RU2191175C2 - Condensed isoindolones as inhibitors of protein kinase c - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, medicine. SUBSTANCE: invention relates to novel condensed isoindolones of the formula (I):

where rings B and F mean independently each of other 6- membered carbocyclic ring; R¹ means H, C₁-C₄-alkyl; A¹ and A² are taken in pairs from a group involving =O, H, -OR'' where R'' means H; B¹ and B² mean in pairs =O; X is taken in all positions independently each of other from a group: a) unsubstituted C₁-C₃-alkylene; b) S-; R³,R⁴,R⁵,R⁶ are taken independently each of other from a group involving H, C₁-C₄-alkyl. Compounds of the formula (I) can be used for inhibition of protein kinase C activity and for suppression of tyrosine kinase activity. The found properties ensure to use compounds (I) for inhibition of proliferation of cancer cells. EFFECT: new compounds indicated above, valuable biochemical and medicinal properties. 3 cl, 15 dwg, 3 tbl, 15 ex

Description

Technical field
This invention relates to fused aryl or heteroaryl substituted isoindole-2- and -2,4-dions, which are hereinafter referred to as “fused isoindolones”. The objects of this invention are also methods for the preparation and use of these compounds.

BACKGROUND OF THE INVENTION
The publications cited in this specification are hereby incorporated by reference.

 The substance released from microorganisms, known as K-252a, has attracted close attention in recent years due to the multilateral functional activity that it exhibits. K-252a is an indolcarbazole alkaloid that was originally isolated from a culture of Nocordiosis sp. (Kase, H. et al., 39 J. Antibiotics 1059, 1986). K-252a is an inhibitor of several enzymes, including protein kinase C ("PKC") and tyrosine kinase (trk). The functional activities of K-252a are numerous and diverse, for example, inhibition of tumor growth (US Pat. Nos. 4,877,776 and 5,063,330; European Patent Publication 238011, issued by Nomato), anti-insecticidal activity (US Pat. No. 4,735,939), inhibition of inflammatory processes (US Pat. No. 4,816,450), treatment of diseases associated with nerve cells (WIPO publication WO 94/02488, issued by Cephalon, Inc. and Kyowa Hakko Kogyo Co., Ltd., published February 3, 1994).

 These indolecarbazoles have several common properties. In particular, they all have a bis-indole heterocyclic moiety. Staurosporin (isolated from Streptomyces sp.) And K-252a (isolated from Nocordiosis sp.) Contain a part of the sugar molecule, which is attached by two N-glycosidic bonds (to the nitrogen atoms of indole). Both K-252a and staurosporin have been comprehensively investigated regarding their use as therapeutic agents. Indolecarbazoles, as a rule, are lipophilic substances, due to which they penetrate relatively easily through biological membranes, and, unlike protein substances, are characterized by a longer half-life in vivo.

 The only drawback of K-252a, which has a diverse and useful effect, is that microorganisms are the source of its production, so this substance must be isolated from the culture medium by fermentation. The scientific literature describes the synthesis of K-252a, but it is not suitable for commercial use (Wood, J. et al., J. Am. Chem. Soc., 1995, 117, 10413). Therefore, compounds possessing the functional action inherent in K-252a, but obtained by chemical synthesis, would have a great advantage compared to the indolecarbazole compounds currently known.

Summary of the invention
This invention relates to compounds, which are hereinafter referred to as "fused isoindolones." These compounds are biologically active. Condensed isoindolones are indole-free molecules that can be synthesized de novo chemically.

 The condensed isoindolones of the present invention differ from indolecarbazoles in that they do not have a nitrogen atom at the 12- or 13-positions (the alphabetical designations of the rings given in Porter et al., 57, J. Org. Chem. 2105, 1992, are used in reference purposes). In addition, condensed isoindolones do not contain a part of the sugar molecule attached by two N-glycosidic bonds. Due to the fact that these compounds lack the indicated part of the sugar molecule, they can be easily synthesized. It is useful and attractive that these indole-free compounds, the source of which are not microorganisms, can be easily synthesized, as well as the fact that they have biological activity that makes them suitable for a number of applications where previously only certain indolecarbazoles were used.

Предпочтительные конденсированные изоиндолоны выражены формулой II

Ниже подробно описываются структурные элементы этих соединений. В соединениях формул I и II элемент "X" в кольцах С и Е не является азотом.The condensed isoindolones of the present invention have the following general formula (formula I):

Preferred fused isoindolones are expressed by formula II

The structural elements of these compounds are described in detail below. In the compounds of formulas I and II, the element "X" in rings C and E is not nitrogen.

 Preferred synthesis methods are also described in this description of the invention, including methods for the preparation of lactam isomers.

 Condensed isoindolones are designed for different purposes, for example, they can be used alone or in combination with one or more neutrotropic factors and / or indolecarbazoles to enhance the functioning and / or viability of nerve cells, to inhibit protein kinase C (PKC) and to suppress tyrosine kinase (trk) activity . The latter action is directly related to the inhibition of proliferation of cancer cells, including cancer of the prostate gland. Due to the diverse action of the compounds of the present invention can find application in a number of areas, including scientific research and therapy.

DETAILED DESCRIPTION OF THE INVENTION
I. Brief Description of the Drawings
In FIG. 1 is a graph showing the effect of the derivatives of I-1 and I-2 of fused isoindolones on the activity of ChAT spinal cord.

 In FIG. 2 is a graph showing the stimulating effect of condensed isoindolones on the activity of ChAT in the base of the forebrain.

 Figure 3 shows a diagram of the synthesis of bisinden derivatives.

 Figure 4 shows a diagram of the synthesis of condensed isoindolones.

 Figure 5 shows a diagram of the synthesis of condensed isoindolones in which X is -C (= 0) -.

 Figure 6 shows a diagram of the synthesis of condensed isoindolones (X = carbonyl) from 1-indanones.

 Figure 7 shows a diagram of the synthesis of condensed isoindolones having two carbonyl groups.

 In FIG. 8 shows a synthesis scheme for condensed isoindolones using the Michael reaction.

 In FIG. 9 shows a synthesis scheme for selected condensed isoindolones using the Wittig reaction.

 Figure 10 shows a synthesis scheme of X-bis-alkylated condensed isoindolones.

 Figure 11 shows a synthesis scheme of heterocyclic isoindolones with a fused ring B.

 12 shows a synthesis scheme for bis-heterocyclic isoindolones with fused rings B and F.

 On Fig shows a diagram of the synthesis of derivatives of bis-benzothiafen.

 On Fig shows a diagram of the synthesis of derivatives of indenylbenzothiafen.

 In FIG. 15 is a diagram of the synthesis of condensed isoindolones using the Diels-Alder reaction using acetylenedicarboxylate.

