be} hydrogen and C ₁ -C ₄ alkyl,
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

Examples of this group are:

example 1

4 (N (4-hydroxyphenyl) aminomethyl) -2H-phthalazin-1-one

Example 2

4 (N (4-N, N-dimethylsulfamoyl) phenylaminomethyl) -2H-phthalazine- 1-on

Example 3

4 (N (4-chlorophenyl) aminomethyl) -2H-phthalazin-1-one

Example 4

4 (N-phenyl) aminomethyl-2H-phthalazin-1-one

Example 5

4 (N (3-trifluoromethyl-phenyl) aminomethyl) -2H-phthalazin-1-one

Example 6

4 (N (2-cyanophenyl) aminomethyl) -2H-phthalazin-1-one

Example 7

4 (N (4-methoxyphenyl) aminomethyl) -2H-phthalazin-1-one  

Example 8

4 (N (2,4-dichlorophenyl) aminomethyl-2H-phthalazin-1-one

Example 9

4 (N (4-nitrophenyl) aminomethyl) -2H-phthalazin-1-one

Example 10

4- (N (3-methylmercapto-phenyl) aminomethyl) -2H-phthalazin-1-one

Example 11

4 (N (2,4-difluorophenyl) aminomethyl) -2H-phthalazin-1-one

Example 12

4 (N (4-phenoxyphenyl) aminomethyl) -2H-phthalazin-1-one

Example 13

4 (N (4-trifluoromethoxy-phenyl) aminomethyl) -2H-phthalazin-1-one

Example 14

4 (N (4-trifluoromethyl-phenyl) aminomethyl-2H-phthalazin-1-one

Example 15

4 (N-methyl-N-phenylaminomethyl) -2H-phthalazin-1-one × HCl

Example 16

4 (S (4-chlorophenyl) mercaptomethyl) -2H-phthalazin-1-one

Example 17

4 (S (1-methylimidazol-2-yl) mercaptomethyl) -2H-phthalazin-1-one

Example 18

4 (N (5-methylmercapto-1,3,4-triazol-2-yl) aminomethyl) -2H- phthalazin-1-one

Example 19

4 (S (2-pyridyl) mercaptomethyl) -2H-phthalazin-1-one

Another group of PARP inhibitors are substituted benzimidazoles of the general formulas I and II

wherein
A means naphthalene, aromatic heteromonocycle, aromatic or partially aromatic heterobicyclic and heterotricyclic, where the ring systems contain a maximum of 15 carbon atoms and up to 4 heteroatoms selected from the group N, O, S and can additionally carry up to 2 oxo groups and Ac with up to can be substituted to three different or identical radicals R ³ and additionally a radical R ⁴ and
R ¹ hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ - Alkyl, where R ¹¹ and R ¹² independently of one another are hydrogen or C ₁ -C ₄ alkyl and R ¹³ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl phenyl or phenyl, and
R ^{2 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl and
R ^{3 is} hydrogen, chlorine, bromine, iodine, fluorine, CF ₃ , OCF ₃ , nitro, NH ₂ , CO-R ⁸ , CO ₂ -R ⁸ , SO ₂ -R ⁸ , OH, OC ₁ -C ₄ alkyl, OC ₀ -C ₄ alkylphenyl, a C ₁ -C ₆ chain which can be saturated, unsaturated or partially unsaturated, and can also be substituted by a radical R ³³ , phenyl, the phenyl rings also having up to three identical or different radicals R ³¹ can be substituted, and pyridyl, can be substituted with up to three radicals R ³² , and
R ³¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ³² OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , CN, and
R ³³ CO-NH-R ⁸ , OH, OC ₁ -C ₆ alkyl, O-CO-R ⁸ , and
R ^{4 means} - (D) _p - (E) _s - (CH ₂ ) _q -B, where
DS, NR ⁴³ and O,
E phenyl and
s 0 and 1 and
B NR ⁴¹ R ⁴² and

means where
p can mean 0 and 1 and
q can be 0, 1, 2, 3 or 4, and
R ^{41 is} hydrogen, C ₁ -C ₆ alkyl, (CH ₂ ) _r -G and
R ^{42 is} hydrogen, C ₁ -C ₆ alkyl, -CO-R ⁸ , SO ₂ -R ⁸ , CO ₂ -R ⁸ , - (C = N) -R ⁸ and - (C = N) -NHR ⁸ and
R ⁴¹ and R ⁴² can form a phthaloyl radical and
R ^{43 is} hydrogen and C ₁ -C ₄ alkyl and
r 0, 1, 2, 3, 4 and
G phenyl, which can carry a maximum of two radicals R, NR ¹¹ R ¹² , NH-C ₁ -C ₄ -alkylphenyl, pyrrolidine, piperidine, 1,2,5,6-tetra hydropyridine, morpholine, homopiperidine, piperazine, which can also be substituted by an alkyl radical C ₁ -C ₆ alkyl, and homopiperazine, which can still be substituted by an alkyl radical C ₁ -C ₆ alkyl, and
R ^{7 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, where the ring can also be substituted by up to two radicals R ⁷¹ , and
R ⁷¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{8 is} C ₁ -C ₆ alkyl, CF ₃ , NR ¹¹ R ¹² , phenyl, C ₁ -C ₄ alkyl phenyl, where the ring can also be substituted by up to two radicals R ⁸¹ , and
R ⁸¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
R ^{9 is} hydrogen, CO-R ⁸ , SO ₂ -R ⁸ , CO ₂ -R ⁸ , C ₁ -C ₆ alkyl, C ₁ -C ₄ alkylphenyl and phenyl, the phenyl rings also containing up to two R ⁹¹ radicals can be substituted, and
R ^{91 can be} OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NH ₂ , and
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, and their prodrugs.

The compounds of the formula I and II are preferred, wherein
R ^{1 is} hydrogen and
R ^{2 is} hydrogen and C ₁ -C ₄ alkyl and
D NR ⁴³ and O and
p 0 and 1 and s 0 and q 0, 1 and 2 if p = 0, or q 2 and 3 if p = 1, and
R ⁴² and R ⁴³ , independently of one another, are hydrogen and C ₁ -C ₄ -alkyl and
R ^{7 is} hydrogen and phenyl and
R ^{9 can be} hydrogen, C ₁ -C ₄ alkyl and C ₀ -C ₄ alkyl phenyl.

Preferred meaning of A are indole, benzimidazole, pyrrole, Imidazole, furan, thiophene, benzothiophene, benzofuran, pyrazole, Thiazole, benzothiazole, phthalimide, indazole, benzotriazole, Phthalizine indoline, isoindoline, pyridine, quinoline, pyrimidine, Pyridazine, isoquinoline, quinoxaline, quinazoline, naphthalene, iso oxazole, oxazole, imidazopyridine, pyrazine.

Compounds of the formula I and II are preferred, where A has the following meaning:
Pyridine, thiophene, thiazole, furan, indole, oxazole, pyrazole, pyrrole, benzofuran, imidazole, benzothiophene, isoxazole, pyrazine, pyrimidine, pyridazine, quinoline, and the heterocycle can be substituted with up to three radicals R ³ and one radical R ⁴ , in which
R ^{3 is} hydrogen, chlorine, bromine, iodine, fluorine, COR ⁸ , CO ₂ R ⁸ , SO ₂ R ⁸ , a C ₁ -C ₆ chain which can be saturated, unsaturated or partially unsaturated, and also with one group O-CO-R ⁸ can be substituted, C ₁ -C ₆ alkylphenyl, phenyl, where the phenyl rings can also be substituted with up to three identical or different radicals R ³¹ , and pyridyl, with up to three radicals R ³² can be substituted, and
R ^{4 is} hydrogen and (D) _p - (E) _s - (CH ₂ ) _q -B, and R ³ and R ^{4 are} not simultaneously hydrogen.

