CA2066457A1 - N-substituted naphthalimides, their preparation and use - Google Patents
N-substituted naphthalimides, their preparation and useInfo
- Publication number
- CA2066457A1 CA2066457A1 CA002066457A CA2066457A CA2066457A1 CA 2066457 A1 CA2066457 A1 CA 2066457A1 CA 002066457 A CA002066457 A CA 002066457A CA 2066457 A CA2066457 A CA 2066457A CA 2066457 A1 CA2066457 A1 CA 2066457A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- melting point
- naphthalimide
- substituted
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical class C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- -1 N-substituted naphthalamides Chemical class 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- GRSMWKLPSNHDHA-UHFFFAOYSA-N Naphthalic anhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=CC3=C1 GRSMWKLPSNHDHA-UHFFFAOYSA-N 0.000 claims description 2
- 230000000719 anti-leukaemic effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 230000000840 anti-viral effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 230000004614 tumor growth Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000002844 melting Methods 0.000 description 31
- 230000008018 melting Effects 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DYWWDZQRZYAPHQ-UHFFFAOYSA-N 3-benzoyl-4-ethyl-4-methyl-2-phenyl-1,3-oxazolidin-5-one Chemical compound O1C(=O)C(CC)(C)N(C(=O)C=2C=CC=CC=2)C1C1=CC=CC=C1 DYWWDZQRZYAPHQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UKPBXIFLSVLDPA-UHFFFAOYSA-N propylhydrazine Chemical compound CCCNN UKPBXIFLSVLDPA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Luminescent Compositions (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The description relates to N-substituted naphthalamides of the formula (I) in which X, Y and R-R4 have the meanings given in the description and their production. The compounds are suitable for combatting diseases.
Description
r~
~~ O.~. 0480~01077 N-Substi~uted naphthalLmides, the preparation and use thereof Description The invention relates to novel N-substitu~ed naphthalimides, to a process for the preparation thereof, and to the use thereof for controlling diseases.
It has been disclosed that certain benzo[de]iso-quinolines have tumor-inhibiting properties (Afinidad 35 tl978) 105, Cance~ Chemother. Pharmacol. 4 (1980) 61, Eur. J. Ned. Chem.-Chimica Ther. 16 (1981) 207, ArzneLm.
Forsch.JDrug Research 34 (II) (1984) 1243, J. Med. Chem.
28 (1985) 1216). However, the actions of these compounds are not satisfactory in every respect.
It has now been found that N-substituted naph-thalLmides of the formula I
O R ll /R3 ~ N-CH-I-N\ I, in which X and Y are identical or different and are hydrogen, nitro, amino or NH-CO R' (R' = Clg-alkyl, phenyl, benzyl or naphthyl), R is a hydrogsn atom or a Cl4-al~yl group/
Rl is a hydrogen atom or a Cl4-alkyl group, RZ is a hydrogen atom or a Cl4-alkyl group, and R3 and R4 are identical or different and are hydrogen atoms, Cl4-alkyl groups or together with the nitro-gen atom a pyrrolidine or piperidine ring, but with at least one of the substituents R, R1 or R2 not being hydrogen, and the salts thereof with physiologi-cally tolerated acids, have an improved action and an improved spectrum of action as tumor-inhibiting 2 2 0 ~ lZ . 0480/01077 substance~ and have antileukemic activity.
The compounds in which R1 i5 a methyl group and R
and R2 are hydrogen atoms are preferred. R3 and R4 are preferably methyl or ethyl groups.
5Phy~iologically tolerated acids suitable for salt formation are organic and inorganic acids such as hydro-chloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic 10acid, malic acid, methanesulfonic acid, isethionic acid, lactic acid, gluconic acid, glucuronic acid, amidosul-fonic acid, benzoic acid, tartaric acid and pamoic acid.
The novel compounds may be in solvated form. Such forms can be formed, or example, with water or ethanol.
15The novel compounds are prepared by reacting a 1,8-naphthalic anhydride of the formula II
x ~0 I I, o Y
in which X and Y have the stated meaning, with an amine of the formula III
2 ~ H ~N--C~ I--N~ I I 1, in which R-R4 have the stated meaning, and converting the re3ulting compounds into their ~alts with physiologically tolera~ed acids where appropriate.