где кольца В и F независимо друг от друга выбирают из группы, включающей
(a) 6-членное карбоциклическое ароматическое кольцо, в котором до 3 атомов углерода замещены атомами азота;
(b) 5-членное карбоциклическое ароматическое кольцо; и
(c) 5-членное карбоциклическое ароматическое кольцо, в котором
(1) один атом углерода замещен атомом кислорода, азота или серы; и
(2) два атома углерода замещены атомом азота и серы или атомом азота и кислорода;
R¹ выбирают из группы, включающей Н; алкил с 1-4 атомами углерода; арил; арилалкил; гетероарил; гетероарилалкил; COR⁹, где R⁹ выбирают из группы, включающей алкил с 1-4 атомами углерода, арил и гетероарил; -OR¹⁰ где R¹⁰ выбирают из группы, включающей Н и алкил с 1-4 атомами углерода; -CONH₂, -NR⁷R⁸, -(CH₂)_n NR⁷R⁸ и -О (СН₂)_n NR⁷R⁸, где n равен 1-4, и
(a) R⁷ и R⁸ независимо друг от друга выбирают из группы, включающей Н и алкил с 1-4 атомами углерода; или
(b) R⁷ и R⁸, вместе взятые, образуют связующую группу формулы - (СН₂)₂-Х¹-(СН₂)₂-, где X¹ выбирают из группы, включающей -О-, -S- и -СН₂-;
А¹ и А² попарно выбирают из группы, включающей Н, Н; Н,
-OR¹¹, где R¹¹ обозначает Н, алкил с 1-4 атомами углерода, арил с 6-10 атомами углерода или гетероарил; Н, -SR¹¹; Н, -N(R¹¹)₂; =0; =S и =NR¹¹, где А¹ и А², вместе взятые, могут обозначать атом с двойной связью;
B¹ и В² попарно выбирают из группы, включающей Н, Н; Н, -OR¹¹; Н, -SR¹¹; H, -N(R¹¹); = 0; =S и -NR¹¹, где В¹ и В², вместе взятые, могут обозначать атом с двойной связью; при условии, что по крайней мере одна из пар А¹ и А², и В¹ и В² обозначает =0;
Х во всех положениях независимо друг от друга выбирают из группы, включающей:
(a) незамещенный алкилен с 1-3 атомами углерода;
(b) алкилен с 1-3 атомами углерода, замещенный R², где R² выбирают из группы, включающей:
(1) OR¹⁰; -SR¹⁰; R¹⁵, где R¹⁵ является алкилом с 1-4 атомами углерода;
фенил; нафтил; арилалкил с 7-15 атомами углерода; Н; -SO₂R⁹; -CO₂R⁹; -COR⁹; алкил, алкенил и алкинил с 1-8 атомами углерода, где
(i) каждый алкил, алкенил или алкинил с 1-8 атомами углерода не замещен; или
(ii) каждый алкил, алкенил или алкинил с 1-8 атомами углерода замещен одним из заместителей, выбираемым из группы, включающей 1-3 арил с 6-10 атомами углерода; гетероарил; F; Cl; Вr; I; -CN; -NO₂; ОН; -OR⁹; -О(СН₂)_nNR⁷R⁸, где n равен 1-4; -OCOR⁹, -OCONHR⁹; 0-тетрагидропиранил; NH₂; -N R⁷R⁸, -NR¹⁰COR⁹; -NR¹⁰CO₂R⁹; -NR¹⁰CONR⁷R⁸; -NHC(=NH)NH₂; -NR¹⁰SO₂R⁹; -S(O)_yR¹¹, где у равен 1 или 2; -SR¹¹; -CO₂R⁹; -CONR⁷R⁸; -CHO; -COR⁹; -CH₂OR⁷; -CH= NNR¹¹R¹², где R¹² выбирают из группы, включающей Н, алкил с 1-4 атомами углерода, арил с 6-10 атомами углерода и гетероарил; -CH=NOR¹¹; -CH=NR⁹; -CH= NNHCH(N= NH)NH₂; -SO₂NR¹²R¹³, где R¹³ выбирают из группы, включающей Н, алкил с 1-4 атомами углерода, арил с 6-10 атомами углерода и гетероарил, либо R¹² и R¹³, вместе взятые, образуют связующую группу; -PO(OR¹¹)₂, -OR¹⁴, где R¹⁴ является остатком аминокислоты, получаемым после удаления гидроксильной группы из карбоксильной группы; или
(2) моносахарид с 5-7 атомами углерода, в котором каждая гидроксильная группа независимо от других может быть не замещена или замещена Н, алкилом с 1-4 атомами углерода, алкилкарбонилоксигруппой с 2-5 атомами углерода или алкоксильной группой с 1-4 атомами углерода; и
с) функциональную группу, выбираемую из группы, включающей
-СН= СН-; -СНОН-СНОН-; -О-; -S-; -S(= O)-; -S(S=O)₂-; -C(R¹⁰)₂-; -C= C(R₂)₂; -C(= O)-; -C(=NOR¹¹); -С(OR¹¹) (R¹¹)-; -C(=O)CH(R¹⁵)-; -CH(R¹⁵)C(= O)-; -(=NOR¹¹)CH(R¹⁵); -CH(R¹⁵)C(=NOR¹¹)-; CONR¹⁵; NR¹⁵CO; -CH₂Z-; -ZCH₂- и -CH₂ZCH₂-, где Z является -CR¹¹; -O-; -S-; -C(=O)OR¹¹; -C(=NOR¹¹) и -NR¹¹;
R³, R⁴, R⁵ и R⁶ независимо друг от друга выбирают из группы, включающей Н; арил; гетероарил; F; Cl; Br; I; -CN; СF₃; -NO₂; ОН; -OR⁹; -O(CH₂)_nNR⁷R⁸; -OCOR⁹; -OCONHR⁹; NH₂; -СН₂ОН; -CH₂OR¹⁴; -NR⁷R⁸; -NR¹⁰OR⁹; -NR¹⁰CONR⁷R⁸; -SR¹¹; -S(O)_yR¹¹, где у равен 1 или 2; -CO₂R⁹; -COR⁹; -CONR⁷R⁸; -CHO; -CH= NOR¹¹; -CH= NR⁹; -CH=NNR¹¹R¹²; -(CH₂)_nSR⁹, где n равен 1-4; -(CH₂)_nS(O)yR⁹; -CH₂SR¹⁵, где R¹⁵ является алкилом с 1-4 атомами углерода; -CH₂S(O)_yR¹⁴;
- (СН₂)_n, NR⁷R⁸; - (CH₂)_nNHR¹⁴; алкил, алкенил, алкинил с 1-8 атомами углерода, где
(a) каждый алкил, алкенил или алкинил с 1-8 атомами углерода не замещен; или
(b) каждый алкил, алкенил или алкинил с 1-8 атомами углерода замещен одним из заместителей, выбираемых из группы, включающей 1-3 арил с 6-10 атомами углерода; гетероарил; F; Cl; Вr; I; -CN; NO₂; ОН; -OR⁹; -O(CH₂)_nNR⁷R⁸; -OCOR⁹; -OCONHR⁹; 0-тетрагидропиранил; NH₂; -NR⁷R⁸; -NR¹⁰COR⁹; -NR¹⁰CO₂R⁹; -NR¹⁰ONR⁷R⁸; -NHC (=NH) NH₂; -NR¹⁰SO₂R⁹; -S(O)_yR¹¹, где у равен 1 или 2; -SR¹¹; -CO₂R⁹; -CONR⁷R⁸; -CHO; COR⁹; -CH₂OR⁷; -CH=NNR¹¹R¹²; -CH= NOR¹¹, -CH= NR⁹; -CH=NNHCH(N=NH)NH₂; -SO₂NR¹²R¹³; -PO(OR¹¹)₂; OR¹⁴ или моносахарид с 5-7 атомами углерода, в котором каждая гидроксильная группа независимо от других может быть не замещена или замещена Н, алкилом с 1-4 атомами углерода, алкилкарбонилоксигруппой с 2-5 атомами углерода или алкоксильной группой с 1-4 атомами углерода.II. Condensed Isoindolones
The object of the present invention are condensed isoindolones of the formula I

where the rings B and F are independently selected from the group including
(a) a 6-membered carbocyclic aromatic ring in which up to 3 carbon atoms are replaced by nitrogen atoms;
(b) a 5 membered carbocyclic aromatic ring; and
(c) a 5 membered carbocyclic aromatic ring in which
(1) one carbon atom is substituted by an oxygen, nitrogen or sulfur atom; and
(2) two carbon atoms are substituted by a nitrogen and sulfur atom or a nitrogen and oxygen atom;
R ^{1 is} selected from the group consisting of H; alkyl with 1-4 carbon atoms; aryl; arylalkyl; heteroaryl; heteroarylalkyl; COR ⁹ , where R ^{9 is} selected from the group consisting of alkyl with 1-4 carbon atoms, aryl and heteroaryl; -OR ¹⁰ where R ^{10 is} selected from the group consisting of H and alkyl with 1-4 carbon atoms; —CONH ₂ , —NR ⁷ R ⁸ , - (CH ₂ ) _n NR ⁷ R ⁸ and —O (CH ₂ ) _n NR ⁷ R ⁸ , where n is 1-4, and
(a) R ⁷ and R ^{8 are} independently selected from the group consisting of H and alkyl with 1-4 carbon atoms; or
(b) R ⁷ and R ⁸ taken together form a linking group of the formula - (CH ₂ ) ₂ —X ¹ - (CH ₂ ) ₂ -, where X ^{1 is} selected from the group consisting of —O—, —S— and - CH ₂ -;
A ¹ and A ² are pairwise selected from the group consisting of H, H; H
-OR ¹¹ where R ¹¹ is H, alkyl with 1-4 carbon atoms, aryl with 6-10 carbon atoms or heteroaryl; H, -SR ¹¹ ; H, -N (R ¹¹ ) ₂ ; = 0; = S and = NR ¹¹ , where A ¹ and A ² taken together can represent a double bond atom;
B ¹ and B ² are pairwise selected from the group consisting of H, H; H, -OR ¹¹ ; H, -SR ¹¹ ; H, -N (R ¹¹ ); = 0; = S and -NR ¹¹ , where B ¹ and B ² taken together can represent a double bond atom; with the proviso that at least one of the pairs A ¹ and A ² , and B ¹ and B ² means = 0;
X in all positions are independently selected from the group consisting of:
(a) unsubstituted alkylene with 1-3 carbon atoms;
(b) alkylene of 1 to 3 carbon atoms substituted with R ² , where R ^{2 is} selected from the group consisting of:
(1) OR ¹⁰ ; -SR ¹⁰ ; R ¹⁵ where R ¹⁵ is alkyl with 1-4 carbon atoms;
phenyl; naphthyl; arylalkyl with 7-15 carbon atoms; H; -SO ₂ R ⁹ ; -CO ₂ R ⁹ ; -COR ⁹ ; alkyl, alkenyl and alkynyl with 1-8 carbon atoms, where
(i) each alkyl, alkenyl or alkynyl with 1-8 carbon atoms is not substituted; or
(ii) each alkyl, alkenyl or alkynyl with 1-8 carbon atoms is substituted with one of the substituents selected from the group consisting of 1-3 aryl with 6-10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; -NO ₂ ; HE; -OR ⁹ ; —O (CH ₂ ) _n NR ⁷ R ⁸ where n is 1-4; -OCOR ⁹ , -OCONHR ⁹ ; 0-tetrahydropyranyl; NH ₂ ; -NR ⁷ R ⁸ , -NR ¹⁰ COR ⁹ ; -NR ¹⁰ CO ₂ R ⁹ ; -NR ¹⁰ CONR ⁷ R ⁸ ; -NHC (= NH) NH ₂ ; -NR ¹⁰ SO ₂ R ⁹ ; -S (O) _y R ¹¹ where y is 1 or 2; -SR ¹¹ ; -CO ₂ R ⁹ ; -CONR ⁷ R ⁸ ; -CHO; -COR ⁹ ; -CH ₂ OR ⁷ ; -CH = NNR ¹¹ R ¹² , where R ^{12 is} selected from the group consisting of H, alkyl with 1-4 carbon atoms, aryl with 6-10 carbon atoms and heteroaryl; -CH = NOR ¹¹ ; -CH = NR ⁹ ; -CH = NNHCH (N = NH) NH ₂ ; —SO ₂ NR ¹² R ¹³ , where R ^{13 is} selected from the group consisting of H, alkyl with 1-4 carbon atoms, aryl with 6-10 carbon atoms and heteroaryl, or R ¹² and R ¹³ taken together form a linking group; -PO (OR ¹¹ ) ₂ , -OR ¹⁴ , where R ¹⁴ is the amino acid residue obtained after removal of the hydroxyl group from the carboxyl group; or
(2) a monosaccharide with 5-7 carbon atoms, in which each hydroxyl group may be independently substituted or substituted with H, alkyl with 1-4 carbon atoms, an alkylcarbonyloxy group with 2-5 carbon atoms or an alkoxy group with 1-4 atoms carbon; and
c) a functional group selected from the group including
-CH = CH-; -CHON-CHON-; -ABOUT-; -S-; -S (= O) -; -S (S = O) ₂ -; -C (R ¹⁰ ) ₂ -; -C = C (R ₂ ) ₂ ; -C (= O) -; -C (= NOR ¹¹ ); -C (OR ¹¹ ) (R ¹¹ ) -; -C (= O) CH (R ¹⁵ ) -; -CH (R ¹⁵ ) C (= O) -; - (= NOR ¹¹ ) CH (R ¹⁵ ); -CH (R ¹⁵ ) C (= NOR ¹¹ ) -; CONR ¹⁵ ; NR ¹⁵ CO; -CH ₂ Z-; -ZCH ₂ - and -CH ₂ ZCH ₂ -, where Z is -CR ¹¹ ; -O-; -S-; -C (= O) OR ¹¹ ; -C (= NOR ¹¹ ) and -NR ¹¹ ;
R ³ , R ⁴ , R ⁵ and R ^{6 are} independently selected from the group consisting of H; aryl; heteroaryl; F; Cl; Br; I; -CN; CF ₃ ; -NO ₂ ; HE; -OR ⁹ ; -O (CH ₂ ) _n NR ⁷ R ⁸ ; -OCOR ⁹ ; -OCONHR ⁹ ; NH ₂ ; -CH ₂ OH; -CH ₂ OR ¹⁴ ; -NR ⁷ R ⁸ ; -NR ¹⁰ OR ⁹ ; -NR ¹⁰ CONR ⁷ R ⁸ ; -SR ¹¹ ; -S (O) _y R ¹¹ where y is 1 or 2; -CO ₂ R ⁹ ; -COR ⁹ ; -CONR ⁷ R ⁸ ; -CHO; -CH = NOR ¹¹ ; -CH = NR ⁹ ; -CH = NNR ¹¹ R ¹² ; - (CH ₂ ) _n SR ⁹ where n is 1-4; - (CH ₂ ) _n S (O) y R ⁹ ; -CH ₂ SR ¹⁵ where R ¹⁵ is alkyl with 1-4 carbon atoms; -CH ₂ S (O) _y R ¹⁴ ;
- (CH ₂ ) _n , NR ⁷ R ⁸ ; - (CH ₂ ) _n NHR ¹⁴ ; alkyl, alkenyl, alkynyl with 1-8 carbon atoms, where
(a) each alkyl, alkenyl or alkynyl with 1-8 carbon atoms is not substituted; or
(b) each alkyl, alkenyl or alkynyl with 1-8 carbon atoms is substituted with one of the substituents selected from the group consisting of 1-3 aryl with 6-10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; NO ₂ ; HE; -OR ⁹ ; -O (CH ₂ ) _n NR ⁷ R ⁸ ; -OCOR ⁹ ; -OCONHR ⁹ ; 0-tetrahydropyranyl; NH ₂ ; -NR ⁷ R ⁸ ; -NR ¹⁰ COR ⁹ ; -NR ¹⁰ CO ₂ R ⁹ ; -NR ¹⁰ ONR ⁷ R ⁸ ; -NHC (= NH) NH ₂ ; -NR ¹⁰ SO ₂ R ⁹ ; -S (O) _y R ¹¹ where y is 1 or 2; -SR ¹¹ ; -CO ₂ R ⁹ ; -CONR ⁷ R ⁸ ; -CHO; COR ⁹ ; -CH ₂ OR ⁷ ; -CH = NNR ¹¹ R ¹² ; -CH = NOR ¹¹ , -CH = NR ⁹ ; -CH = NNHCH (N = NH) NH ₂ ; -SO ₂ NR ¹² R ¹³ ; -PO (OR ¹¹ ) ₂ ; OR ¹⁴ or a monosaccharide with 5-7 carbon atoms, in which each hydroxyl group, independently of the others, may be unsubstituted or substituted by H, alkyl with 1-4 carbon atoms, alkylcarbonyloxy group with 2-5 carbon atoms or alkoxy group with 1-4 atoms carbon.

Предпочтительно А¹ и А² попарно выбирают из группы, включающей Н, Н; Н, ОН; и =0; и В и В попарно выбирают из группы, включающей Н, Н; Н, ОН; и =0; при условии, что А¹ и А² или В¹ и В² обозначают = 0.Preferred embodiments of the invention relate to fused isoindolones of formula II

Preferably, A ¹ and A ² are pairwise selected from the group consisting of H, H; H, OH; and = 0; and B and B are selected in pairs from the group comprising H, H; H, OH; and = 0; provided that A ¹ and A ² or B ¹ and B ² are = 0.

R ^{1 is} preferably H. When R ¹ is COR ⁹ and R ⁹ is aryl, R ^{9 is} preferably phenyl or naphthyl.

X in one of the positions or in both positions is preferably unsubstituted alkylene with 1-3 carbon atoms, —O— or —S—. When X is substituted with R ² , a preferred group of R ² is OR ¹⁰ . When R ² is arylalkyl having from 7 to 14 carbon atoms, such a group is preferably benzyl. When R ² is alkyl, alkenyl or alkynyl, such a group is preferably alkyl, alkenyl or alkynyl with 1-4 carbon atoms. When R ² is substituted alkyl, alkenyl or alkynyl, where the substituent is aryl, this aryl is preferably phenyl or naphthyl. When the substituent of the group R ² is —S (O) _y R ¹¹ , where R ¹¹ is aryl, it is preferably phenyl or naphthyl. When the substituent of the group R ² is —CH═NNR ¹¹ R ¹² or —SO ₂ NR ¹² R ¹³ , where R ¹² or R ¹³ is aryl, it is preferably phenyl or naphthyl. When R ¹² and R ¹³ taken together represent a linking group, such a linking group is preferably - (CH ₂ ) ₂ —X ¹ - (CH ₂ ) ₂ -, where X ^{1 is} selected from the group consisting of —O—, —S - and -CH ₂ -.

R ³ , R ⁴ , R ⁵ and R ⁶ are preferably H. When at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is aryl, it is preferably an aryl of 6-10 carbon atoms, more preferably it is phenyl or naphthyl, provided that R ³ or R ⁴ is H and R ⁵ or R ⁶ is H. When at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is alkyl, alkenyl or alkynyl with 1 -8 carbon atoms, it is preferably alkyl, alkenyl or alkynyl with 1-4 carbon atoms, with the proviso that R ³ or R ⁴ is H and R ⁵ or R ⁶ is N.

 The numerical ranges given here include all of the numbers indicated. For example, the range defined as “1-4 carbon atoms” covers the values 1, 2, 3, and 4. Unless otherwise indicated, the terms “aryl” or “heteroaryl” suggest that the aryl or heteroaryl group may be substituted or unsubstituted .

As used in the definition of R ^{14, the} term “amino acid” means a molecule containing both an amino group and a carboxyl group. The definition of this term includes an "a-amino acid", which is a carboxylic acid, to the carbon atom of which, adjacent to the carboxyl group, is attached a functional amino group. a-amino acids can be natural or synthetic. Amino acids may also include “dipeptides,” which are defined herein as two amino acids linked by a peptide bond. Thus, the structural elements of dipeptides are not limited to α-amino acids and can be any molecule containing both an amino group and a carboxyl group. Preference is given to a-amino acids, dipeptides such as lysyl-β-alanine, and aminoalkanoic acids with 2-8 carbon atoms, for example 3-dimethylaminobutyric acid.

 Pharmaceutically acceptable salts of the condensed isoindolone derivatives are also within the scope of the present invention. As used herein, “pharmaceutically acceptable salts” means inorganic acid addition salts such as hydrochloride, sulfate and phosphate, or organic acid addition salts such as acetate, maleate, fumarate, tartrate and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of pharmaceutically acceptable ammonium salts are the ammonium salt and the tetramethylammonium salt. Examples of pharmaceutically acceptable organic amine addition salts are morpholine and piperidine salts. Examples of pharmaceutically acceptable amino acid addition salts are lysine, glycine and phenyl alanine salts.

The compounds contemplated herein may be formulated into pharmaceutical compositions prepared by admixing said compounds with pharmaceutically acceptable non-toxic excipients and diluents. As indicated above, such compositions can be used for parenteral administration, for example, in the form of liquid solutions or suspensions;
for oral administration, for example, in the form of tablets or capsules; for nasal administration, for example, in the form of powders, drops in the nose or aerosols;
or for dermal use, for example, in the form of a band-aid.

 These compositions can be used in the form of dosage forms and can be obtained by methods known in pharmacology, for example, in accordance with the description given in the Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). Formulations for parenteral administration may contain, as diluents, distilled water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes and the like. In particular, useful excipients that control the release of active compounds are biocompatible and biodegradable lactides, copolymers of lactide and glycolide or copolymers of polyoxyethylene and polyoxypropylene. Other potentially useful substances promoting the parenteral administration of these active compounds are ethylene vinyl acetate copolymers, osmotic pumps, implantable injection systems and liposomes. Inhalation preparations contain lactose as fillers or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions used as drops in the nose or gel applied to the nasal mucosa. These preparations may also contain glycocholate for buccal administration, salicylate for rectal administration, or citric acid for vaginal administration. Formulations for adhesive plasters are preferably lipophilic emulsions.

 The substances of the present invention can be used as the sole active ingredient in a pharmaceutical composition or in combination with other active ingredients, for example, other growth factors that enhance nerve cell viability or axon regeneration in the treatment of cancer or HIV infection.

 The content of the compounds of the present invention in drug compositions depends on a number of factors, including the dose of the drug, the chemical properties (e.g. hydrophobicity) of the compounds used and the route of administration. Typically, the compounds of this invention can be used for parenteral administration in an aqueous physiological buffer solution containing from about 0.1 to 10% of the compound in terms of weight to volume. Typical doses are from about 1 μg / kg to about 1 g / kg of body weight per day; a preferred dose is from about 0.01 mg / kg to 100 mg / kg body weight per day. The required dose of the drug administered, apparently, depends on the type and severity of the disease, the general state of health of the subject in need, the relative biological effectiveness of the selected compound, the composition of the excipients and the method of use of the drug.

III. The use of condensed isoindolones
Condensed isoindolones have important functional pharmacological activity, which can be used in a number of areas, including research and therapy. Condensed isoindolones, as a rule, have a positive effect on the functioning and / or viability of trophic factor responsive cells and inhibit enzymatic activity, in particular, enzymes such as trk and PKC.

 Effects on the functioning and / or viability of trophic factor responsive cells, such as nerve cells, can be determined using any of the following assays: (1) cholinacetyltransferase ("ChAT") assay in spinal cord cell culture; or (2) analysis of ChAT activity in a nerve cell culture of the forebrain base ("BFN"). Suppression of enzymatic activity can be determined using assays for the inhibition of PKC and trk tyrosine kinase.

 The term “impact”, used in conjunction with the terms “functioning” and “vitality”, means a positive or negative change in their activities. A positive effect can be considered as “enhancement” or “stimulation”, and a negative effect is defined as “inhibition” or “suppression”.

 The terms “enhancing” or “stimulating”, used in conjunction with the terms “functioning” or “viability”, means that the presence of condensed isoindolone has a positive effect on the functioning and / or viability of cells that are responsive to trophic factor, compared with cells not exposed exposure to condensed isoindolone. In particular, using non-limiting cholinergic neurons as an example, it can be shown that fused isoindolone enhances the viability of cholinergic neurons with an increased risk of death (due to damage, disease, degenerative state or natural development) compared to cholinergic neurons that are not exposed to such condensed isoindolone if the period of functioning of the treated cell population increases compared to the untreated population cell population.

 As used herein, the terms “inhibition” and “inhibition” mean that said reaction of a particular substance (eg, enzymatic activity) does not occur in the presence of a condensed isoindolone.

 As used herein, the term "neuron", "cell line of neurons" and "nerve cell" means, but is not limited to, a heterogeneous population of types of nerve cells having one or more mediators and / or performing one or more functions; such cells are preferably cholinergic and sensory neurons. The phrase "cholinergic neurons" as used herein means neurons of the central and peripheral nervous system, of which acetylcholine is a neurotransmitter; examples of such cells are neurons of the base of the forebrain and spinal cord. The phrase “sensory neurons” as used herein means neurons that respond to stimuli (eg, temperature, movement) of the skin, muscles and joints; examples of such cells are DRG neurons.

 The “trophic factor responsive cells” discussed herein are receptor cells with which the trophic factor can specifically bind; examples of such cells are neurons (eg, cholinergic and sensory neurons) and non-neuron cells (eg, monocytes and neoplastic cells).

 The term "trk" refers to a family of high-affinity neurotrophin receptors, which includes trk A, trk B and trk C, as well as other membrane-related proteins with which neurotrophin can bind.

A. Impact on the functioning and / or viability of trophic factor responsive cells
Considered condensed isoindolones can be used to enhance the functioning and / or viability of the cell line of neurons. In this regard, condensed isoindolones can be used separately or together with other condensed isoindolones, as well as in combination with other effective molecules, such as indolecarbazoles, which also have the ability to affect the functioning and / or viability of these cells.

 A number of neurological disorders are associated with death, damage, destruction of axons, an increased risk of nerve cell death, etc. These disorders include, but are not limited to, Alzheimer's disease; diseases associated with motor neurons (e.g. amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (e.g., stroke, ischemia); Huntington's disease; dementia in AIDS; epilepsy multiple sclerosis; peripheral neuropathy (for example, damage to DRG neurons in peripheral neuropathy due to chemotherapy), including diabetic neuropathy; disorders caused by excitatory amino acids; disturbances associated with concussions or penetrating injuries of the brain or spinal cord.

 As shown in the examples given in this section of the description of the invention, the ability of a condensed isoindolone to enhance the functioning and / or viability of a cell line of neurons can be determined using (1) analysis of ChAT activity of the spinal cord or (2) analysis of ChAT activity of the forebrain base.

 ChAT catalyzes the synthesis of neurotransmitter acetylcholine and is considered an enzymatic marker for functional cholinergic neurons. Functional neurons are also capable of survival. Neuronal viability is analyzed by quantifying the specific uptake and enzymatic conversion of a dye (e.g. calcein AM) by viable neurons.

 Due to the diverse action of condensed isoindolones, they are effective in a number of assays. These compounds can be used to create in vitro models of nerve cell viability, their functioning and identification, or to analyze other synthetic compounds that have the same effect as condensed isoindolones. These compounds can be used in research work, the purpose of which is the study, detection and determination of target cells at the molecular level related to functional reactions. For example, if condensed isoindolones that cause certain cell functions (e.g., mitogenee) are labeled with a radioactive isotope, it is possible to identify, isolate and purify the target cells to which the condensed isoindolones bind, with a view to their subsequent investigation.

Degeneration, death or non-functioning of neurons are signs of many neurological disorders in humans, which include, but are not limited to, Alzheimer's disease; diseases associated with motor neurons (e.g. amyotrophic lateral sclerosis);
Parkinson's disease; cerebrovascular disorders (e.g., stroke, ischemia); Huntington's disease; dementia in AIDS; epilepsy; multiple sclerosis; disturbances associated with concussions or penetrating injuries of the brain or spinal cord; peripheral neuropathy; disorders caused by excitatory amino acids. Since the considered compounds effectively increase the activity of ChAT, the scope of the present invention includes the use of these compounds for the treatment of disorders associated, for example, with reduced activity or death of DRG neurons.

Example III (A) (1). Analysis of the activity of ChAT spinal cord
As indicated above, ChAT is a specific biochemical marker for functional cholinergic neurons. Cholinergic neurons are directly related to the formation of the hippocampus, olfactory nuclei, nuclei of the brain, cortex, amygdala and parts of the thalamus. Motor neurons located in the spinal cord are cholinergic neurons containing ChAT (Phelps et al., J. Comp. Neurol. 273: 459-472 (1988)). ChAT activity is used to study the effects of neurotrophins (e.g., NGF or NT-3) on the viability and / or functioning of cholinergic neurons. ChAT analysis also serves to determine changes in ChAT levels in cholinergic neurons.

 Derivatives of condensed isoindolones increase the activity of ChAT when performing analysis in a culture of a dissociated spinal cord of a rat embryo (Fig. 1). Compound 1-2 increases the activity of ChAT by 150% compared to control cultures (which were not treated with condensed isoindolone) after culturing the cells on the plate for 2-3 hours in order to attach them to control wells with tissue culture. When performing these analyzes, the condensed isoindolone is added directly to the dissociated spinal cord culture. The compounds of the present invention increase ChAT activity of the spinal cord. Active are compounds that increase the activity of ChAT by at least 120% compared with the activity of the control culture. An increase in ChAT activity is observed after a single injection of condensed isoindolone. The specified compound was administered on the same day when a culture of dissociated spinal cord cells was obtained. An increase in ChAT activity was detected after 48 hours.

 Methods

Rat embryonic spinal cord cells were dissociated and used to perform assays in accordance with the methods described (Smith et al., J. Cell Biology 101: 1608-1621 (1985); Glicksman et al., J. Neurochem. 61: 210-221 ( 1993)). Dissociated cells were obtained from rat spinal cord (day 14-15 of embryo development) using standard trypsin dissociation methods (Smith et al., J. Cell Biology 10: 1608-1621 (1985)). Cells were placed at 6 x 10 ⁵ cells / cm ² in tissue culture wells of a plastic tablet coated with poly-1-ornithine in N ₂ medium without serum supplemented with 0.05% bovine serum albumin (Bottenstein et al., PNAS USA 76: 514-517 (1979)). The cultures were incubated for 48 hours at a temperature of 37 ^{° C.} in a humid atmosphere consisting of 5% CO ₂ and 95% air. ChAT activity was determined after 2 days in vitro using the Fonnum method (Fonnum, J. Neurochem. 24: 407-409 (1975)), modified by McManaman et al. And Glixman et al. (McManaman et al. Developmental Biology 125: 311- 320 (1988); Glicksman et al., J. Neurochem. 61: 210-221 (1993)).

Example III (A) (2). Analysis of ChAT activity of the forebrain base
Condensed isoindolone derivatives were analyzed for their ability to increase ChAT activity in forebrain base cultures. It was found that condensed isoindolones increase the activity of ChAT in cultures of the base of the forebrain (figure 2). Control cultures were not treated with condensed isoindolone.

 When performing preliminary analyzes of ChAT activity, the forebrain bases of compounds 1-3 and 1-4 did not increase ChAT activity.

 Methods

In rat embryos, the forebrain base was dissected (day 17 or 18 of embryo development) and cells were dissociated with a neutral protease (Dispase ^™ , Collaborative Research). Neurons were placed at a density of 5 x 10 ⁴ cells / well (1.5 x 10 ⁵ cells / cm ² ) on plates coated with poly-1-ornithine and laminin. Cells were cultured at 37 ^{° C.} in N ₂ medium without serum containing 0.05% bovine serum albumin in a humid atmosphere consisting of 5% CO ₂ and 95% air. ChAT activity was determined 5 days after cultivation using the ChAT assay described in Example III (A) (1).

B. Inhibition of enzymatic activity
The ability of indolcarbazole K-252a to inhibit the enzymatic activity of PKC is well known and described in the scientific literature. Inhibition of PKC activity is considered one of the possible ways to suppress, mediate, weaken and / or prevent various diseases, including inflammatory diseases, allergic and cancerous conditions, as indicated in the following references, namely, US patents 4877776 and 4923986; in the published description of the invention to European patent 558962 (issued September 8, 1993 by ER Squibb & Sons, Inc.); Tadka, T. et al., 170 (3) Biochem. Biophys. Res. Comm. 1151, 1980). The tyrosine kinases to which trk belongs are enzymes that catalyze the transfer of adenosine triphosphate γ-phosphate (ATP) to the tyrosine hydroxyl group of many basic proteins. It has been established that tyrosine kinases of activated proteins are the products of about half of the known oncogenes (see Chang, CJ & Geahlen, RL 55 (11) J. Nat. Prods. 1529, 1992), therefore, to suppress, mediate, weaken and / or prevent a number of cancer, it is necessary to inhibit the activity of protein kinase (see above, Chang, CJ).

 Due to the relationship that exists between protein kinase activity and certain diseases and disorders (for example, cancer), condensed isoindolones can be effectively used in research and medical practice. In research work, these compounds can be used, for example, to create assays and models to understand the role played by protein kinase inhibition (e.g., PKC, trk tyrosine kinases) in the mechanism of the occurrence of certain disorders and diseases. In medical practice, compounds that inhibit such enzymatic activity can be used to eliminate the deleterious effects of these enzymes, resulting in the occurrence of disorders such as cancer.

 The data below indicate inhibition of the enzymatic activity by the considered condensed isoindolones as a result of the following analyzes: (1) analysis of the inhibition of PKC activity; (2) analysis of inhibition of trkA tyrosine kinase activity.

Example III (B) (1). PKC Activity Inhibition Assay. Condensed isoindolones inhibit the activity of protein kinase C (Table VI). The protein kinase C analysis described in the literature (Murakata et al., US Pat. No. 4,923,986; Kikkawa et al., J. Biol. Chem. 257: 13341-13348 (1982)) was performed at several concentrations of condensed isoindolones and the concentration allowing 50% to be inhibited was determined. protein kinases C (IC ₅₀ ), table I and III.

Example III (B) (2). TrkA tyrosine kinase activity inhibition assay
Condensed isoindolones inhibit tyrosine kinase activity by performing an enzyme-linked immunosorbent assay (ELISA). trkA is a high affinity receptor for neurotrophins. Condensed isoindolones were placed on 96-well microtiter plates that were pre-coated with a phosphorylating substrate (phospholipase C-γ (PLCγ) / pGEX fusion protein) (see Rotin et al., 11 EMBO J. 559, 1992). These compounds were then analyzed for their ability to inhibit substrate phosphorylation with trkA tyrosine kinase, table. II and III
Methods
96-well plates for performing enzyme-linked immunosorbent assay (Nunc) coated 100 μl / well of phosphorylating substrate (40 μg / ml PLCγ / pGEX fusion protein) in 20 mmol Trisbuffer, pH 7.6, 137 mmol NaCl and 0.02% NaN ₃ and left overnight at a temperature of 4 ^o C. Then the tablets were washed three times with TBST (20 mmol Tris buffer, pH 7.6, 137 mmol NaCl, 0.2% Tween-20) and blocked 3% bovine serum albumin in TBST for 1 hour at a temperature of 37 ^o C. the Tablets were washed three times with TBST, and then washed twice with TBS (TBST without Tween-20). Then, to the reaction mixture (50 mmol N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4, 5 mmol MnCl ₂ , 5 ml MgCl ₂ , 140 mmol NaCl, 16 μmol adenosine triphosphate and 15 ng trkA in a total volume of 100 μl) condensed pyrrolocarbazoles were added in different amounts. To obtain a negative control sample, 100 mmol of ethylenediaminetetraacetic acid (EDTA) was added to the reaction solution. Then the plates were incubated at a temperature of 37 ^o C for 15 minutes. Identifying antibodies, in particular monoclonal antibodies against phosphotyrosine (UBI), were added at a dilution ratio of 1: 2000 in TBST and incubated for 1 hour at 37 ^° C. Then the plates were washed three times with TBST and incubated for 1 hour at 37 ^{° C.} with goat anti-mouse immunoglobulin labeled with alkaline phosphatase (with a ratio of 1: 2000 in TBST (Bio-Rad)). The culture was washed three times with TBST and then washed twice with TBS, resulting in a colored product when using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a substrate for alkaline phosphatase and carrying out the reactions of combining diaphorase and dehydrogenase alcohol (GIBCO-BRL amplification system by ELISA). The colored product was identified at 490 nm in a spectrophotometer for reading tablets (Bio-tek).

IV. General Description of Synthesis Methods
The compounds of the present invention are prepared according to the general preparation methods described below. Compounds in which X = CH ₂ , CH ₂ are shown in FIG. 3. The well-known 2-2'-binden (3, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (2)) was obtained using an improved method for combining 2- (tributylstannyl) indene (2 ) with 2-bromindene (1) catalyzed by palladium. 2- (Tributylstannyl) indene (2) (Example IV (1)) (FIG. 3) was obtained from 2-bromodendene (1) according to the method described in the scientific literature (J. Org. Chem., 1982, 47, 705) . Aryl-substituted 2-bromoindenes can be obtained from indenes or 1 or 2-indanones using methods known in the field of organic synthesis.

The cycloaddition of compounds of general formula 3 to maleic acid imide (method 1), preferably carried out at a temperature of 160-200 ^{° C.} , gives the corresponding tetrahydroisoindolyl dione 4 (R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; example IV (3)). The cycloaddition reactions of 2- (2-indenyl) indenes have not been previously described. Cycladdition reactions of dienes to maleic acid imides are well known (see, for example, J. Chem. Soc., Perkin Trans. 1, 1990, 2475). The compound of Example IV (3) is dehydrogenated by known methods using, for example, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, activated carbon Pd, sulfur or sodium nitrite (US Pat. No. 4,912,197 and the references therein). reference), to obtain the corresponding aromatized derivative 5 of isoindolonimide (Example IV (4)) (compound 1-1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H). Lactams of general formula 6 (Example IV (5), compound 1-2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H) can be obtained by reducing imide 5 with reducing agents (for example, zinc amalgam, gaseous hydrogen chloride, zinc amalgam in acetic acid, zinc in glacial acetic acid or hydride reducing agents such as lithium aluminum hydride). In cases where R ² , R ³ , R ⁴ , R ⁵ or R ⁶ are not H, isomers of the position of the lactam are obtained (general formulas 6 and 7). Isomers of the position of the lactam can be separated by standard methods, such as recrystallization
or chromatography, for example, column chromatography or high performance liquid chromatography. Imides can be reduced to hydroxylactams (8, FIG. 3), in which A ¹ , A ² or B ¹ , B ² = H, OH, using hydride reducing agents such as borohydrides or aluminum hydrides (US Pat. Nos. 4,192,107 and 4,923,986 and them links). The resulting hydroxyl group can be easily converted to an alkoxyl or thioalkyl group (US Pat. No. 4,923,986). Derivatives in which A ¹ , A ² or B ¹ , B ² taken together are S or N are prepared as described in European Patent Application 0508792 Al.

According to method II (FIG. 15), cycloaddition of the corresponding diene to acetylenedicarboxylates (R = lower alkyl) gives the corresponding aromatic compounds of the general formula 39. Isobenzofurans (general formula 40) can be obtained by dealkylation of the ester with nucleophiles (for example, Lil, NaCN, NaSCH ₃ , NaSCN, etc.) followed by the preparation of anhydride in acetic anhydride. Imides of general formula 41 can be obtained by reacting isobenzofurans of formula 40 with 1,1,1,3,3,3-hexamethyldisilazane and methanol (Tetrahedron Lett. 1990, 31, 5201-5204). Lactams of general formula 42 can be prepared by reducing imide with 41 reducing agents (e.g., zinc amalgam, hydrogen chloride gas, zinc amalgam in acetic acid, zinc in glacial acetic acid, or hydride reducing agents such as lithium aluminum hydride). In cases where R ² , R ³ , R ⁴ , R ⁵ or R ⁶ are not H or the X groups have different meanings, isomers of the position of the lactam are obtained (general formulas 42 and 43). Lamam position isomers can be separated by standard methods such as recrystallization or chromatography, for example, column chromatography or high-performance liquid chromatography. Imides can be reduced to hydroxylactams (44, FIG. 15) as described above.

In particular, compounds in which X = S are shown in FIG. 13. 2,2'-Dibenzothiafen (25, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (6)) was prepared according to the method described for compound 3. Cycle addition of compounds of general formula 25 to diethylacetylene dicarboxylate, preferably at a temperature of 180-200 ^{° C.,} gives the corresponding carboethoxy dibenzothiafen (26, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (7)). The cycloaddition reactions of 2,2'-bisbenzothiaphenes have not been previously described. Carboethoxy dibenzothiaphenes can be converted to the corresponding isobenzofurans (27, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (8)) by dealkylation of the ester with nucleophiles (e.g. Lil, NaCN, NaSCH ₃ , NaSCN, etc.) followed by the preparation of anhydride in acetic anhydride (method II). Imides of general formula 28 ((compound 1-3), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (9)) can be obtained by reacting isobenzofuran of formula 27 with 1.1 , 1,3,3,3, -hexamethyldisilazane and methanol as described above (method II). Lactams of general formula 29 ((compound 1-4), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; example IV (10)) can be obtained by reducing imide 28 with reducing agents as described in method I. Imides can be reduced to hydroxylactams (30, Fig.13) in accordance with the above description.

The synthesis of asymmetric indenylbenzothiafen (X = S, CH ₂ ) is shown in FIG. 14. 2- (2'-Indenyl) benzothiafen (31, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (11)) was prepared according to the method described above for the compound of formula 3 The cycloaddition of compounds of general formula 31 to diethylacetylene dicarboxylate affords the corresponding carboethoxy dibenzothiafen (32, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (12)). Carboethoxy dibenzothiophenes 32 are converted to the corresponding isobenzofurans (33, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (13)) by dealkylation of the ester with nucleophiles followed by the preparation of anhydride in acetic anhydride, such as described above. The imides of general formula 34 ((compound 1-5), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; example IV (14)) can be obtained in accordance with the methods shown in Fig.13 . Lactams of general formula 35 ((compound I-6), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ = H; Example IV (10)) can be obtained by reducing imide with 34 reducing agents (for example, zinc amalgam hydrogen chloride gas, zinc amalgam in acetic acid, zinc in glacial acetic acid or hydride reducing agents such as lithium aluminum hydride). In cases where R ² , R ³ , R ⁴ , R ⁵ or R ⁶ are not H, isomers of the position of the lactam are obtained. Isomers of the position of the lactam can be separated by standard methods, such as recrystallization or chromatography, for example, column chromatography or high-performance liquid chromatography. Imides can be reduced to hydroxylactams (37, Fig. 14) as described above.

Derivatives of condensed isoindolones of the general formula II in which X = CH ₂ CH ₂ or CH = CH are prepared using the methods described for compounds of formula 6 or 7 (FIG. 3), except that instead of 2-bromindene and / or 2 - (tributylstannyl) indene, a 2-bromo- or 2- (tributylstannyl) -3,4-dihydronaphthalene derivative is used (FIG. 4). Aryl-substituted 2-bromo-3,4-dihydronaphthalenes can be obtained from 1- or 2-tetralones in accordance with organic synthesis methods. Replacing the indene derivatives with a 2-benzocycloheptene derivative (J. Am. Chem. Soc. 13: 1344, (1991); J. Org. Chem. 44: 1342 (1979)) gives condensed isoindolones of formula II in which X = CH ₂ CH ₂ CH ₂ . Derivatives of a ketone in which X denotes C = 0 can be obtained by oxidation of imide (5) or lactam (6 or 7) with standard oxidizing agents (e.g. SeO ₂ , CrO ₃ , Na ₂ CrO ₇ or MnO ₂ ) (Fig. 5) . Alternatively, derivatives (11) in which X = (C = 0, H) can be obtained using 2-bromoinden-1-one (9) as the starting material (J. Org. Chem., 1994, 59, 3453 ), with which you can get 2- (tributylstannyl) -inden-1-one (10) according to the method described in example IV (1) (Fig.6). Similarly, derivatives (12) in which X = (C = 0, C = 0) can be obtained as a result of the interaction of 2-bromoinden-1-one (9) with 2- (tributylstannyl) -inden-1-one ( Fig.7).

Compounds with other groups X, such as X = S, O or C = 0 (Formula II), can be prepared by cycloaddition to the corresponding diene or imide of maleic acid, as described in Method I (FIG. 4), or in accordance with methods described for method II (FIG. 15). For example, 2- (2 - (1-oxoindenyl)) indene (X = (C = 0), CH ₂ ), 2,2 '- (1-oxo) biinden (X = (C = 0), (C = 0)), 2- (2-indenyl) benzothiophene (X = CH ₂ , S), 2- (2-indenyl) benzofuran (X = CH ₂ , O), 2,2'-dibenzothiophene (X = S, S ), 2- (2-benzothienyl) benzofuran (X = S, O) can be obtained by combining the corresponding 2-tri-butylstannyl derivative with the corresponding 2-bromaryl or heteroaryl derivative. The desired compounds can also be obtained by treating, for example, 2- (2-benzothienyl) benzofuran (X = S, O) or 2- (2-benzothienyl) benzothiophene (X = S, S) with maleic acid imide in the presence of an acid catalyst such as trifluoroacetic acid or Lewis acid (SnCl ₄ , Et ₂ AlCl), which gives the compound of General formula 13 (Fig.8). These compounds can be cyclized to produce the corresponding derivatives of 14 condensed isoindolones by treating with a catalyst, for example, Pd (OAc) ₂ in glacial acetic acid or Pd (OAc) ₂ , tetrachloro-1,4-benzoquinone in C ₂ H ₄ Cl ₂ (FIG. 8).

 The palladium-catalyzed crosslinking method, which is well known in the field of organic synthesis, is used to prepare other derivatives, for example, those in which X shown in FIG. 8 represents 1-3 carbon atoms (inclusive), for which the vinyl coupling reaction is performed A -2- (trifluoromethanesulfonate) derivative of the corresponding cyclic ketone or a 2-triflate derivative of the corresponding aryl or heteroaryl moiety with an acceptable tin derivative described above.

Derivatives in which nitrogen having an R ¹ group is attached by a hydrogen atom can be converted to an R ¹ group as described for compounds of formula I (US Pat. No. 4,923,986).

Derivatives of the formula I, in which the substituents R ³ , R ⁴ , R ⁵ or R ⁶ are not H, are prepared according to the procedures described above, using a properly substituted intermediate as the starting compound, or using standard methods used in the field of organic synthesis for interconversion of functional groups.

Derivatives with the substituent R ² in which the group X is an olefin with a double bond (formula II) can be obtained by olefination of derivatives in which X = (C = 0, C = 0 or C = 0, H) (Fig. 9) , as a result of Wittig reactions known in the field of organic synthesis. The obtained alkenes (15) can be reduced to compounds of the general formula (16) (Fig. 9). Derivatives in which X = CH ₂ can easily be alkylated by reaction with a strong base such as BuLi, NaNH ₂ or LiN (iPr) ₂ , and subsequent treatment with an acceptable electrophile (J. Med. Chem, 1992, 35, 3919; J. Org. Chem, 1991, 56, 4499) (FIG. 10).

Condensed isoindolones of the formula I, in which rings B and / or F can independently contain nitrogen, oxygen or sulfur atoms, as described above for E ¹ and E ² , can be obtained in the same way as carbocyclic analogues (11 and 12).

The preparation of derivatives in which ring B is a 6-membered nitrogen-containing heterocyclic ring (nitrogen is in any of 6 positions) is shown in FIG. 11. The cycloaddition of a compound of general formula 17 to maleic acid amide gives compounds of general formula 18. Dehydrogenation of intermediate 18, similarly to the method for preparing the compound of Example IV (4) (FIG. 3), gives imide derivatives of general formula 19 (FIG. 11). The lactam isomers of general formula 20 can be obtained by reacting derivatives of the imide of general formula 19 with reducing agents, such as zinc amalgam and HCl, zinc amalgam in acetic acid or hydride reducing agents, for example, lithium aluminum hydride. The positional isomers can be separated by standard methods such as recrystallization or chromatography, for example, column chromatography or high-performance liquid chromatography. The imides are reduced to hydroxylactams, in which A ¹ , A ² or B ¹ , B ² = H, OH, hydride reducing agents such as borohydrides or aluminum hydrides.

 Compounds in which ring B or F is a 5-membered ring containing oxygen or sulfur can be prepared using furylpyrroles or thienpyrroles instead of indenes as starting materials according to the synthesis schemes shown in FIGS. 3 and 4. Condensed furyl pyrroles rings can be obtained in accordance with the methods described in the literature or their modifications (Coll. Czech. Chem. Commun. 53: 1770 (1988); Can. J. Chem. 56: 1429 (1978); CR Hebd. Seances Acad. Sci. Ser. C 281: 793 (1975)). Condensed ring thienyl pyrroles can also be prepared according to the methods described in the literature and their modifications (Belgian patent application BE 899925; Ind. J. Chem. 20B: 271 (1981); Can J. Chem. 56: 1429 (1978); Bull. Soc. Chim. Fr. 11-12 pt2: 2511 (1975); CR Hebd. Seances Acad. Sci., Ser. C 277: 1149 (1973)).

Alternatively, compounds in which ring B or F contains nitrogen atoms can be prepared using cycloalkane-condensed pyridine derivatives (X = C ₁ -C ₃ alkylene) as starting compounds. Methods for the synthesis of cycloalkanone pyridine derivatives are described in the literature (J. Med. Chem. 36: 3381 (1993), Chem Ber., 1970, 103, 2403) and these compounds can be used to prepare intermediates of the general formula 21 or 22 (FIG. 12) . Condensed ring derivatives of cycloalkyl or cycloalkanone pyridine can be converted to cyclic vinyl bromides using known organic synthesis techniques. Intermediates, such as vinyl bromide, are acceptable substrates for the tin crosslinking method of FIGS. 3 and 4.

Compounds in which the ring F contains an oxygen atom can be prepared using furyl condensed cycloalkanones or cycloalkenyl derivatives (X = C ₁ -C ₃ alkylene) as starting compounds. Compounds in which ring F contains sulfur atoms can be prepared using fused cycloalkenylthiophenes as starting materials. Thienyl and furyl derivatives with a fused cycloalkyl ring can be obtained using methods described in the literature (Acta Chem. Scand. 25: 1287 (1971); J. Am. Chem. Soc. 103: 2760 (1981)) or their modifications. These intermediates can be converted to furyl or thienyl cyclopentanones or furyl or thienyl cyclopentenes. The starting materials can alternatively be converted to the corresponding cyclic vinyl bromides using known methods of organic synthesis. Intermediates, such as vinyl bromide, can be used to prepare the desired intermediates by the tin crosslinking methods of FIGS. 3 and 4.

 Rings B and F can be simultaneously substituted with heteroatoms, as shown in FIG. Intermediate 23 can be prepared from tin intermediate 22 substituted with a heteroatom in ring B and cyclic vinyl bromide 21 substituted with a heteroatom in ring F (or a triflate of the corresponding cyclic ketone intermediate). Derivatives of imide and lactam containing heteroatoms in rings B and F can be obtained according to the methods shown in figures 3 and 4. Derivatives of imide of General formula 20 (Fig. 11) and 24 (Fig. 12) can alternatively be obtained using the addition reaction Michael and the subsequent ring closure reaction catalyzed by palladium, which is presented in Fig. 8. The reduction of imides in accordance with the previously described methods gives isomers of lactam.

Legend
¹ H NMR - ¹ H NMR spectrum; (s) - singlet, (d) - doublet, (m) - multiplet, (bs) - wide singlet, (q) - quartet, (t) - triplet, (dd) - doublet of doublets;
MS is the mass spectrum; ES - electrostatic ionization; APCI - chemical ionization at atmospheric pressure; DMF - dimethylformamide; DMSO - dimethyl sulfoxide; THF - tetrahydrofuran; etc. - the melting temperature.

Example IV (1). 2- (Tributylstannyl) inden
Palladium (II) acetate (304 mg, 11.4 mmol), tetrakis (triphenylphosphine) palladium (0) are added to a round-bottom flask containing 2-brominindene (1.64 g, 8.4 mmol) in 75 ml of Et ₃ N. (775 mg, 0.7 mmol) and hexabutyl diol tin (6.4 ml, 12.7 mmol). The reaction mixture was heated to reflux and the progress of the reaction was monitored by thin layer chromatography (silica gel, EtOAc: hexane, 1: 5). After 1 hour, the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, diluted with CH ₂ Cl ₂ and filtered through celite. The solvent was removed under reduced pressure, and the resulting compound was purified on a silica gel column (5% EtOAc-hexane mixture), which afforded 4.7 g of 2-tributylstannylindinene as a clear oil (containing trace amounts of hexabutyl diol). This compound is used in the next step without further purification. ¹ H NMR (300 MHz, CDC1 ₃ ): δ_0.9 (m, 15H), 1.2 (m, 6H), 1.6 (m, 6H), 3.5 (s, 2H), 7.10 (s, 1H), 7.5- 7.2 (m, 4H).

Example IV (2). 2,2'-Biinden
A 100 ml round bottom flask equipped with a reflux condenser was charged with 1.2 g (6.3 mmol) of 2-bromodenden, 3.4 g (8.4 mmol) of 2-tributylstannilindene (Example IV (1)) and 70 ml of ethanol. To this mixture was added 442 mg (0.63 mmol) of bis (triphenylphosphine) palladium (II) chloride. The reaction mixture was stirred at reflux for 16 hours, after which it was allowed to cool to room temperature, diluted with diethyl ether (50 ml) and filtered through a layer of alumina. The solvent was concentrated under reduced pressure, and the obtained product was recrystallized from toluene, which afforded 870 mg (60%) of 2,2'-bindene, etc. = 238 ^° C (the literature indicates the like = 238 ^° C;
Chem. Ber., 1988, 121, 2195).

¹ H NMR (300 MHz, CDC1 ₃ ): δ 3.73 (s, 4H), 6.93 (s, 2H), 7.30 (m, SH). MS (ES ⁺ ) m / z = 231 (M +1)
Example IV (3). 1a, 3a, 4,7-Tetrahydroindenyl [2,3-c] indenyl [2,3-e] isoindole-1,3-dione
98 mg (0.4 mmol) of 2,2'-bindene (Example IV (2)), 43 mg (0.44 mmol) of maleic acid imide, 5 mg of 2,6-di-tert are loaded into a hermetically sealed tube from borosilicate -butyl-p-cresol (BHT) and 1 ml of CH ₂ Cl ₂ . The tube is sealed and the reaction mixture is heated to 130 ^{° C.} for 24 hours, after which it is allowed to cool to room temperature and the solvent is concentrated under reduced pressure. The crude solid is purified by column chromatography (silica gel, 10-75% EtOAc-hexane) to give 50 mg (38%) of a white solid, etc. 244-247 ^o C.

¹ H NMR (300 MHz, CDC1 ₃ ): δ 3.68 (s, 4H), 3.80 (m, 2H), 4.00 (bs, 2H), 7.24 (m, 7H), 7.53 (d, J = 7 Hz, 2H ), MS (ES ⁺ ) m / z = 328 (M +1)
Example IV (4). 1 H-Indenyl [2,3-c] -1H-indenyl [2,3-e] isoindole-1,3-dione (compound I-1)
To the mixture of the compound of Example IV (3) (50 mg, 0.15 mmol) in toluene (4 ml), solid 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (79 mg, 0) is added in one portion , 35 mmol). The reaction mixture is heated in nitrogen atmosphere at a temperature of 65-70 ^o C for 4 hours. The solution was cooled in an ice bath and the solid was collected by filtration. The crude residue was washed with cold methanol to give a pale yellow solid (28 mg, 63%), etc. 244-247 ^o C.

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.17 (d, 4 Hz, 2H), 7.55 (m, 7H), 4.15 (s, 4H); MS (ES): m / z 346 (M + 1).

Example IV (5). 1 H-Indenyl [2,3-c] -1 H-indenyl [2,3-e] -3H-isoindol-1-one (compound I-2)
A zinc amalgam is obtained, for which 122 mg (1.9 mmol) of zinc dust are suspended in 1 ml of water and 35 mg (0.08 mmol) of HgCl ₂ and 4 drops of conc. Hcl. This mixture was stirred for 10 minutes, after which the aqueous layer was drained. The amalgam is washed with water and again with ethanol.

The above zinc amalgam was suspended in 5 ml of ethanol and compound I-1 (Example IV (4)) (10 mg, 0.03 mmol) was added. Add a few drops of conc. Hcl, after which the reaction mixture was heated under reflux for 3 hours. When the mixture is heated for the first hour, the yellow color disappears. The reaction mixture was allowed to cool to room temperature, after which the solution was concentrated under reduced pressure. The residue was dissolved in 10 ml of a mixture of THF - EtOAc (1: 1), washed with saturated solutions of NaHCO ₃ and NaCl and dried (MgSO ₄ ). The desiccant is removed by filtration and the solvent is concentrated under reduced pressure to obtain 8 mg (88%) of lactam as a white solid, etc. 256 ^o C.

¹ H NMR (300 MHz, CDC1 ₃ ): δ 9.20 (d, 8 Hz, 1H), 7.50 (m, 6H), 6.24 (s, 1H), 4.83 (s, 2H), 4.05 (s, 2H), 3.95 (s, 2H); MS (ES): m / z 310 (M + 1).

Example IV (6). 2,2'-Dibenzothiafen
3.3 g (15.6 mmol) of 2-bromobenzothiafene, 7.3 g (17 mmol) of 2- (tri-n-butyltin) benzothiaphene and 40 ml of toluene are charged into a two-necked round bottom flask equipped with a reflux condenser. To this mixture was added 360 mg (0.3 mmol) of tetrakis (triphenylphosphine) palladium (0) and 5 mg of 2,6-di-tert-butyl-p-cresol (BHT). The reaction mixture was heated under reflux for 16 hours, after which it was cooled to room temperature and the solvent was removed in vacuo. The reaction mixture was dissolved in DMF and filtered through celite. The solvent was removed in vacuo and the solid was triturated with hexanes to give 3.58 g (13.4 mmol, 85% yield) of 2,2'-dibenzothiaphene as a silver-black solid, etc. = 260- 262 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ 7.98 (m, 2H), 7.62 (s, 1H), 7.36 (m, 2H), 7.25 (s, 1H).

Example IV (7). 3,4-Carboethoxybenzothienyl [1,2-a] dibenzothiafen
1.02 g (3.8 mmol) of 2,2'-dibenzothiaphene, 3.1 ml (19 mmol) of diethylacetylene dicarboxylate and 5 mg of 2,6-di-tert-butyl-p-cresol (BHT) are charged into a sealed glass tube ) The reaction vessel is sealed in an atmosphere of N ₂ and heated at a temperature of 190 ^o C. the Reaction mixture is left to interact for 24 hours. Then the reaction vessel was cooled and its contents were transferred to a round bottom flask by adding CHCl ₃ , and the solvent was removed in vacuo. The solid is taken up in diethyl ether and filtered to give 468 mg (1.07 mmol, 28%) of 3,4-carboethoxybenzothienyl [1,2-a] dibenzothiaphene as a pale yellow solid, etc. 206-207 ^o C. The second crystallization gives another 280 mg of substance, resulting in a total yield of 45%.

¹ H NMR (300 MHz, DMSO ₆ ) δ 8.27 (d, 7.4 Hz, 2H), 8.05 (d, 7.9 Hz, 2H), 7.65 (m, 4H), 4.57 (q, 7.1 Hz, 4H), 1.38 ( t, 7.1 Hz, 6H).

Example IV (8). Benzothienyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione
500 mg (1.15 mmol) of 3,4-carboethoxybenzothienyl [1,2-a] dibenzothiafen and 50 ml of DMF are charged into a round bottom flask. To this mixture were added 124 mg (2.5 mmol) of sodium cyanide and 476 mg (2.5 mmol) of solid lithium iodide trihydrate. The reaction mixture is heated to a temperature of 150 ^o C and analyzed by thin layer chromatography. An additional amount of NaCN and LiI are then added. The reaction lasts 36 hours, and during this time a total of 4 equivalents of NaCN and LiI are added, after which the starting material is completely consumed. The reaction mixture was cooled to room temperature and poured onto a cold (0 ^° C) aqueous HCl solution. The mixture is filtered and washed with water. The resulting solid was dried in vacuo.

The above crude solid was charged into a round bottom flask and 50 ml of acetic anhydride was added. Then the reaction mixture is heated to the boiling temperature under reflux. The mixture is heated under reflux for 4 hours, after which the results of thin-layer chromatography show that the reaction is complete (new spot at Rf 0.65 in a mixture of EtOAc; hexanes, 1: 1). The solvent was removed and the crude oil was purified by flash chromatography to give a bright yellow-orange solid. This solid was triturated with diethyl ether to give 160 mg (0.44 mmol, 40% yield) of benzothienyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione as bright yellow solid, etc. > 300 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ 9.54 (dd, 5.2 Hz, 2.5 Hz, 2H), 8.34 (dd, 4.0 Hz, 3.3 Hz, 2H), 7.73 (m, 4H).

Example IV (9). Benzothiene [2,3-c] benzothiene [2,3-e] isoindole-1,3-dione (compound I-3)
Benzothienyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione (75 mg, 0.2 mmol) was dissolved in 3 ml of DMF. To this mixture was added 4.4 ml (20.8 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 30 μl (1 mmol) of methanol. After about 15 minutes, the suspension becomes clear. After 1 hour, thin layer chromatography is performed, which shows that the starting material has been consumed almost completely. The reaction mixture was stirred overnight, with a total reaction time of 18 hours. The solvent was removed to give 65 mg (0.18 mmol, 80% yield) of benzothien [2,3-c] benzothien [2,3-e] isoindole-1,3-dione as a yellow solid, etc. > 300 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ 9.8 (dd, 5.0 Hz, 4.1 Hz, 2H), 8.25 (dd, 4.9 Hz. 4.1 Hz, 2H), 7.70 (m, 4H):
Example IV (10). Benzothiene [2,3-c] benzothiene [2,3-e] isoindol-1-one (compound I-4)
To a 10 ml suspension of zinc amalgam (3 equivalents) in ethanol, 68 mg (0.18 mmol) of benzothien [2,3-c] benzothien [2,3-e] isoindole-1,3-dione are added as a solution in 10 ml acetic acid. 5 ml of concentrated HCl was added to the reaction mixture and it was heated to reflux. The reaction mixture is heated under reflux overnight, after which it becomes transparent and acquires a slightly tan color. The reaction mixture is cooled and the mercury layer is drained. Most of the solvent was removed, after which the mixture was diluted with ethyl acetate and washed twice with saturated NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and the solvent removed. The crude reaction mixture was purified by column chromatography to give 65 mg (0.18 mmol, 100% yield) of benzothien [2,3-c] benzothien [2,3-e] isoindol-1-one as a tan solid , etc. 225-226 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ 10.17 (dd, 6.4 Hz, 2.7 Hz, 1H), 8.22 (s, 1H), 8.21 (dd, 4.1 Hz, 3.7 Hz, 2H), 8.11 (dd, 6.5 Hz, 2.2 Hz, 1H), 7.63 (s, 3.7 Hz, 2H), 7.55 (t, 3.7 Hz, 2H), 5.19 (s, 2H).

Example IV (11): 2- (2'-Indenyl) benzothiafen
A two-necked round bottom flask equipped with a reflux condenser was charged with 2 g (13.3 mmol) of 2-bromodenden, 5.1 g (11.9 mmol) of 2- (tri-n-butyltin) benzothiaphene and 50 ml of toluene. To this mixture was added 1 g (1.5 mmol) of bis (triphenylphosphine) palladium (II) dichloride and 5 mg of 2,6-di-tert-butyl-p-cresol (BHT). The reaction mixture was refluxed for 16 hours and cooled. The solvent is removed, the reaction mixture is taken up in a mixture of DMF - THF and filtered through celite. The solvent was removed and the solid was triturated with hexanes to give 1.4 g (5.6 mmol, 47% yield) of 2- (2'-indenyl) benzothiaphene as an orange solid, etc. = 260-265 ^o C.

¹ H NMR (DMSO d ₆ ) δ 7.82 (m, 4H), 7.61 (s, 1H), 7.35 (m, 5H), 3.97 (s, 2H).

Example IV (12). 3,4-Carboethoxyindenyl [1,2-a] dibenzothiafen
480 mg (3.95 mmol) of 2- (2'-indenyl) benzothiaphene, 3.2 ml (19 mmol) of diethylacetylenedicarboxylate and 10 mg of 2,6-di-tert-butyl-p-cresol are charged into a sealed glass tube VNT). The reaction vessel is sealed in an atmosphere of N ₂ and heated at a temperature of 190 ^o C. the Reaction mixture is left to interact for 24 hours. The reaction vessel is cooled, its contents are transferred to a round bottom flask by adding CHCl ₃ , and the solvent is removed. The crude material is passed through a silica gel column and the upper fractions are collected. The resulting solid was taken up in diethyl ether and filtered to give 538 mg (1.29 mmol, 23%) of 3,4-carboethoxyindenyl [1,2-a] dibenzothiaphene as a pale orange solid, etc. 186 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ 8.15 (d, 7.4 Hz, 1H), 7.95 (d, 7.4 Hz, 1H), 7.71 (m. 2H), 7.56 (m, 2H), 7.41 (m, 2H), 4.50 (q, 7.0 Hz, 4H), 4.22 (s, 2H), 1.33 (t, 7.0 Hz, 6H).

Example IV (13). Indenyl [4, 5-a] benzothienyl [6, 7-a] isobenzofuran-1,3-dione
250 mg (0.6 mmol) of 3,4-carboethoxyindenyl [1,2-a] dibenzothiafen and 10 ml of pyridine are charged into a round bottom flask. To this mixture was added 677 mg (3.6 mmol) of lithium iodide trihydrate. The reaction mixture is heated to 115 ^{° C.} and analyzed by thin layer chromatography. Then add an additional amount of LiI. The reaction lasts 36 hours, and during this time a total of 5 equivalents of LiI are added, after which the starting material is completely consumed. The reaction mixture was cooled to room temperature and poured onto a cold (0 ^° C) aqueous HCl solution. The mixture is filtered and washed with water. The resulting solid was dried in vacuo.

The above crude solid was charged into a round bottom flask and 50 ml of acetic anhydride was added. The reaction mixture was heated to reflux. The mixture is heated under reflux for 4 hours, after which thin-layer chromatography is performed, which indicates the completion of the reaction (new spot at Rf 0.6 in a mixture of EtOAc hexanes, 1: 1). The solvent was removed and the crude oil was purified by flash chromatography to give a bright yellow-orange solid. This solid was triturated with diethyl ether to give 160 mg (0.44 mmol, 40% yield) of indenyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione as bright yellow solid, etc. > 300 ^o C.

¹ H NMR (300 MHz, DMSO d ₆ ) δ_9.65 (d, J = 7.2 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.15 (s, J = 7.4 Hz, 1H), 7.78 -7.38 (m, 5H); 4.97 (s, 2H).

Example IV (14). Indenyl [2, 3-c] benzothienyl [2, 3] isoindole-1,3-dione (compound I-5)
Indenyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione (120 mg, 0.35 mmol) was dissolved in 3 ml of DMF. 7.4 ml (35 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 50 μl (1 mmol) of methanol are added to this mixture. After about 15 minutes, the suspension becomes clear. Thin layer chromatography, which is performed after 1 hour, shows that the starting material is almost completely consumed. The reaction mixture was stirred overnight, with a total reaction time of 18 hours. The solvent was removed to give 35 mg (0.18 mmol, 30% yield) of indenyl [2,3-c] benzothienyl [2,3-e] isoindole-1,3-dione as an orange solid.

¹ H NMR (300 MHz, DMSO d ₆ ) δ_12.72 (s, 1H), 9.84 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.82-7.28 (m, 5H), 5.03 (s, 2H), MS (APcI) 342 (M + H)
Example IV (15). Indenyl [2,3-c] benzothienyl [2,3-e] isoindol-1- and -3-one (compound I-6)
To a 2 ml suspension of Zn amalgam (3 equivalents) in ethanol was added 10 mg (0.3 mmol) indenyl [2,3-c] thianaphthene [2,3-e] isoindole-1,3-dione as a solution in 10 ml acetic acid. 1 ml of concentrated HCl was added to the reaction mixture and it was heated to reflux. The reaction mixture is heated under reflux for 3 hours, as a result of which it becomes transparent and acquires a slightly tan color. The reaction mixture is cooled and the mercury layer is drained. Most of the solvent is removed, the mixture is diluted with ethyl acetate and washed twice with saturated NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and the solvent removed to give the compound as a mixture of indenyl [2,3-c] thianaphthene [2,3-e] isoindol-1- and -3-one, which is a tan solid substance.

 Mass spectrum (chemical ionization at atmospheric pressure) 329 (M + H).

 Despite the detailed description of the present invention, it is not limited to this description, and its scope is determined by the attached claims and all equivalent modifications.

Claims (3)

1. Condensed isoindolones of the formula

where rings B and F independently represent a 6-membered carbocyclic aromatic ring;
R ^{1 is} selected from the group consisting of H and alkyl with 1-4 carbons;
A ¹ and A ² are pairwise selected from the group consisting of = O, H, —OR ¹¹ , where R ¹¹ is H;
In ¹ and In ² are = O;
X in all positions is independently selected from the group consisting of (a) unsubstituted alkylene with 1-3 carbon atoms and (b) -S-;
R ³ , R ⁴ , R ⁵ and R ^{6 are} independently selected from the group consisting of H and alkyl with 1-4 carbons.  2. The compound according to claim 1, where X in any position or in both positions is unsubstituted alkylene with 1-3 carbon atoms.  3. The compound of claim 1, wherein X in either position or in both positions is —S—.

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