Compounds according to formulas I and II are preferred, where A has the following meaning:
Pyridine, pyrazine, pyrimidine, pyridazine, quinoline, thiazole, thiophene, pyrrole and pyrazole and the heterocycle can be substituted by a radical R ³ and a radical R ⁴ , where
R ^{3 is} hydrogen, chlorine, bromine, iodine, fluorine, C ₁ -C ₄ alkyl, and
R ^{4 is} (D) _p - (E) _s - (CH ₂ ) _q -B.

Compounds according to formulas I and II are particularly preferred, where A can be pyridine, thiophene and thiazole and the heterocycle is substituted with a radical R ⁴ , where R ^{4 is} (D) _p - (E) _s - (CH ₂ ) _q -B and R ^{3 is} hydrogen.

Examples of this group are:

example 1

2-pyridin-4-yl-benzimidazole-4-carboxamide

Example 2

2-pyridin-4-yl-benzimidazole-4-carboxamide × 2 methanesulfone acid

Example 3

2- (benzimidazol-5-yl) benzimidazole-4-carboxamide

Example 4

2- (1- (2 (N, N-Diethylamino) -1-ethyl) benzimidazol-5-yl) benz imidazole-4-carboxamide × 3 HCl

Example 5

2- (1 (2 (N, N-diethylamino) eth-1-yl) indol-3-yl) benzimidazol-4- carboxamide

Example 6

2- (pyrazin-2-yl) benzimidazole-4-carboxamide

Example 7

2- (quinolin-6-yl) benzimidazole-4-carboxamide  

Example 8

2- (1- (2- (N, N-diethylamino) eth-1-yl) pyrrol-3-yl) benzimidazole 4-carboxamide

Example 9

2- (1- (N, N-Dimethylamino) -naphthalen-4-yl) -benzimidazole-4-carbon acid amide × HCl

Example 10

2-pyridin-3-yl-benzimidazole-4-carboxamide

Example 11

2- (2-aminomethylthiazol-4-yl) benzimidazole-4-carboxylic acid amide × HCl

Example 12

2-isoxazol-5-yl-benzimidazole-4-carboxamide

Example 13

2- (2- (2- (N, N-Diethylamino) eth-1-yl-amino) -pyridin-3-yl) benz imidazole-4-carboxamide × 2 HCl

Example 14

2- (2 - ((2- (N, N-Diethylamino) -eth-1-yl) -methylamino) -pyridin-3-yl) - benzimidazole-4-carboxamide × 2 HCl

Example 15

2- (6 - ((2- (N, N-Diethylamino) -eth-1-yl) -methylamino) -pyridin-3-yl) - benzimidazole-4-carboxamide × 2 HCl

Example 16

2- (6- (4-propyl-piperazin-1-yl) pyridin-3-yl) benzimidazol-4- carboxamide

Example 17

2- (2- (3- (N, N-Diethylamino) prop-1-ylamino) pyridin-3-yl) benz imidazole-4-carboxamide × 2 HCl

Example 18

2- (3-Amino-thiophene-4-yl) benzimidazole-4-carboxamide × HCl

Example 19

2- (2- (2- (N, N-Diethylamino) -eth-1-yl-oxy) -pyridin-3-yl) -benz imidazole-4-carboxamide × HCl  

Example 20

2- (1-phenylsulfonyl) pyrrol-3-yl-benzimidazole-4-carboxamide

Example 21

2-pyrrol-3-yl-benzimidazole-4-carboxamide

Example 22

2- (2-methylimidazo [1,5-a] pyridin-8-yl) benzimidazole-4-carbon acid amide

Example 23

2- (pyrazol-4-yl) benzimidazole-4-carboxamide

Example 24

2- (2- (3- (N, N-Diethylamino) prop-1-ylamino) pyridin-4-yl) benz imidazole-4-carboxamide

Example 25

2- (2 - ((2- (N, N-Diethylamino) -eth-1-yl) -methylamino) -pyridin-4-yl) - benzimidazole-4-carboxamide × ½ fumaric acid

Example 26

2- (2- (2- (N, N-Diethylamino) eth-1-yl-amino) -pyridin-4-yl) benz imidazole-4-carboxamide × 2 HCl

Example 27

2- (2- (2- (Pyrrolidin-1-yl) -eth-1-yl-amino) -pyridin-4-yl) benz imidazole-4-carboxamide

Example 28

2- (2- (3- (4-Methyl-piperazin-1-yl) -prop-1-yl-amino) -pyridin-4-yl) - benzimidazole-4-carboxamide × 2 fumaric acid

Example 29

2- (6- (2- (Pyrrolidin-1-yl) -eth-1-yl-amino) -pyridin-2-yl) benz imidazole-4-carboxamide

Example 30

2- (6- (3- (N, N-Diethylamino) prop-1-ylamino) pyridin-2-yl) benz imidazole-4-carboxamide

Example 31

2- (6- (2- (N, N-Diethylamino) eth-1-yl-amino) -pyridin-2-yl) benz imidazole-4-carboxamide × ½ fumaric acid  

Example 32

2- (6- (3- (4-Methyl-piperazin-1-yl) -prop-1-yl-amino) -pyridin-2-yl) - benzimidazole-4-carboxamide

Example 33

2- (6- (2 - ((N, N-Diethylamino) -eth-1-yl) -methylamino) -pyridin-2-yl) - benzimidazole-4-carboxamide × 3 fumaric acid

Example 34

2- (6- (4-phenyl-piperazin-1-yl) pyridin-3-yl) benzimidazol-4- carboxamide × 2 HCl

Example 35

2- (6- (4-Benzylpiperazin-1-yl) pyridin-3-yl) benzimidazol-4- carboxamide × 2 HCl

Example 36

2- (6- (4-tert-Butylpiperazin-1-yl) pyridin-3-yl) benzimida zol-4-carboxamide

Example 37

2- (6- (4-n-butyl) piperazin-1-yl-pyridin-3-yl) benzimidazol-4- carboxamide × HCl

Example 38

2- (6- (piperidin-1-yl) pyridin-3-yl) benzimidazole-4-carboxylic acid amid

Example 39

2- (6- (Pyrrolidin-1-yl) pyridin-3-yl) benzimidazole-4-carboxylic acid amid

Example 40

2- (6- (2- (Pyrrolidin-1-yl) -eth-1-yl-amino) -pyridin-3-yl) benz imidazole-4-carboxamide

Example 41

2- (6- (piperazin-1-yl) pyridin-3-yl) benzimidazole-4-carboxylic acid amid

Example 42

2- (6- (4-methyl-piperazin-1-yl) pyridin-3-yl) benzimidazol-4- carboxamide  

Example 43

2- (6- (4-ethylpiperazin-1-yl) pyridin-3-yl) benzimidazol-4- carboxamide

Example 44

2- (6- (2- (Piperidin-1-yl) -eth-1-yl-amino) -pyridin-3-yl) benz imidazole-4-carboxamide

Example 45

2- (6- (3- (N, N-Dimethylamino) prop-1-ylamino) pyridin-3-yl) benz imidazole-4-carboxamide

Example 46

2- (6- (3- (4-Methylpiperazin-1-yl) -prop-1-yl-amino) -pyridin-3-yl) - benzimidazole-4-carboxamide

Example 47

2- (6- (2- (N, N-Diethylamino) -eth-1-yl-amino) -pyridin-3-yl) benz imidazole-4-carboxamide

Example 48

2- (6- (2- (N, N-Diethylamino) -eth-1-yl-oxy) -pyridin-2-yl) benz imidazole-4-carboxamide × fumaric acid

Example 49

2- (6 - ((2- (piperidin-1-yl) -eth-1-yl) -oxy) -pyridin-2-yl) benz imidazole-4-carboxamide

Example 50

2- (6 - ((3- (N-Benzyl-, N-methylamino) prop-1-yl) oxy) pyridine - 2-yl) benzimidazole-4-carboxamide

Example 51

2- (6 - ((3- (N, N-Diethylamino) prop-1-yl) oxy) pyridin-2-yl) benz imidazole-4-carboxamide

Example 52

2- (6 - ((3- (4-methyl-piperazin-1-yl) -prop-1-yl) -oxy) -pyridine- 2-yl) benzimidazole-4-carboxamide × 2 fumaric acid

Example 53

2- (6 - ((3- (N, N-Diethylamino) prop-1-yl) oxy) pyridin-3-y1) benz imidazole-4-carboxamide × HCl

Example 54

2- (6- (Benzyl-oxy) pyridin-3-yl) benzimidazole-4-carboxamide  

Example 55

2- (6 - ((3- (N-Benzyl-, N-methylamino) prop-1-yl) oxy) pyridine - 3-yl) benzimidazole-4-carboxamide

Example 56

2- (6 - ((3- (4-methyl-piperazin-1-yl) -prop-1-yl) -oxy) -pyridine- 3-yl) benzimidazole-4-carboxamide

Example 57

2- (6 - ((2-piperidin-eth-1-yl) -oxy) -pyridin-3-yl) -benzimidazole- 4-carboxamide

Example 58

2- (6 - ((2- (N, N-Diethylamino) -eth-1-yl) -oxy) -pyridin-3-yl) benz imidazole-4-carboxamide

Example 59

2- (6- (4-benzylaminophenyloxy) pyridin-3-yl) benzimidazol-4- carboxamide

Example 60

2- (2- (4-methylphenyl) oxazol-4-yl) benzimidazole-4-carboxylic acid amid

Example 61

2- (1- (4-fluorophenyl) -5-methyl-pyrazol-4-yl) benzimidazole - 4-carboxamide

Example 62

2- (1- (4-chlorophenyl) pyrazol-5-yl) benzimidazole-4-carboxylic acid amid

Example 63

2- (2- (4-chlorophenyl) oxazol-4-yl) benzimidazole-4-carboxamide
MS: m / e = 340 (M ⁺ + H)

Example 64

2- (3-propyl-isoxazol-5-yl) benzimidazole-4-carboxamide

Example 65

2- (3-ethyloxycarbonyl-pyrazol-5-yl) benzimidazole-4-carboxylic acid amid

Example 66

2- (1- (4-bromophenyl) pyrrol-3-yl) benzimidazole-4-carboxamide  

Example 67

2 - ((5-Acetyloxymethyl) furan-2-yl) benzimidazole-4-carboxamide

Example 68

2- (N-methylindol-3-yl) benzimidazole-4-carboxamide

Example 69

2-pyrrol-2-yl-benzimidazole-4-carboxamide

Example 70

2- (2-methyl-5-nitro-indol-3-yl) benzimidazole-4-carboxamide

Example 71

2- (N-acetylindol-3-yl) benzimidazole-4-carboxamide

Example 72

2- (5-chloroindol-3-yl) benzimidazole-4-carboxamide

Example 73

2- (1- (4-methoxyphenyl) pyrrol-3-yl) benzimidazole-4-carboxylic acid amid

Example 74

2- (1,2,5-trimethyl-pyrrol-3-yl) benzimidazole-4-carboxamide

Example 75

2- (2-methylindol-3-yl) benzimidazole-4-carboxamide

Example 76

2- (3-phenyl-pyrazol-4-yl) benzimidazole-4-carboxamide

Example 77

2- (6-methoxycarbonyl-indol-3-yl) benzimidazole-4-carboxamide

Example 78

2- (2-ethylimidazol-4-yl) benzimidazole-4-carboxamide

Example 79

2- (4- (2,6-difluorophenyl-1-carbonyl) -1-methyl-pyrrol-2-yl) benz imidazole-4-carboxamide

Example 80

2- (4- (4-Fluorophenyl-1-carbonyl) -1-methyl-pyrrol-2-yl) benz imidazole-4-carboxamide  

Example 81

2- (1-methyl-4- (phenyl-1-carbonyl) -pyrrol-2-yl) -benzimidazole- 4-carboxamide

Example 82

2- (1- (4-chlorophenyl) pyrrol-3-yl) benzimidazole-4-carboxamide

Example 83

2- (2- (2,4-dichlorophenyl) oxazol-4-yl) benzimidazole-4-carbon acid amide

Example 84

2- (1- (2,4-dichlorophenyl) -5-methyl-pyrazol-4-yl) benzimidazole - 4-carboxamide

Example 85

2- (2,5-dibromothiophen-3-yl) benzimidazole-4-carboxamide

Example 86

2- (2-phenyl-oxazol-4-yl) benzimidazole-4-carboxamide

Example 87

2- (3-hydroxy-5-hydroxyethyl-2-methyl-pyridin-4-yl) benzimidazole - 4-carboxamide

Example 88

2- (1- (2,3,4-trichlorophenyl) pyrrol-3-yl) benzimidazole-4-carbon acid amide

Example 89

2- (indol-3-yl) benzimidazole-4-carboxamide

Example 90

2- (1- (4-chloro-2-nitro-phenyl) pyrrol-3-yl) benzimidazole-4-carbon acid amide

Example 91

2- (6-methyl-pyridin-2-yl) benzimidazole-4-carboxamide

Example 92

2- (1- (benzylamino-carbonyl-methyl) -pyrrol-2-yl) -benzimidazole- 4-carboxamide

Example 93

2- (4-methyl-5- (4-trifluoromethylphenyl) isoxazol-3-yl) benz imidazole-4-carboxamide  

Example 94

2- (1-phenyl-pyrazol-4-yl) benzimidazole-4-carboxamide

Example 95

2- (1- (4-chlorophenyl) pyrazol-4-yl) benzimidazole-4-carboxylic acid amid

Example 96

2- (5-methyl-1-phenyl-pyrazol-4-yl) benzimidazole-4-carboxamide

Example 97

2- (1- (3-cyano-4-methoxy-pyridin-2-yl) pyrrol-2-yl) benzimidazole 4-carboxamide

Example 98

2- (1- (4-Tolylsulfonyl) indol-3-yl) benzimidazole-4-carboxamide

Example 99

2- (5-methoxy-indol-3-yl) benzimidazole-4-carboxamide

Example 100

2- (2-phenyl-imidazol-4-yl) benzimidazole-4-carboxamide

Example 101

2- (1- (2-nitro-phenylsulfonyl) pyrrol-2-yl) benzimidazole 4-carboxamide

Example 102

2- (4-bromo-1- (4-chlorophenylmethyl) pyrazol-5-yl) benzimidazole 4-carboxamide

Example 103

2- (2- (4-fluoro-phenyl-carbonyl) -benzofuran-5-yl) -benzimidazole- 4-carboxamide