~he reaction is carried out in a suitable solvent ; 25 ~uch as dimethylformamide, methanol, ethanol, propanol or ; acetone, u~ually at room temperature. The compound according to the invention separates out of the reaction mixture and can be purified by chromatography a~d~or recrystallization.
.
~ _ 3 ~ 57 o.z. 0480/0107i The compounds obtained in this way can be conver~
ted in a conventional manner into their salts, eg. by reaction with an acid.
The starting compounds of the formula XI are known or can be prepared by known processes.
The starting compounds II in which X and/or Y are acylamino groups can be react:ed [5iC] from the corre~pon~
ding amino compounds by reaction with the appropria~e anhydrides or acid chlorides for example with the addi-tion of an inorganic or organic base (Na2CO3, R2C0~
N(CzH5)3r pyridine) in an inert solvent such as DMFp toluene, dioxane, THF or methylene chloride where ap-propriate with the addition of an acylation catalyst suGh as N,N-dimethylaminopyridine between room temperature and the reflux temperature of the solvent. It is also pos-sible to prepare the amides by the methods customary in peptide chemistry for forming amide linkages, for example by reacting the amines with carboxylic acids using condensing agents such as carbodiimides.
The compounds according to the invention can be administered orally or parenterally in a conventional manner. They can be used in the conventional solid or liquid pharmaceutical forms, eg. as uncoated or film- or sugar-coated tablets, capsules, granules or solutions.
These are prepared in a conventional manner. This may entail the active compounds being processed with conven-tional pharmaceutical auxiliaries such a tablet binder~
filler3, preservatives, tablet disintegrants, flow regulators, pla3ticizer , wetting agents, dispersantR, emulsifierY, ~olvents, retardants and~or antioxidants (cf. H. Sucker et al.: Pharmazeutisrhe Teohnologie, Thieme-Verlag, Stuttgart, 1978). The forms obtained in this way normally contain the active compound in an amount of from 10 to 9a% by weight.
Example 1 A suspension of 4.9 g (20 mmol) o 3-nitro-1,8-naphthalic anhydride and 2.1 g (20 ~mol) of 2 dimethyl-2 ~ $ ~
- 4 - O.ZO 0~80/01077 amino-l-propylamine in 60 ml of ethanol was stirred at room temperature for 24 h. The precipitate was filtered off and recrystallized from ethanol. 4.5 g (70~) of N-~2-methyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalimide (melting point 176C) were obtained.
The following were prepared in analogy to Example 2. N~ Methyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalLmide, melting point 146C (ethanol), 3. N-(2,2-Dimethyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalLmide, melting point 154C (cyclohexane), 4. N-~2-Diethylamino-2-m~thylethyl)-3-nitro-1,8-naphthalimide, melting point 151C (ethanol), 5. N-~2-Methyl-2-(1-pyrrolidinyl)ethyl]-3-nitro-1,8-naphthalimide, melting poin~ 175C (ethanol), 6. N-[2-Methyl-2-(1-piperidinyl~ethyl]-3-nitro-1,8-naphthalimide, melting point 1~5C (ethanol), 7. 3-Amino-N-(2-methyl-2-dimethylaminoethyl)-1,8-naphthalLmide, melting point 195C (methanol), 8. 3-Amino-N-(1-methyl-2-dimethylaminoethyl)-lt8-naphthalimide, melting point 170C (toluene), 9. 3-Amino-N-(2,2-dimethyl-2-dimethylaminoethyl)-1,8-naphthalimide, melting point 220C (toluene), 10. 3-Amino N-(2-diethylamino-2-methylethyl)~1,8-naphthalimide, melting point 183C (ethanol), 11. 3-Amino-N-[2-methyl-2-(1-pyrrolidinyl)ethyl]-1,8-naphthalLmide, melting point 169~C (toluene), 12. 3-Amino-N-[2-methyl-2-(1-piperidinyl)ethyl]-1,8-naphthalimide, melting point 135C (ethanol~
~~ O.~. 0480~01077 N-Substi~uted naphthalLmides, the preparation and use thereof Description The invention relates to novel N-substitu~ed naphthalimides, to a process for the preparation thereof, and to the use thereof for controlling diseases.
It has been disclosed that certain benzo[de]iso-quinolines have tumor-inhibiting properties (Afinidad 35 tl978) 105, Cance~ Chemother. Pharmacol. 4 (1980) 61, Eur. J. Ned. Chem.-Chimica Ther. 16 (1981) 207, ArzneLm.
Forsch.JDrug Research 34 (II) (1984) 1243, J. Med. Chem.
28 (1985) 1216). However, the actions of these compounds are not satisfactory in every respect.
It has now been found that N-substituted naph-thalLmides of the formula I
O R ll /R3 ~ N-CH-I-N\ I, in which X and Y are identical or different and are hydrogen, nitro, amino or NH-CO R' (R' = Clg-alkyl, phenyl, benzyl or naphthyl), R is a hydrogsn atom or a Cl4-al~yl group/
Rl is a hydrogen atom or a Cl4-alkyl group, RZ is a hydrogen atom or a Cl4-alkyl group, and R3 and R4 are identical or different and are hydrogen atoms, Cl4-alkyl groups or together with the nitro-gen atom a pyrrolidine or piperidine ring, but with at least one of the substituents R, R1 or R2 not being hydrogen, and the salts thereof with physiologi-cally tolerated acids, have an improved action and an improved spectrum of action as tumor-inhibiting 2 2 0 ~ lZ . 0480/01077 substance~ and have antileukemic activity.
The compounds in which R1 i5 a methyl group and R
and R2 are hydrogen atoms are preferred. R3 and R4 are preferably methyl or ethyl groups.
5Phy~iologically tolerated acids suitable for salt formation are organic and inorganic acids such as hydro-chloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic 10acid, malic acid, methanesulfonic acid, isethionic acid, lactic acid, gluconic acid, glucuronic acid, amidosul-fonic acid, benzoic acid, tartaric acid and pamoic acid.
The novel compounds may be in solvated form. Such forms can be formed, or example, with water or ethanol.
15The novel compounds are prepared by reacting a 1,8-naphthalic anhydride of the formula II
x ~0 I I, o Y
in which X and Y have the stated meaning, with an amine of the formula III
2 ~ H ~N--C~ I--N~ I I 1, in which R-R4 have the stated meaning, and converting the re3ulting compounds into their ~alts with physiologically tolera~ed acids where appropriate.
~he reaction is carried out in a suitable solvent ; 25 ~uch as dimethylformamide, methanol, ethanol, propanol or ; acetone, u~ually at room temperature. The compound according to the invention separates out of the reaction mixture and can be purified by chromatography a~d~or recrystallization.
.
~ _ 3 ~ 57 o.z. 0480/0107i The compounds obtained in this way can be conver~
ted in a conventional manner into their salts, eg. by reaction with an acid.
The starting compounds of the formula XI are known or can be prepared by known processes.
The starting compounds II in which X and/or Y are acylamino groups can be react:ed [5iC] from the corre~pon~
ding amino compounds by reaction with the appropria~e anhydrides or acid chlorides for example with the addi-tion of an inorganic or organic base (Na2CO3, R2C0~
N(CzH5)3r pyridine) in an inert solvent such as DMFp toluene, dioxane, THF or methylene chloride where ap-propriate with the addition of an acylation catalyst suGh as N,N-dimethylaminopyridine between room temperature and the reflux temperature of the solvent. It is also pos-sible to prepare the amides by the methods customary in peptide chemistry for forming amide linkages, for example by reacting the amines with carboxylic acids using condensing agents such as carbodiimides.
The compounds according to the invention can be administered orally or parenterally in a conventional manner. They can be used in the conventional solid or liquid pharmaceutical forms, eg. as uncoated or film- or sugar-coated tablets, capsules, granules or solutions.
These are prepared in a conventional manner. This may entail the active compounds being processed with conven-tional pharmaceutical auxiliaries such a tablet binder~
filler3, preservatives, tablet disintegrants, flow regulators, pla3ticizer , wetting agents, dispersantR, emulsifierY, ~olvents, retardants and~or antioxidants (cf. H. Sucker et al.: Pharmazeutisrhe Teohnologie, Thieme-Verlag, Stuttgart, 1978). The forms obtained in this way normally contain the active compound in an amount of from 10 to 9a% by weight.
Example 1 A suspension of 4.9 g (20 mmol) o 3-nitro-1,8-naphthalic anhydride and 2.1 g (20 ~mol) of 2 dimethyl-2 ~ $ ~
- 4 - O.ZO 0~80/01077 amino-l-propylamine in 60 ml of ethanol was stirred at room temperature for 24 h. The precipitate was filtered off and recrystallized from ethanol. 4.5 g (70~) of N-~2-methyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalimide (melting point 176C) were obtained.
The following were prepared in analogy to Example 2. N~ Methyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalLmide, melting point 146C (ethanol), 3. N-(2,2-Dimethyl-2-dimethylaminoethyl)-3-nitro-1,8-naphthalLmide, melting point 154C (cyclohexane), 4. N-~2-Diethylamino-2-m~thylethyl)-3-nitro-1,8-naphthalimide, melting point 151C (ethanol), 5. N-~2-Methyl-2-(1-pyrrolidinyl)ethyl]-3-nitro-1,8-naphthalimide, melting poin~ 175C (ethanol), 6. N-[2-Methyl-2-(1-piperidinyl~ethyl]-3-nitro-1,8-naphthalimide, melting point 1~5C (ethanol), 7. 3-Amino-N-(2-methyl-2-dimethylaminoethyl)-1,8-naphthalLmide, melting point 195C (methanol), 8. 3-Amino-N-(1-methyl-2-dimethylaminoethyl)-lt8-naphthalimide, melting point 170C (toluene), 9. 3-Amino-N-(2,2-dimethyl-2-dimethylaminoethyl)-1,8-naphthalimide, melting point 220C (toluene), 10. 3-Amino N-(2-diethylamino-2-methylethyl)~1,8-naphthalimide, melting point 183C (ethanol), 11. 3-Amino-N-[2-methyl-2-(1-pyrrolidinyl)ethyl]-1,8-naphthalLmide, melting point 169~C (toluene), 12. 3-Amino-N-[2-methyl-2-(1-piperidinyl)ethyl]-1,8-naphthalimide, melting point 135C (ethanol~
13. N-(2-Nethyl-2-dimethylaminoethyl)-3,6-dinitro-1,8-naphthalimide, melting point 215C (ethanol), - 14. N-(1-Nethyl-2-dimethylaminoethyl)-3,6-dinitro-1,8-naphthalimide, melting point 220C (ethanol), 15. N-(2,2-Dimethyl-2-dimethylaminoethyl)-3,6-dinitro-1,8-naphthalimide, mel~in~ point 200C (ethanol), 16. N-(2-Diethylamino-2-methylethyl)-3,6-dinitro-1,8-naphthalimide, melting point 195C (ethanol), 2 ~ 15 ' : - 5 - O.ZO 0480/01077 17. N-[2-Methyl-2~ pyrrolidinyl)ethyl]-3,6-dinitro-1,8-naphthalimide, melting point 210C (ethanol), 18. N-[2-Methyl-2-(1-piperidinyl)ethyl]-3,6-dinitro-1,8-naphthalLmide, melting point 160C (ethanol), 19. N-~2,2-Dimethyl-2-(1-piperidinyl)ethyl]-3,6-dinitro-1,8-naphthalimide, melting point 218C (ethanol), 20. 3-Amino-N-(2-methyl-2-climethylaminoethyl)-6-nitro-1,8-naphthalimide, melting point 270~C (toluene), 21. 3-Amino-N-(1-methyl-2-climethylaminoethyl)-6-nitro-1,8-naphthalimide, melting point 250C (toluene), 22. 3-Amino~N-(2,2-dimethyl-2-dimethylaminoethyl)-6-nitro-1,8~naphthalimide, melting point 265C
(toluene), 23. 3-Amino-N-(2-diethylamino-2-methylethyl)-6~nitro-1,8-naphthalimide, melting point 247C (toluene), 24. 3-Amino-N-~2-methyl-2-(1-pyrrolidinyl)ethyl~-6-nitro-1,8-naphthalimide, melting point 230C (toluene), 25. 3~Amino-N- r 2-methyl-(1-piperidinyl)ethyl]-6-nitro-1,8-naphthalimide, melting point 235C (toluene), 26. 3-Amino-N-~2,2-dimethyl-2-(1-piperidinyl)ethyl]-6-nitro-1,8-naphthalimide, melting point 258C
(toluene), 27. 3,6-Diamino-~-(2-methyl~2-dimethylaminoethyl)-1,8-naphthalimide, melting point 276C (methanol)/
(toluene), 23. 3-Amino-N-(2-diethylamino-2-methylethyl)-6~nitro-1,8-naphthalimide, melting point 247C (toluene), 24. 3-Amino-N-~2-methyl-2-(1-pyrrolidinyl)ethyl~-6-nitro-1,8-naphthalimide, melting point 230C (toluene), 25. 3~Amino-N- r 2-methyl-(1-piperidinyl)ethyl]-6-nitro-1,8-naphthalimide, melting point 235C (toluene), 26. 3-Amino-N-~2,2-dimethyl-2-(1-piperidinyl)ethyl]-6-nitro-1,8-naphthalimide, melting point 258C
(toluene), 27. 3,6-Diamino-~-(2-methyl~2-dimethylaminoethyl)-1,8-naphthalimide, melting point 276C (methanol)/
28. 3,6-Diamino-N-(l-methyl-2-dimethylaminoethyl)-1,8-naphthalLmide, melting point 190C (methanol), 29. 3,5-Diamino-N-(2-diethylamino-2-methylethyl~-1,8-naphthalimide, melting point 200C (methanol), 30. 3,6-Diamino-N-t2-methyl-2-~l-pyrrolidinyl)e~hyl]-1,8-3~ naphthalLmide, mel~ing point 225C (methanol), 31. 3,6-Diamino-N-[2-methyl-2-tl-piperidinyl~ethyl~-l,S~
naphthalLmide, melting point 198C (methanol), 32. 3,6-Diamino-N-(2,2-dimsthyl-2-dimethylaminoethyl)-1,8-naphthalimide, melting point 280C (methanol), 33. 3,6-Diamino-N-t2,2-dimethyl-2-tl-piperidinyl)ethyl]-1,8-naphthalimide, melting point 223C (methanol).
naphthalLmide, melting point 198C (methanol), 32. 3,6-Diamino-N-(2,2-dimsthyl-2-dimethylaminoethyl)-1,8-naphthalimide, melting point 280C (methanol), 33. 3,6-Diamino-N-t2,2-dimethyl-2-tl-piperidinyl)ethyl]-1,8-naphthalimide, melting point 223C (methanol).
Claims (4)
1. N-Substituted naphthalimides of the formula I
I, in which X and Y are identical or different and are hydrogen, nitro, amino or NH3CO3R' (R' = C1-C9-alkyl, phenyl, benzyl or naphthyl), R is a hydrogen atom or a C1-4-alkyl group, R1 is a hydrogen atom or a C1-4-alkyl group, R2 is a hydrogen atom or a C1-4-alkyl group, and R3 and R4 are identical or different and are hydrogen atoms, C1-4-alkyl groups or together with the nitrogen atom a pyrrolidine or piperidine ring, but with at least one of the substituents R, R1 or R2 not being hydrogen, and the salts therein [sic] with physio-logically tolerated acids.
I, in which X and Y are identical or different and are hydrogen, nitro, amino or NH3CO3R' (R' = C1-C9-alkyl, phenyl, benzyl or naphthyl), R is a hydrogen atom or a C1-4-alkyl group, R1 is a hydrogen atom or a C1-4-alkyl group, R2 is a hydrogen atom or a C1-4-alkyl group, and R3 and R4 are identical or different and are hydrogen atoms, C1-4-alkyl groups or together with the nitrogen atom a pyrrolidine or piperidine ring, but with at least one of the substituents R, R1 or R2 not being hydrogen, and the salts therein [sic] with physio-logically tolerated acids.
2. Process for the preparation of the N-substituted naphthalimides according to claim 1, characterised in that a 1,8-naphthalic anhydride of the formula II
II, in which X and Y have the stated meaning, is reacted with an amine of the formula III
III, in which R-R4 have the stated meaning, and the resulting compounds are converted into their salts with physiologi-cally tolerated acids where appropriate.
II, in which X and Y have the stated meaning, is reacted with an amine of the formula III
III, in which R-R4 have the stated meaning, and the resulting compounds are converted into their salts with physiologi-cally tolerated acids where appropriate.
3. N-Substituted naphthalamides [sic] of the formula I
according to claim 1 for use for controlling diseases.
according to claim 1 for use for controlling diseases.
4. Use of the N-substituted naphthalamides [sic] of the formula I according to claim 1 for the preparation of drugs which inhibit tumor growth or have antileukemic or antiviral actions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3942280.1 | 1989-12-21 | ||
| DE3942280A DE3942280A1 (en) | 1989-12-21 | 1989-12-21 | N-SUBSTITUTED NAPHTHALIMIDES, THEIR PRODUCTION AND USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2066457A1 true CA2066457A1 (en) | 1991-06-22 |
Family
ID=6396009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002066457A Abandoned CA2066457A1 (en) | 1989-12-21 | 1990-12-13 | N-substituted naphthalimides, their preparation and use |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0505400B1 (en) |
| JP (1) | JPH05503509A (en) |
| AT (1) | ATE177424T1 (en) |
| CA (1) | CA2066457A1 (en) |
| DE (2) | DE3942280A1 (en) |
| DK (1) | DK0505400T3 (en) |
| ES (1) | ES2128313T3 (en) |
| WO (1) | WO1991009850A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033912A (en) * | 2017-12-28 | 2018-05-15 | 广西师范大学 | Low 1,8- Naphthalamide derivatives of a kind of toxicity and its preparation method and application |
| CN108147995A (en) * | 2017-12-28 | 2018-06-12 | 广西师范大学 | A kind of low 1,8- Naphthalamide derivatives of toxicity and its synthetic method and application |
| CN108164463A (en) * | 2017-12-28 | 2018-06-15 | 广西师范大学 | A kind of 1,8- Naphthalamide derivatives and its synthetic method and application with non-small cell lung cancer selective inhibitory |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5329048A (en) * | 1991-03-27 | 1994-07-12 | The Dupont Merck Pharmaceutical Company | Process of preparing tetraamino intermediates |
| GB9601651D0 (en) * | 1996-01-26 | 1996-03-27 | Ciba Geigy Ag | Antiretroviral bases |
| KR100364205B1 (en) | 1998-07-03 | 2002-12-11 | 다이호야쿠힌고교 가부시키가이샤 | Naphtalimidobenzamide derivatives |
| US8119656B2 (en) | 2007-12-07 | 2012-02-21 | The Board Of Regents Of The University Of Texas System | Inhibitors of the influenza virus non-structural 1 protein |
| WO2016041511A1 (en) * | 2014-09-19 | 2016-03-24 | Yen-Ta Lu | Benzo-heterocyclic compounds and their applications |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4146720A (en) * | 1976-10-27 | 1979-03-27 | Laboratorios Made, S.A. | N-aminoethyl-substituted-3-nitronaphthalimides |
| ES459497A1 (en) * | 1977-06-04 | 1978-04-16 | Made Labor Sa | N(Aminoalkyl)-naphthalimides and their derivatives |
| DE3481120D1 (en) * | 1983-04-01 | 1990-03-01 | Warner Lambert Co | 3,6-DISUBSTITUTED-1,8-NAPHTHALIMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE. |
| DE3635711A1 (en) * | 1986-10-21 | 1988-04-28 | Knoll Ag | 5-NITROBENZO (DE) ISOCHINOLIN-1,3-DIONE, THEIR PRODUCTION AND USE |
-
1989
- 1989-12-21 DE DE3942280A patent/DE3942280A1/en not_active Withdrawn
-
1990
- 1990-12-13 WO PCT/EP1990/002163 patent/WO1991009850A1/en not_active Ceased
- 1990-12-13 ES ES91900221T patent/ES2128313T3/en not_active Expired - Lifetime
- 1990-12-13 AT AT91900221T patent/ATE177424T1/en not_active IP Right Cessation
- 1990-12-13 DE DE59010865T patent/DE59010865D1/en not_active Expired - Fee Related
- 1990-12-13 JP JP3500958A patent/JPH05503509A/en active Pending
- 1990-12-13 CA CA002066457A patent/CA2066457A1/en not_active Abandoned
- 1990-12-13 DK DK91900221T patent/DK0505400T3/en active
- 1990-12-13 EP EP91900221A patent/EP0505400B1/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033912A (en) * | 2017-12-28 | 2018-05-15 | 广西师范大学 | Low 1,8- Naphthalamide derivatives of a kind of toxicity and its preparation method and application |
| CN108147995A (en) * | 2017-12-28 | 2018-06-12 | 广西师范大学 | A kind of low 1,8- Naphthalamide derivatives of toxicity and its synthetic method and application |
| CN108164463A (en) * | 2017-12-28 | 2018-06-15 | 广西师范大学 | A kind of 1,8- Naphthalamide derivatives and its synthetic method and application with non-small cell lung cancer selective inhibitory |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0505400B1 (en) | 1999-03-10 |
| DK0505400T3 (en) | 1999-09-27 |
| DE59010865D1 (en) | 1999-04-15 |
| ATE177424T1 (en) | 1999-03-15 |
| EP0505400A1 (en) | 1992-09-30 |
| DE3942280A1 (en) | 1991-06-27 |
| WO1991009850A1 (en) | 1991-07-11 |
| JPH05503509A (en) | 1993-06-10 |
| ES2128313T3 (en) | 1999-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5367076A (en) | Process for imidazo[4,5-C]quinolin-4-amines | |
| CA2209904C (en) | Di-substituted 1,4-piperidine esters and amides having 5-ht4 antagonistic activity | |
| US5661147A (en) | Imidazoquinazoline derivatives | |
| CZ18593A3 (en) | Benzimidazolyl derivatives, medicaments in which said compounds are comprised, and process for producing thereof | |
| SK283197B6 (en) | N-substituted heterocycle derivatives, their preparation, compositions containing them | |
| EP0319429B1 (en) | 9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient | |
| EP0698025B1 (en) | Ampa antagonists and a method of treatment therewith | |
| CA2219261A1 (en) | Antithrombotic amidinotetrahydropyridylalanine derivatives | |
| CA2066457A1 (en) | N-substituted naphthalimides, their preparation and use | |
| AU744402B2 (en) | Synthesis of acridine derivative multidrug-resistant inhibitors | |
| US5571832A (en) | Nitrogen-containing cyclohetero alkylamino aryl derivatives for CNS disorders | |
| CA1331177C (en) | 3-oxo-1,2,4-triazolo[4,3-a]pyrimidine-6-carboxylic acid esters | |
| US6803467B2 (en) | Intermediates for the production of quinolone carboxylic acid derivatives | |
| JP2003509494A (en) | Muscarinic antagonist | |
| US5843945A (en) | AMPA antagonists and a method of treatment | |
| WO1994006768A1 (en) | Cyclic benzylamino, benzylamido and benzylimido derivatives as antipsychotic agents | |
| JPH06228112A (en) | @(3754/24)1h,4h)quinoxaline derivative | |
| AU620195B2 (en) | New bis(aryl)alkene derivatives, processes for preparing them and pharmaceutical compositions containing them | |
| US5679679A (en) | Aralkyl diazabicycloalkane derivatives for CNS disorders | |
| GB2281860A (en) | Substituted benzene compounds as transferase inhibitors | |
| EP0040332B1 (en) | Antihypertensive lactams | |
| US5856318A (en) | Nitrogen-containing cyclohetero cyclo-heteroaminoaryl derivatives for CNS disorders | |
| US5025011A (en) | Fused pyridines active on the cardiovascular system | |
| