Title:
NEW 2,3-BENZODIAZEPINE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2001/004122
Kind Code:
A2
Abstract:
The invention relates to new 2,3-benzodiazepine derivatives of general Formula (I), (wherein R?1¿ stands for methyl, formyl, carboxy, cyano, -CH=NOH, -CH=NNHCONH¿2? or -NR?5¿R?6¿, wherein R?5¿ and R?6¿ independently from each other represent hydrogen or lower alkyl or together with the nitrogen atom, they are attached to, form a 5- or 6-membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R?2¿ is nitro or amino; R?3¿ stands for hydrogen, lower alkanoyl or CO-NR?7¿R?8¿, wherein R?7¿ and R?8¿ independently from each other stand for hydrogen, lower alkoxy, lower alkyl or lower cycloalkyl or together with the nitrogen atom, they are attached to, form a 5- or 6-membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R?4¿ is hydrogen or lower alkyl; the dotted lines have the following meaning: if R?3¿ and R?4¿ are not present, the bond between positions C?8¿ and C?9¿ is a single bond and the bond between positions C?8¿ and N?7¿ is a double bond; if R?3¿ and R?4¿ are present, the bonds between positions C?8¿ and C?9¿ and between position C?8¿ and N?7¿ are single bonds; and if R?3¿ is present and R?4¿ is missing, the bond between positions C?8¿ and C?9¿ is a double bond and the bond between positions C?8¿ and N?7¿ is a single bond) and salts thereof. The invention compounds have neuroprotective effect.
Inventors:
GREFF ZOLTAN (HU)
SZABO GEZA (HU)
BARKOCZY JOZSEF (HU)
RATKAI ZOLTAN (HU)
BLASKO GABOR (HU)
SIMIG GYULA (HU)
GIGLER GABOR (HU)
MARTONNE MARKO BERNADETT (HU)
LEVAY GYOERGY (HU)
TIHANYI KAROLY (HU)
EGYED ANDRAS (HU)
SIMO ANNAMARIA (HU)
SZABO GEZA (HU)
BARKOCZY JOZSEF (HU)
RATKAI ZOLTAN (HU)
BLASKO GABOR (HU)
SIMIG GYULA (HU)
GIGLER GABOR (HU)
MARTONNE MARKO BERNADETT (HU)
LEVAY GYOERGY (HU)
TIHANYI KAROLY (HU)
EGYED ANDRAS (HU)
SIMO ANNAMARIA (HU)
Application Number:
PCT/HU2000/000074
Publication Date:
January 18, 2001
Filing Date:
July 04, 2000
Export Citation:
Assignee:
EGYT GYOGYSZERVEGYESZETI GYAR (HU)
GREFF ZOLTAN (HU)
SZABO GEZA (HU)
BARKOCZY JOZSEF (HU)
RATKAI ZOLTAN (HU)
BLASKO GABOR (HU)
SIMIG GYULA (HU)
GIGLER GABOR (HU)
MARTONNE MARKO BERNADETT (HU)
LEVAY GYOERGY (HU)
TIHANYI KAROLY (HU)
EGYED ANDRAS (HU)
SIMO ANNAMARIA (HU)
GREFF ZOLTAN (HU)
SZABO GEZA (HU)
BARKOCZY JOZSEF (HU)
RATKAI ZOLTAN (HU)
BLASKO GABOR (HU)
SIMIG GYULA (HU)
GIGLER GABOR (HU)
MARTONNE MARKO BERNADETT (HU)
LEVAY GYOERGY (HU)
TIHANYI KAROLY (HU)
EGYED ANDRAS (HU)
SIMO ANNAMARIA (HU)
International Classes:
A61K31/551; A61P1/08; A61P13/00; A61P21/00; A61P25/00; A61P25/04; C07D491/056; A61P25/06; A61P25/08; A61P25/16; A61P25/18; A61P25/22; A61P25/28; A61P25/30; C07D491/04; C07D243/00; C07D317/00; (IPC1-7): C07D491/04; A61K31/551; A61P25/00
Domestic Patent References:
| WO1999007707A1 | 1999-02-18 | |||
| WO1992011262A1 | 1992-07-09 | |||
| WO1997034878A1 | 1997-09-25 | |||
| WO1995001357A1 | 1995-01-12 |
Foreign References:
| EP0492485A1 | 1992-07-01 |
Attorney, Agent or Firm:
Advopatent (P.O. Box 11, Budapest, HU)
Download PDF:
Claims:
What we claim is,
| 1. | Compounds of the general Formula (wherein R'stands for methyl, formyl, carboxy, cyano,CH=NOH, CH=NNHCONH2 orNR5R6, wherein R5 and R6 independently from each other represent hydrogen or lower alkyl or together with the nitrogen atom, they are attached to, form a 5 or 6membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R2 is nitro or amino; R3 stands for hydrogen, lower alkanoyl or CONR'R8, wherein R7 and R8 independently from each other stand for hydrogen, lower alkoxy, lower alkyl or lower cycloalkyl or together with the nitrogen atom, they are attached to, form a 5or 6 membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom (s); R4 is hydrogen or lower alkyl; the dotted lines have the following meaning: if R3 and R4 are not present, the bond between positions C8 and C9 is a single bond and the bond between positions C8 and N7 is a double bond; if R3 and R4 are present, the bonds between positions C8 and C9 and between positions C8 and N7 are single bonds; and if R3 is present and R4 is missing, the bond between positions C8 and C9 is a double bond and the bond between positions C8 and N7 is a single bond) and pharmaceutically acceptable salts thereof. |
| 2. | Compounds of the general Formula (wherein Rr and R2 are as stated in Claim 1) and pharmaceutical acceptable acid addition salts thereof. |
| 3. | Compounds of the general Formula (wherein R1, R2, R3 and R4 are as stated in Claim 1) and pharmaceutically acceptable acid addition salts thereof. |
| 4. | Compounds of the general Formula (wherein R', R2and R3 are as stated in Claim 1) and pharmaceutically acceptable acid addition salts thereof. |
| 5. | Compounds according to any of Claims 14 wherein R2 is amino. |
| 6. | Compounds of the general Formula IB according to Claim 5. |
| 7. | Compounds according to Claim 6 wherein R' stands for methyl or cyano; R2 is amino; R3 represents lower alkanoyl orCONR7R8; R7 is hydrogen; R8 is lower alkyl, lower alkoxy or lower cycloalkyl and R4 represents hydrogen or methyl. |
| 8. | The following compound according to Claim 7: 7acetyl5(4amino3methylphenyl)7,8dihydro8methyl 9H1,3dioxolo [4,5h] [2,3] benzodiazepine. |
| 9. | The following compounds according to Claim 7: 5 (3methyl4aminophenyl)7propionyl7,8dihydro8 methyl9H1,3dioxolo [4,5h] [2,3] benzodiazepine; <BR> <BR> <BR> 5 (4amino3methylphenyl)7 (Ncyclopropylcarbamoyl)7,8 dihydro8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4amino3methylphenyl)7 (Nmethoxycarbamoyl)7,8 dihydro8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4amino3methylphenyl)7 (Nmethylcarbamoyl)7,8 dihydro8methyl9H1,3dioxolo [4,5h] [2,3] benzodiazepine; <BR> <BR> <BR> 5 (4amino3methylphenyl)7acetyl8cyano7, 8dihydro8 methyl9H1,3dioxolo [4,5h] [2,3] benzodiazepine; 5(4amino3methylphenyl)8cyano7propionyl7,8dihydro 8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine. |
| 10. | Compounds according to Claim 4 wherein R'is methyl; R2 stands for amino; R3 is lower alkanoyl orCO NR7R8; R7 is hydrogen and R8 represents lower alkyl, lower alkoxy or lower cycloalkyl. |
| 11. | The following compounds according to Claim 10: 7acetyl5 (4amino3methylphenyl)8rhethyl7H1,3 dioxolo [4, 5h] [2,3]benzodiazepine; 7 (Nmethylcarbamoyl) 5 (4amino3methylphenyl)8 methyl7H1,3dioxolo [4,5h] [2,3] benzodiazepine ; 7 (Ncyclopropylcarbamoyl) 5 (4amino3methylphenyl)8 methyl7H1,3dioxolo [4,5h] [2,3] benzodiazepine. |
| 12. | Process for the preparation of compounds of the general Formula I (wherein R'stands for methyl, formyl, carboxy, cyano,CH=NOH, CH=NNHCONH2 orNR5R5, wherein R5 and R6 independently from each other represent hydrogen or lower alkyl or together with the nitrogen atom, they are attached to, form a 5 or 6membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R2 is nitro or amino; R3 stands for hydrogen, lower alkanoyl or CoNR7R8, wherein R7 and R8 independently from each other stand for hydrogen, lower alkoxy, lower alkyl or lower cycloalkyl or together with the nitrogen atom, they are attached to, form a 5or 6 membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R4 is hydrogen or lower alkyl; the dotted lines have the following meaning: if R3 and R4 are not present, the bond between positions C8 and C9 is a single bond and the bond between positions C8 and N7 is a double bond; if R3 and R4 are present, the bonds between positions C8 and C9 and between positions C8 and N7 are single bonds; and if R3 is present and R4 is missing, the bond between positions C8 and C9 is a double bond and the bond between positions C8 and N7 is a single bond) and pharmaceutically acceptable acid addition salts thereof which comprises a) for the preparation of 8formyl5 (3methyl4nitro phenyl)9H1,3dioxolo [4,5h] [2,3] benzodiazepine of the Formula III, oxidizing 8methyl5 (4nitro3methylphenyl)9H1,3 dioxolo [4,5h] [2,3] benzodiazepine of the Formula or b) for the preparation of 5 (3methyl4nitrophenyl) 9H1, 3dioxolo [4,5h] [2,3] benzodiazepine8carboxylic acid of the Formula oxidizing8formyl5(3methyl4nitrophenyl)9H1,3 dioxolo [4,5h] [2,3] benzodiazepine of the Formula III ; or c) for the preparation of compounds of the general Formula (wherein Y stands for a leaving group), reacting the compound of the Formula IV with a compound capable of introducing group Y; or d) for the preparation of the compound of the general Formula (wherein R7 and R3 are as stated above), reacting the carboxylic acid of the Formula IV or a reactive derivative thereof of the Formula V with an amine of the general Formula HNR7R8; or e) for the preparation of compounds of the general Formula (wherein R'stands for cyano,CH=NOH or CH=NNHCONH2), converting in the compound of the Formula III the formyl group into an R'group; or for the preparation of compounds of the general Formula (wherein R'and R4 are as stated above), saturating the C8N7 double bond by addition or reduction; or g) for the preparation of compounds of the general Formula (wherein R3 is lower alkanoyl), reacting a compound of the general Formula VIII with a compound capable of introducing a lower alkanoyl group; or h) for the preparation of compounds of the general Formula (wherein Y is a leaving group and R'and R4 are as stated above), reacting a compound of the general Formula Vlil with a compound capable of introducing theCOY group; or i) for the preparation of compounds of the general Formula (wherein R', R4, R7 and R8 are as stated above), reacting a compound of the general Formula X or the corresponding free carboxylic acid with an amine of the general Formula HNR R I or j) for the preparation of compounds of the general Formula (wherein Z stands for a leaving group), reacting the compound of the Formula II with a compound capable of introducing theCOZ group; or k) for the preparation of compounds of the general Formula (wherein R7 and R8 are as stated above), reacting a compound of the general Formula Xll with an amine of the general Formula HNR7R8; or I) for the preparation of compounds of the general Formula I, wherein R2 stands for amino, reducing the corresponding compound of the general Formula I, wherein R2 is nitro; and, if desired, converting a compound of the general Formula I into a pharmaceutically acceptable acid addition salt thereof or setting free a compound of the general Formula I from a salt. |
| 13. | Process according to process 1) of Claim 12 which comprises reducing a compound of the general Formula II, VII, IX, orXIII.XII. |
| 14. | Process according to Claim 13 which comprises carrying out reduction by using stannous (II) chloride, sodium dithionite or by means of catalytic hydrogenation. |
| 15. | Process according to Claim 14 which comprises using a Raneynickel, palladium or platinum catalyst, and as hydrogen source hydrogen, hydrazine, hydrazine hydrate, formic acid, trialkyl ammonium formate or an alkali formate. |
| 16. | Pharmaceutical composition which comprises as active ingredient a compound of the general Formula I (wherein R'stands for methyl, formyl, carboxy, cyano,CH=NOH, CH=NNHCONH2 orNR5R6, wherein R5 and R6 independently from each other represent hydrogen or lower alkyl or together with the nitrogen atom, they are attached to, form a 5 or 6membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom (s); R2 is nitro or amino; stands for hydrogen, lower alkanoyl or CoNR7R8, wherein R7 and R8 independently from each other stand for hydrogen, lower alkoxy, lower alkyl or lower cycloalkyl or together with the nitrogen atom, they are attached to, form a 5or 6 membered, saturated or unsaturated heterocyclic ring optionally containing one or more further nitrogen, sulfur and/or oxygen atom(s); R4 is hydrogen or lower alkyl; the dotted lines have the following meaning: if R3 and R4 are not present, the bond between positions C8 and C9 is a single bond and the bond between positions C8 and N7 is a double bond; if R3 and R4 are present, the bonds between positions C8 and C9 and between positions C8 and N7 are single bonds; and if R3 is present and R4 is missing, the bond between positions C8 and C9 is a double bond and the bond between positions C8 and N7 is a single bond) or a pharmaceutically acceptable acid addition salt thereof. |
| 17. | Pharmaceutical composition according to Claim 16 which comprises as active ingredient a compound of the general Formula I wherein R2 is amino. |
| 18. | Pharmaceutical composition according to Claim 17 which comprises as active ingredient a compound of the general Formula IB. |
| 19. | Pharmaceutical composition according to Claim 18 which comprises as active ingredient a compound of the general Formula IB, wherein R'stands for methyl or cyano; R2 is amino; R3 represents lower alkanoyl orCONR7R8; R7 is hydrogen; R8 is lower alkyl, lower alkoxy or lower cycloalkyl and R4 represents hydrogen or methyl. |
| 20. | Pharmaceutical composition according to Claim 19 which comprises as active ingredient 7acetyl5 (4amino3 methylphenyl)7, 8dihydro8methyl9H1, 3dioxolo[4,5 h] [2,3] benzodiazepine. |
| 21. | Pharmaceutical composition according to Claim 19 which comprises as active ingredient 5 (3methyl4amino phenyl)7propionyl7, 8dihydro8methyl9H1, 3dioxolo[4,5 h] [2,3] benzodiazepine; <BR> <BR> <BR> <BR> 5 (4amino3methylphenyl)7 (Ncyclopropylcarbamoyl)7,8 dihydro8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4amino3methylphenyl)7 (Nmethoxycarbamoyl)7,8 dihydro8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4amino3methylphenyl)7 (Nmethylcarbamoyl)7,8 dihydro8methyl9H1, 3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4amino3methylphenyl)7acetyl8cyano7, 8d ihydro8 methyl9H1,3dioxolo [4,5h] [2,3] benzodiazepine; 5 (4am ino3methylphenyl)8cyano7propionyl7, 8d ihyd ro 8methyl9H1,3dioxolo [4,5h] [2,3] benzodiazepine. |
| 22. | Pharmaceutical composition according to Claim 16 which comprises as active ingredient a compound of the general Formula IC wherein R'is methyl ; R2 stands for amino; R3 is lower alkanoyl orCONR7R8; R7 is hydrogen and R8 represents lower alkyl, lower alkoxy or lower cycloalkyl. |
| 23. | Pharmace. utical composition according to Claim 22 which comprises as active ingredient 7acetyl5 (4amino3methylphenyl)8methyl, 7H1,3 dioxolo [4,5h] [2,3] benzodiazepine; 7 (Nmethylcarbamoyl) 5 (4amino3methylphenyl)8 methyl7H1, 3dioxolo [4,5h] [2,3] benzodiazepine; <BR> <BR> <BR> <BR> 7 (Ncyclopropylcarbamoyl) 5 (4amino3methylphenyl)8 methyl7H1,3dioxolo [4,5h] [2,3] benzodiazepine. |
| 24. | Pharmaceutical compositions having neuroprotective effect, useful in the treatment of symptoms accompanied by all kinds of acute and chronical neurodegeneration, especially Parkinson disease, Alzheimer disease, amyotropic lateral sclerosis, stroke, acute head injuries, epilepsy, against spasms, alleviation of pain, to influence vomitting, schisophreny, migraine, urination problems, as anxyolitics, against drug addiction and to alleviate the symptoms of Parkinsonism. |
| 25. | Process for the preparation of pharmaceutical compositions according to Claims 1623 which comprises admixing a compound of the general Formula I or a pharmaceutically acceptable acid addition salt thereof with inert solid or liquid pharmaceutical carriers and bringing the mixture to a galenic form. |
| 26. | Use of compounds of the general Formula I and pharmaceutically acceptable acid addition salts thereof for the preparation of pharmaceutical compositions having neuroprotective effect, useful in the treatment of symptoms accompanied by all kinds of acute and chronical neurodegeneration, especially Parkinson disease, Alzheimer disease, amyotropic lateral sclerosis, stroke, acute head injuries, epilepsy, against spasms, alleviation of pain, to influence vomitting, schisophreny, migraine, urination problems, as anxyolitics, against drug addiction and to alleviate the symptoms of Parkinsonism. |
| 27. | Method of treatment of diseases according to Claim 26 which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the general Formula I or a pharmaceutically acceptable acid addition salt thereof. |
Description:
INTERNATIONAL SEARCH REPORT | Inte ionalApplicationNo ! nte jona! App)! cation No) PCT/HU 00/00074 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y WO 95 01357 A (GYOGYSZERKUTATO INTEZET 1-27 KFT.) 12 January 1995 (1995-01-12) the whole document 1 INTERNATIONAL SEARCH REPORT Inte'ional Application No Information on patent family members PCT/HU 00/00074 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9907707 A 18-02-1999 HU 9701380 A 28-06-1999 HU 9701381 A 28-06-1999 AU 8818198 A 01-03-1999 CN 1272846 T 08-11-2000 EP 1003749 A 31-05-2000 NO 20000655 A 10-04-2000 PL 338680 A 20-11-2000 WO 9211262 A 09-07-1992 HU 59683 A 29-06-1992 AU 9122691 A 22-07-1992 CA 2098291 A 22-06-1992 EP 0565557 A 20-10-1993 JP 6506442 T 21-07-1994 WO 9734878 A 25-09-1997 AU 2527097 A 10-10-1997 EP 1021418 A 26-07-2000 JP 2000506890 T 06-06-2000 US 5891871 A 06-04-1999 EP 492485 A 01-07-1992 HU 59684 A 29-06-1992 US 5459137 A 17-10-1995 AT 160350 T 15-12-1997 AU 641578 B 23-09-1993 AU 8996391 A 25-06-1992 BR 9105517 A 01-09-1992 CA 2057504 A 22-06-1992 CN 1062730 A, B 15-07-1992 CN 1191111 A 26-08-1998 CZ 9103985 A 19-01-1994 DE 69128236D 02-01-1998 DE 69128236 T 14-05-1998 DK 492485 T 27-07-1998 ES 2112848 T 16-04-1998 FI 916032 A 22-06-1992 GR 3026127 T 29-05-1998 HR 920677 A 31-08-1994 IL 100449 A 31-12-1995 JP 2756742 B 25-05-1998 JP 5070463 A 23-03-1993 KR 169134 B 15-01-1999 MX 9102734 A 01-06-1992 NO 300376 B 20-05-1997 NZ 241110 A 27-04-1994 SI9111966 A30-04-1998 RU 2102387 C 20-01-1998 US 5604223 A 18-02-1997 US 5536832 A 16-07-1996 US 5519019 A 21-05-1996 US 5521174 A 28-05-1996 US 5639751 A 17-06-1997 ZA 9110064 A 28-10-1992 WO 9501357 A 12-01-1995 HU 67611 A 28-04-1995 AU 7236394 A 24-01-1995