Example 104

2- (1- (2,4-difluorophenylsulfonyl) pyrrol-2-yl) benzimidazole 4-carboxamide

Example 105

2- (1- (4-methylphenyl) pyrrol-2-yl) benzimidazole-4-carboxylic acid amid

Example 106

2- (4- (4-chlorophenylcarbonyl) -1-methyl-pyrrol-2-yl) benz imidazole-4-carboxamide  

Example 107

2- (2- (4-fluoro-phenyl) indol-3-yl) benzimidazole-4-carboxamide

Example 108

2- (3,7-dichloro-quinolin-8-yl) benzimidazole-4-carboxamide

Example 109

2- (5-chloro-3-methyl-1-phenyl-pyrazol-4-yl) benzimidazole-4-carbon acid amide

Example 110

2- (5-methyl-furan-2-yl) benzimidazole-4-carboxamide

Example 111

2- (1- (2-chlorophenyl) -5-trifluoromethyl-pyrazol-4-yl) benz imidazole-4-carboxamide

Example 112

2- (1- (2,4-dichlorophenyl) -5-trifluoromethyl-pyrazol-4-yl) benz imidazole-4-carboxamide

Example 113

2- (1-tert-butyl-pyrazol-4-yl) benzimidazole-4-carboxamide

Example 114

2- (5-methyl-imidazol-4-yl) benzimidazole-4-carboxamide

Example 115

2- (4-chloro-5-nitro-benzothiophene-2-yl) benzimidazole-4-carbon acid amide

Example 116

2- (1-dimethylamino-3-methoxy-isoquinolin-4-yl) benzimidazole 4-carboxamide

Example 117

2- (1-phthalimido-butyl-indol-3-yl) benzimidazole-4-carboxamide

Example 118

2- (1-methyl-pyrazol-4-yl) benzimidazole-4-carboxamide

Example 119

2- (2- (2,6-dimethylphenyl) pyrrol-3-yl) benzimidazole-4-carbon acid amide  

Example 120

2- (2-Dimethylamino-thiazol-5-yl -) - benzimidazole-4-carboxamide

Example 121

2- (1-tert-butyl-pyrrol-3-yl) benzimidazole-4-carboxamide

Example 122

2- (3-but-2-yl-isoxazol-5-yl) benzimidazole-4-carboxamide

Example 123

2- (3-iso-butyl-isoxazol-5-yl) benzimidazole-4-carboxamide

Example 124

2- (3- (4-tert-Butylphenyl) isoxazol-5-yl) benzimidazole-4-carbon acid amide

Example 125

2- (3-tert-butyl-isoxazol-5-yl) benzimidazole-4-carboxamide

Example 126

2- (3-phenyl-isoxazol-5-yl) benzimidazole-4-carboxamide

Example 127

2- (3-tert-butyl-5-phenyl-isoxazol-4-yl) benzimidazole-4-carbon acid amide

Example 128

2- (1- (4-chlorophenyl) -5-methyl-pyrazol-4-yl) benzimidazole - 4-carboxamide

Example 129

2- (1- (4-chlorophenyl) -3-methyl-pyrazol-4-yl) benzimidazole - 4-carboxamide

Example 130

2- (1- (4-bromophenyl) pyrazol-4-yl) benzimidazole-4-carboxamide

Example 131

2- (1- (4-chlorophenyl) -3,5-dimethylpyrazol-4-yl) benzimidazole 4-carboxamide

Example 132

2- (1- (4-methoxyphenyl) -5-trifluoromethylpyrazol-4-yl) benz imidazole-4-carboxamide  

Example 133

2- (4-methyl-5-phenyl-isoxazol-3-yl) benzimidazole-4-carboxylic acid amid.

Another group of PARP inhibitors relates to substituted benzimidazoles of the general formulas I and II

wherein
A denotes a saturated or monounsaturated carbocycle with 3 to 8 carbon atoms, which may additionally have fused on a benzene ring, the rings being able to be substituted with one or two different or identical radicals R ³ and the radical R ⁴ , and
R ¹ hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, OH, nitro, CF ₃ , CN, NR ¹¹ R ¹² , NH-CO-R ¹³ , OC ₁ -C ₄ - Alkyl, wherein
R ¹¹ and R ¹² independently of one another are hydrogen or C ₁ -C ₄ alkyl and
R ^{13 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl phenyl or phenyl, and
R ^{2 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl and
R ³ C ₁ -C ₆ alkyl, OH, OC ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl phenyl, NR ¹¹ R ¹² , phenyl, C ₁ -C ₄ alkyl phenyl, CF ₃ , COOH, COOC ₁ -C ₄ alkyl, CONH-C ₁ -C ₄ alkyl, CONH ₂ , where the phenyl rings can also be substituted with a maximum of two identical or different radicals R ³¹ , and
R ³¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NR ¹¹ R ¹² , and
R ^{4 means} - (O) _p - (CH ₂ ) _q -B, where
B NR ⁴¹ R ⁴² and

means where
p can mean 0 and 1 and
q can be 0, 1, 2 or 3, where if q = 0 also p = 0, and
R ^{41 is} hydrogen, C ₁ -C ₆ alkyl, (CH ₂ ) _r -E and R ^{42 is} hydrogen, C ₁ -C ₆ alkyl, -CO-R ⁸ , SO ₂ -R ⁸ , - (C = N) -R ⁸ and
- (C = N) -NHR ⁸ and
r 0, 1, 2, 3, 4 and
E phenyl, which can still carry a maximum of two radicals R ⁷² , and, if r ≠ 0.1, also NR ¹¹ R ¹² , NH-C ₁ -C ₄ alkylphenyl, pyrrolidine, piperidine, dihydropiperidine, morpholine, homopiperidine , Piperazine, which can also be substituted with C ₁ -C ₆ alkyl and C ₁ -C ₄ alkyl phenyl, and homopiperazine, which can also be substituted with C ₁ -C ₆ alkyl and C ₁ -C ₄ alkyl phenyl can be substituted, and
R ^{7 is} hydrogen, C ₁ -C ₆ alkyl, phenyl, where the ring can also be substituted with up to two identical or different radicals R ⁷¹ , and
R ⁷¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NR ¹¹ R ¹² , and
R ⁷² OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NR ¹¹ R ¹² , and
R ^{8 is} C ₁ -C ₆ -alkyl, phenyl, C ₁ -C ₄ -alkyl-phenyl-OC ₁ -C ₄ -alkyl-phenyl, it being possible for the ring to be substituted by up to two identical or different radicals R ⁸¹ , and
R ⁸¹ OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NR ¹¹ R ¹² , and
R ^{9 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl phenyl, phenyl, where the rings can also be substituted by up to two radicals R ⁹¹ , and
R ^{91 can be} OH, C ₁ -C ₆ alkyl, OC ₁ -C ₄ alkyl, chlorine, bromine, iodine, fluorine, CF ₃ , nitro, NR ¹¹ R ¹² .

Preferred at A are carbocycles that are at least single substi are acted upon. Preferred carbocycles are: tetralin, indane, cyclo heptane, cyclohexane, cyclopentane, cyclobutane and cyclopropane.

Preference is given to the compounds of the formulas I and II, where A is a cyclohexane ring, R ¹ , R ² and R ^{3 is} hydrogen and R ^{4 has} the meaning as above, where p is 0 and 1 and q is 0, 1 and 2 are, R ⁴¹ and R ⁴² , independently of one another, are hydrogen and C ₁ -C ₄ -alkyl, R ^{7 is} hydrogen, C ₁ -C ₄ -alkyl and phenyl, R ^{9 is} hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₂ alkylphenyl, and R ^{4 can be} in the 3- and 4-position on the cyclohexane ring, both the cis and the trans forms or mixtures thereof being included.

The compounds of the general formulas I and II are particularly preferred, where A is a cyclohexane ring and R ¹ , R ² and R ^{4 is} hydrogen and R ^{4 has} the meaning as above, where p is 0 and 1 and q is 0, 1 and 2, R ⁴¹ and R ⁴² , independently of one another, are hydrogen and C ₁ -C ₄ -alkyl, R ^{7 is} hydrogen, R ^{9 is} hydrogen, C ₁ -C ₄ -alkyl and benzyl, and R ^{4 is} in the 4-position on Cyclohexane ring can stand, both the cis and the trans forms as well as their mixtures are included.

Examples of PARP inhibitors mentioned above Group are:

example 1

2- (cis-4-amino-1-cyclohexyl) benzimidazole-4-carboxamide × 2 HCl

Example 2

2 (3-methoxy-cyclohexyl) benzimidazole-4-carboxamide

Example 3

2 (4-methoxy-cyclohexyl) benzimidazole-4-carboxamide  

Example 4

2 (4 (2-N, N-diethylaminoeth-1-yloxy) cyclohexyl) benzimidazole - 4-carboxamide × 2 HCl

Example 5

trans-2 (4-aminocyclohexyl) benzimidazole-4-carboxamide

Example 6

trans-2 (4- (aminomethyl) cyclohexyl) benzimidazole-4-carboxamide

Example 7

2- (4-methylcyclohexyl) benzimidazole-4-carboxamide

Example 8

2- (3-methylcyclohexyl) benzimidazole-4-carboxamide

Example 9

2- (2-methylcyclohexyl) benzimidazole-4-carboxamide

Example 10

2- (3-benzyloxyamido-cyclohexyl) benzimidazole-4-carboxamide

Example 11

2- (3-aminocyclohexyl) benzimidazole-4-carboxamide × HCl

Another group of PARP inhibitors are substituted benzimidazoles of the general formula I.

wherein
R ^{1 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, where a C atom of the alkyl radical is also OR ⁵ (where R ^{5 is} hydrogen or C ₁ -C ₄ alkyl), or a C atom in the Chain can also carry a = O group or a group NR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another are hydrogen or C ₁ -C ₄ alkyl and NR ⁸ R ⁹ together are a cyclic amine having 4 to 8 ring atoms can, wherein the C chains in R ⁸ or R ⁹ or the ring formed by NR ⁸ R ⁹ can still carry a radical R ⁶ , which independently of R ^{2 can have the} same meaning as R ² and
R ^{4 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, chlorine, bromine, fluorine, nitro, cyano, NR ⁸ R ⁹ , NH-CO-R ¹⁰ , OR ⁸ , where R ⁸ and R ⁹ independently of one another are hydrogen or C ₁ -C ₄ alkyl and NR ⁸ R ⁹ together can be a cyclic amine having 4 to 8 ring atoms, the ring still being a radical (branched and unbranched C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalk - C ₁ -C ₄ alkyl, CO-R ⁴¹ , COOR ⁴¹ and phenyl), and R ^{10 can be} hydrogen, C ₁ -C ₄ alkyl or phenyl and R ^{41 can have the} same meanings as R ²¹ ,
A is a saturated or monounsaturated heterocyclic, 4- to 8-membered ring which contains one or two nitrogen atoms, it being additionally possible for an oxygen or sulfur atom to be incorporated, which is substituted by the substituents R ² and R ³ is substituted, wherein
R ^{2 is} hydrogen, branched and unbranched C ₁ -C ₈ -alkyl, which may also be substituted by R ²³ and may carry a C atom of the chain of an = O group, C ₃ -C ₇ -cycloalk-C ₁ -C ₄ alkyl, -CO- (NH) _0.1 -R ²¹ , COOR ²¹ and phenyl, where R ^{21 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalk-C ₁ -C ₄ alkyl, phen-C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl and phenyl and each radical can still carry (CH ₂ ) _0-2 -R ²³ , and the respective phenyl ring in turn can be substituted with 1, 2 or 3 of the following radicals: chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₄ alkyl, nitro, CF ₃ , cyano, - (CH ₂ ) _0-2 -NR ²⁴ R ²⁵ , NH-CO-R ¹⁰ , OR ¹⁰ , COOR ¹⁰ , SO ₂ -C ₁ -C ₄ alkyl, SO ₂ Ph, SO ₂ NH, NHSO ₂ -C ₁ -C ₄ alkyl, NHSO ₂ Ph and CF ₃ , where R ²⁴ and R ²⁵ independently of one another are hydrogen or C ₁ -C ₄ alkyl and NR ²⁴ R ²⁵ together can be a cyclic amine having 4 to 8 ring atoms, the ring another radical branched and unbranched C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalk-C ₁ -C ₄ alkyl, CO-R ²² , COOR ²² (with R ²² being hydrogen, branched or unbranched C ₁ - C ₆ alkyl, C ₃ -C ₇ cycloalk-C ₁ -C ₄ alkyl, phen-C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl and phenyl) and phenyl, and R ^{10 can be} hydrogen , C ₁ -C ₄ alkyl or phenyl, and
R ²³ denotes NR ²⁶ R ²⁷ , where R ²⁶ and R ^{27 are} hydrogen, C ₁ -C ₆ alkyl, C ₀ -C ₄ alkylphenyl, the phenyl ring also containing up to 3 radicals Cl, F, Br, J , C ₁ -C ₄ alkyl, CF ₃ , CN, SO ₂ -C ₁ -C ₄ alkyl, SO ₂ phenyl, NO ₂ , NH ₂ , NHCO-C ₁ -C ₄ alkyl, NHCO-phenyl, OH, OC ₁ -C ₄ alkyl, OC ₁ -C ₄ alkylphenyl can be substituted, and NR ²⁶ R ^{27 can} also be a cyclic amine having 3 to 8 members, with an additional hetero atom such as O, N and S can be present and the ring can also be substituted by a radical R ²⁸ , where R ^{28 can be} C ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl phenyl,
R ³ is hydrogen, branched and unbranched C ₁ -C ₈ alkyl, optionally substituted by C ₁ -C ₆ -alkyl-substituted C ₃ -C ₇ -cycloalkyl alk-C ₁ -C ₄ alkyl, optionally substituted by C ₁ -C ₆ - Alkyl substituted C ₃ -C ₇ cycloalkyl, where one C atom of the radical can also carry a phenyl ring which in turn can be substituted with 1, 2 or 3 of the following radicals: chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₄ alkyl, nitro, CF ₃ , cyano, (CH ₂ ) _0-2 -NR ³² R ³³ , NH-CO-R ¹⁰ , OR ¹⁰ , COOR ¹⁰ , SO ₂ -C ₁ - C ₄ alkyl, SO ₂ Ph, CH ₃ , SO ₂ NH, NHSO ₂ -C ₁ -C ₄ alkyl, NHSO ₂ Ph and CF ₃ , where R ³² and R ³³ independently of one another are hydrogen or C ₁ -C ₄ - Are alkyl and NR ³² R ³³ together can be a cyclic amine having 4 to 8 ring atoms, the ring still being a branched and unbranched C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalk-C ₁ -C ₄ - Can carry alkyl, CO-R ³¹ , COOR ³¹ and phenyl, and R ^{10 is} hydrogen, C ₁ -C ₄ alkyl or phenyl, and R ^{31 has} the same meaning as R ²¹ ,
as well as their tautomeric forms, possible enantiomeric and diastereomeric forms, their prodrugs, as well as possible physiologically compatible salts.

The compounds of the general formula I in which R ^{1 is} hydrogen are preferred.

The compounds of the general formula I in which R ^{2 is} hydrogen are preferred.

The compounds of the general formula I in which R ^{4 is} hydrogen are preferred.

The compounds of the general formula I in which R ³ is bonded to the nitrogen of A are preferred.

The compounds of the general formula I in which R ^{3 is} hydrogen, C ₁ -C ₆ -alkyl, benzyl and phenethyl are preferred.

Particular preference is given to the compounds of the general formula I in which R ¹ , R ² and R ^{4 are} hydrogen and A is piperidine which is bonded to the 4-position on the benzimidazole and R ^{3 is} hydrogen, C ₁ -C ₆ -alkyl, benzyl and means phenethyl and is bonded to the piperidine ring in the 1-position.

The respective meanings of R ⁵ to R ¹⁰ in the radicals R ¹ to R ^{4 are} independent of one another.

The preferred meaning of NR ⁸ R ⁹ , NR ²⁴ R ²⁵ and NR ³² R ³³ as cyclic amine are piperidine, pyrrolidine, piperazine and homo piperazine. In the case of piperazine and homopiperazine, the ring can preferably also carry a radical of branched and unbranched C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalk-C ₁ -C ₄ -alkyl, CO-R ⁷ and phenyl.

The preferred meaning of A is piperidine, pyrrolidine, Piperazine, morpholine or homopiperazine.

The compounds of the general are particularly preferred Formula I, wherein A is piperazine or piperidine.

Examples of the above group are given below guided:

example 1

2-piperidin-4-yl-benzimidazole-4-carboxamide × 2 HCl

Example 2

2-piperidin-4-yl-benzimidazole-4-carboxamide

Example 3

2- (N-acetyl-piperidin-4-yl) benzimidazole-4-carboxamide

Example 4

2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide

Example 5

2-piperidin-3-yl-benzimidazole-4-carboxamide × 2 HCl

Example 6

2- (N (O-tert-butyloxycarbonyl) piperidin-3-yl) benzimidazole 4-carboxamide

Example 7

2 (N-benzylpiperidin-3-yl) benzimidazole-4-carboxamide

Example 8

2 (N-methylpiperidin-3-yl) benzimidazole-4-carboxamide × 2 HCl

Example 9

2-piperazin-4-yl-benzimidazole-4-carboxamide  

Example 10

2 (N-propylpiperidin-3-yl) benzimidazole-4-carboxamide × 2 HCl

Example 11

2 (N (3-phenylprop-1-yl) piperidin-3-yl) benzimidazole-4-carbon acid amide × 2 HCl

Example 12

2 (N-benzoylpiperidin-3-yl) benzimidazole-4-carboxamide

Example 13

2 (N-benzylpiperidin-4-yl) benzimidazole-4-carboxamide × 2 HCl

Example 14

2 (1 (1-methylpiperidin-4-yl) piperidin-4-yl) benzimidazole-4-carbon acid amide × 3 HCl

Example 15

2 (N-n-pentylpiperidin-4-yl) benzimidazole-4-carboxamide

Example 16

2 (N-isobut-1-yl-piperidin-4-yl) benzimidazole-4-carboxamide

Example 17

2 (N-n-butylpiperidin-4-yl) benzimidazole-4-carboxamide × HCl

Example 18

2 (N- (3-Methylbut-1-yl) piperidin-4-yl) benzimidazole-4-carbon acid amide × HCl

Example 19

2 (1,4-dimethylpiperazin-2-yl) benzimidazole-4-carboxamide × 2 HCl

Example 20

2-piperazin-2-yl-benzimidazole-4-carboxamide × 2 HCl

Example 21

2 (N-isopropylpiperidin-4-yl) benzimidazole-4-carboxamide × HCl

Example 22

2 (4- (2-Ethyl-prop-1-yl) piperidin-4-yl) benzimidazole-4-carbon acid amide  

Example 23

2 (1,4-dibenzylpiperazin-2-yl) benzimidazole-4-carboxamide × 2 HCl

Example 24

2 (N-benzylpiperidin-4-yl) -1- (1-benzylpiperidin-4-ylcarbonyl) - benzimidazole-4-carboxamide

Another group of PARP inhibitors are substituted 2-phenylbenzimidazoles and 2-phenylindoles of the general formula I:

wherein
AN or CH means
R ^{1 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, where a C atom of the alkyl radical can also carry OR ¹¹ or a group R ⁵ , where
R ^{11 is} hydrogen or C ₁ -C ₄ alkyl, and
R ^{2 is} hydrogen, chlorine, fluorine, bromine, iodine, branched and unbranched C ₁ -C ₆ alkyl, nitro, CF ₃ , CN, NR ²¹ R ²² , NH-CO-R ²³ , OR ²¹ , where
R ²¹ and R ^{22 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{23 is} hydrogen, C ₁ -C ₄ alkyl or phenyl, and
R ^{3 is} - (CH ₂ ) _q -NR ³¹ R ³² , (CH ₂ ) _q NR ³³ R ³⁴ , where q can be 0, 1, 2 or 3,
R ³¹ denotes hydrogen, C ₁ -C ₆ alkyl, (CH ₂ ) _r NR ³³ R ³⁴ ,
R ³² means (CH ₂ ) _r NR ³³ R ³⁴ ,
wherein R ³¹ and R ³² independently of one another are r 2, 3, 4, 5 or 6 and R ³³ and R ³⁴ independently of one another are hydrogen, C ₁ -C ₆ -alkyl, together with the nitrogen is a ring of 3 to 8 atoms , which can carry an additional heteroatom selected from O, NC ₁ -C ₄ alkyl, NC ₀ -C ₂ phenyl or NH, phenyl-C ₁ -C ₄ alkyl, the phenyl ring having up to 3 identical or different substituents selected from the group C ₁ -C ₆ alkyl, halogen, nitro, SO ₂ NR ³⁵ R ³⁶ (with R ³⁵ , R ³⁶ independently of one another hydrogen, C ₁ -C ₄ alkyl or together with the nitrogen like a ring 3 to 8 atoms, which can carry an additional heteroatom selected from O, S, SO ₂ , NC ₁ -C ₄ alkyl, NC ₀ -C ₂ phenyl or NH), C ₁ -C ₄ alkoxy, S ( O) _0-2 -R ³⁷ (where R ³⁷ is hydrogen, C ₁ -C ₄ alkyl), CF ₃ , (CH ₂ ) _0-4 -COR ³⁷ , (CH ₂ ) _0-4 NR ³⁵ R ³⁶ , (CH ₂ ) _0-4 CONR ³⁵ R ³⁶ , (CH ₂ ) _0-4 OR ³⁷ -CH ₂ COOR ³⁷ ,
R ^{4 is} hydrogen, branched and unbranched C ₁ -C ₆ alkyl, chlorine, bromine fluorine, nitro, cyano, NR ⁴¹ R ⁴² , NH-CO-R ⁴³ , OR ⁴¹ , where
R ⁴¹ and R ^{42 are} independently hydrogen or C ₁ -C ₄ alkyl and
R ^{43 is} C ₁ -C ₄ alkyl or phenyl.

Preferred positions for the radical R ² in the general formula I are the 3-position and the 4-position relative to the benzimidazole ring. For the radical R ³ , the 3-position or 4-position relative to the benzimidazole ring is also preferred.

The preferred meaning of A is nitrogen.

The preferred meaning of R ¹ is hydrogen.

The preferred meaning of R ² is hydrogen, branched or unbranched C ₁ -C ₆ alkyl, nitro, CN, NH ₂ , OC ₁ -C ₄ alkyl. R ² is particularly preferably hydrogen. <19395 00070 552 001000280000000200012000285911928400040 0002010021468 00004 19276PAR <The preferred meaning for R ³ is (CH ₂ ) _1,2 NR ³⁵ R ³⁶ and N (R ³⁷ ) - (CH ₂ ) _2-3 NR ³⁵ R ³⁶ , where R ^{37 is} hydrogen and C ₁ -C ₄ alkyl, R ³⁵ and R ³⁶ independently of one another are hydrogen and C ₁ -C ₄ alkyl and together as NR ³⁵ R ³⁶ also cyclic aliphatic amines such as piperidine, pyrrolidine, azepine and piperazine can be, where the piperazine on the second N atom can also be substituted with hydrogen or C ₁ -C ₄ alkyl.

The preferred meaning of R ⁴ is hydrogen.

The respective combinations of are very particularly preferred preferred meanings above.

Examples of group PARP inhibitors are:

example 1

2 (4- (N, N-2- (N, N-diethylamino) eth-1-yl-methylamino) phenyl) benz imidazole-4-carboxamide

Example 2

2 (4- (N, N-2- (N, N-Dimethylamino) eth-1-yl-methylamino) phenyl) benz imidazole-4-carboxamide

Example 3

2 (3 (2 (N, N-dimethylamino) eth-1-yl) -4-nitrophenyl) benzimidazol-4- carboxamide

The cosmetic and dermatological invention Formulations can be composed as usual and for Treatment, care and cleaning of the skin or hair and serve as a make-up product in cosmetics. They contain preferably 1 µg / 100 g to 10 wt .-% of the active ingredient. The together setting depends on the effectiveness of the inhibitor, the penetration properties of the active substance through the stratum Corneum and its ability to form a depot in the skin.

The PARP inhibitor is used according to the invention advantageous through regular application, e.g. B. in the form of a cosmetic or dermatological preparation, over time span away. This is based on the desired goal, d. H. the time span can vary over the lifetime of the user extend, preferably over a period of up to three months, particularly preferred over a week to two months if that's it The goal is to build up a depot in the skin. For an after-sun Application is considered the duration of use in the sense of the invention single application, but preferably a period of at least one day, particularly preferably over three days to three months, particularly preferably over one to two weeks.

For the purposes of the invention, it is recommended that the cosmetic or dermatological preparation of the PARP inhibitors be present in an amount of 0.1 μg / cm ² to 2 mg / cm ² , between once a week and 4 to 5 times a day, preferably 3 times a day Weekly up to 3 times a day, particularly preferably one or two times a day, topical application.

Both the Ki and the corresponding IC ⁵⁰ values can be used to determine the effectiveness of the active substance. For the purposes of the invention, it is important to take into account that for an after-sun application an IC ⁵⁰ value is determined in such a way that the active ingredient is only added after the relevant time. Active agents intended for after-sun applications advantageously have penetration properties which enable the substance to penetrate the skin quickly. In contrast, for applications with a "preconditioned" character, rapid penetration is unimportant, but the ability to build up a depot in the skin is an advantage.

Surprisingly, when the active substance is used according to the invention, it is an effective treatment but also a prevention of

• - prematurely aged skin (e.g. wrinkles, age spots, tele angiectasia, pigment disorders) and / or prematurely aged Skin appendages
• - radiation-related skin damage or radiation-related negative changes in the skin and / or skin appendage formed
• - environmental (ozone, free radicals, singlet oxygen, reactive oxygen or nitrogen compounds, cigarettes smoke, toxins) skin damage or environmental negative Changes in the skin and / or skin appendages
• - photosensitive, inflammatory, erythematous, allergic or autoimmune reactive changes in the Skin and / or the appendages of the skin (in particular acne, oily or dry skin, keratoses, rosaceae, dermatoses, atopic eczema, seborrheic eczema, photodermatosis, polymorphic light dermatosis)
• - deficient, sensitive or hypoactive conditions of the skin and / or the skin appendages
• - itching
• - dry skin conditions and horny layer barrier disorders  
• - hair loss and reduced hair growth

possible.

However, the active ingredient according to the invention or cosmetic and dermatological preparations according to the invention also serve in a surprising and unpredictable manner

• - Soothing sensitive and irritated skin
• - Regulation of collagen, hyaluronic acid, elastin synthesis
• - Stimulation of DNA synthesis, especially in the case of deficient ones or hypoactive skin conditions
• - Regulation of transcription and translation of matrix-degrading Enzymes, especially the MMPs
• - Increasing cell renewal and skin regeneration
• - Increase in the skin's own protection and repair mechanisms for DNA, lipids and / or proteins
• - pre- and post-treatment during surgical interventions, especially to counteract skin irritation and the Promote regeneration processes of the injured skin.

The cosmetic and dermatological preparations in the usual for cosmetics Apply to the skin and / or hair in sufficient quantities upset.

For example, the active compounds according to the invention are described in cosmetic agents for cleaning the skin, such as bar soaps, Toilet soaps, core soaps, transparent soaps, luxury soaps, Deodorant soaps, cream soaps, baby soaps, skin protection soaps, abrasive soaps, syndets, liquid soaps, pasty soaps, soft soaps, Washing pastes, liquid washing, showering and bathing preparations, e.g. B. Washing lotions, shower baths, shower gels, foam baths, cream foam baths, oil baths, bath extracts, scrub preparations, in-situ Products, shaving foams, shaving lotions, shaving creams set.

They are also suitable for skin cosmetic preparations such as W / O or O / W skin and body creams, day and night creams, Eye creams, sunscreen, after sun products, hand care products, face creams, multiple emulsions, jellies, micro emulsions, liposome preparations, niosome preparations, anti-wrinkles  creams, facial oils, lipogels, sports gels, moisturizing creams, Bleaching creams, vitamin creams, skin lotions, skin care lotions, Ampoules, after shave lotions, pre-shaves, moisturizing lotions, Tanning lotions, cellulite creams, depigmenting agents, Massage preparations, body powder, facial tonic, face masks, Deodorants, antiperspirants, nose strips, antiacne agents, Repellent, shaving, hair removal, intimate hygiene medium, foot care products, baby care products and others.

In addition, the active compounds according to the invention can be used in cosmetic Hair care products such as hair treatments, hair lotions, hair conditioners, hair emulsions, tip fluids, leveling agents for Perms, hot oil treatment preparations, conditioners, setting agents lotions, shampoos, hair tinting and coloring agents, hair sprays, Hair dryer lotions, gloss sprays, hair brilliants, hair styling products, hair lotions, alopecia care products and others used become.

The active compounds according to the invention are also suitable for Use in cosmetic preparations for the decorative Cosmetics, for example as make-up, powder, blush, eye shadow, Eye pencils, eyeliner, eye foundation cream, lipsticks, eyes brewing pencils, contour pencils, masking pencils, theater make-up, Mascara, eyelash tinting, coloring, make-up removal products and others.

Cosmetic, hygienic, dermatological or pharmaceutical Depending on the area of application, medicinal preparations can be used as Spray (pump spray or aerosol), foam, gel, gel spray, lotion, Cream, mousse, ointment, suspensions or powder can be prepared.

It is also advantageous to have the active ingredients in encapsulated form to present, e.g. B. as cellulose encapsulation, in gelatin, with Polyamides, in niosomes, wax matrices, with cyclodextrins or encapsulated liposomally.

Preparations according to the invention can be cosmetic auxiliaries contain, as they usually ver in such preparations be applied, e.g. B. preservatives, bactericides, perfumes, Anti-foaming agents, dyes, pigments, Thickeners, surface-active substances, emulsifiers, softening substances, softening agents, fats, oils, waxes or other common ingredients of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, Foam stabilizers, solubilizers, electrolytes, organic Acids, organic solvents or silicone derivatives.  

According to the invention, the preparations can be in addition to mentioned active ingredients contain other compounds that antioxidant, as a radical scavenger, moisturizing or moisturizing the skin sustained, anti-inflammatory, anti-inflammatory or anti-allergic act to complement or enhance their effect. Ins In particular, these compounds can be selected from the Group of vitamins, plant extracts, alpha and beta hydroxy acids, ceramides, anti-inflammatory, anti-microbial or UV filtering substances, as well as their derivatives and mixtures from it.

The antioxidants are advantageously selected from the group consisting of amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g. urocanic acid) and their derivatives, peptides such as D, L-carnosine, D- Carnosine, L-carnosine and their derivatives (e.g. anserine), carotenoids, carotenes (e.g. α-carotene, β-carotene, lycopene) and their derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g. As dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and Lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds ( e.g. Buthioninsulfoximine, Homocysteinsulfoximin, Buthionin s ulfones, penta-, hexa, heptathioninsulfoximine) in very low tolerable doses (e.g. B. pmol to µmol / kg), also (metal) chelators (e.g. α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, Bile extracts, bilirubin, biliverdin, EDTA, EGTA and their derivatives, unsaturated fatty acids and their derivatives (e.g. γ-linolenic acid, linoleic acid, oleic acid), folic acid and their derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and derivatives ( e.g. ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (e.g. vitamin E acetate), vitamin A and derivatives (vitamin A palmitate) and coniferyl benzoate of benzoin, rutinic acid and their derivatives , Butylated hydroxytoluene, butylated hydroxyanisole, norihydroguajak resin acid, nordihydroguajaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, sesamol, sesamoline, zinc and its derivatives (e.g. ZnO, ZnSO ₄ ), selenium and its derivatives (e.g. Selen me thionine), stilbene and their derivatives (e.g. As stilbene oxide, trans-stilbene oxide) and the derivatives suitable according to the invention (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of these active ingredients.

The amount of the aforementioned antioxidants in the preparations, alone or in combination, is preferably 0.001 to 30% by weight.

Preparations according to the invention can also be advantageous Contain substances that contain UV radiation in UV-B and / or UV-A Absorb area.

It is also advantageous to have additional oil-soluble organic UV-A filter and / or UV-B filter in the lipid phase and / or water-soluble organic UV-A filters and / or UV-B filters in the use aqueous phase, the total amount of filters substances z. B. 0.1 wt .-% to 30 wt .-%, preferably 0.5 to 15 wt .-%, in particular 1 to 10 wt .-%, based on the Total weight of the preparations to make up cosmetic preparations To provide the skin in front of the entire area of the Protect ultraviolet radiation.

Light stabilizers used alone or as a mixture with the Compounds of formula I can be used, for. B.

Table 1

Other combinable light stabilizers include the following compounds:

The list of UV filters mentioned in combination with the active substance combinations according to the invention can be used, should of course not be limiting.

The total amount of filter substances is usually 0.1 wt% to 30 wt%, preferably 0.5 to 15 wt%, ins particularly 1 to 10% by weight, based on the total weight of the preparations to make cosmetic preparations available put the skin in front of the entire range of ultraviolet Protect radiation.  

The lipid phase is advantageously selected from the group of substances of mineral oils, mineral waxes, branched and / or unbranched hydrocarbons and waxes, triglycerides of saturated and / or unsaturated, branched and / or unbranched C ₈ -C ₂₄ alkane carboxylic acids; they can be selected from synthetic, semi-synthetic or natural oils such as olive oil, palm oil, almond oil or mixtures; Oils, fats or waxes, esters from saturated and / or unsaturated, branched and / or unbranched C ₃ -C ₃₀ alkane carboxylic acids and saturated and / or unsaturated, branched and / or unbranched C ₃ -C ₃₀ alcohols, from aromatic Carboxylic acids and saturated and / or unsaturated, branched and / or unbranched C ₃ -C ₃₀ alcohols, for example isopropyl myristate, isopropyl stearate, hexyldecyl stearate, oleyl oleate; also synthetic, semi-synthetic and natural mixtures of such esters such as jojoba oil, alkyl benzoates or silicone oils such. B. cyclomethicone, dimethylpolysiloxane, diethylpoly siloxane, octamethylcyclotetrasiloxane and mixtures thereof or dialkyl ether.

The aqueous phase of the preparations according to the invention contains optionally advantageous alcohols, diols or polyols lower C number and their ethers, preferably ethanol, isopropanol, Propylene glycol, glycerin, ethylene glycol monoethyl ether.

Known W / O- are preferably used as emulsifiers also O / W emulsifiers such as polyglycerol esters, sobitan esters or partially esterified glycerides into consideration.

Particularly suitable solubilizers are ethoxylated ones Sorbitan esters, ethoxylated lanolin alcohols and ethoxylated To call castor oil.

Usual native and synthetic thickeners or gel formers in formulations are cross-linked polyacrylic acids and their Derivatives, polysaccharides such as xanthan gum or alginates, carboxy methyl cellulose or hydroxycarboxymethyl cellulose, hydrocolloids such as gum arabic or motmorillonite minerals such as bentonite or fatty alcohols, polyvinyl alcohol and polyvinyl pyrrolidone.

The usual propellants for aerosols according to the invention are Propellants in question, for example propane, butane, pentane and other.  

Examples of cosmetic preparations

example 1

Soft skin fluid

Example 2

Hand Protection Cream

Example 3

Sun care lotion

Example 4

Multiple emulsion

Example 5

Microemulsion

Example 6

Liposome angel

Example 7

Blunted Oil Gel

Example 8

Oil gel

Example 9

Sun Care Lip Protection Stick

Example 10

Cooling body splash

Example 11

Make up

Example 12

Fluid makeup

Example 13

Sun Care Oil

Example 14

Facial Scrub Cleanser

Example 15

hair conditioner

Example 16

Hair wax

Example 17

Anti-Dandruff Hair Tonic

Example 18

Foot deodorant spray

Example 19

Hair spray

Claims (2)

1. Cosmetic preparation for protecting the human epidermis or human hair, characterized in that it contains a cosmetically effective amount of a PARP inhibitor and a UV absorber in a cosmetically suitable carrier. 2. Use of PARP inhibitors for the production of medication agents or cosmetic preparations for medical purposes or cosmetic treatment of human epidermis or human hair after exposure to sunlight.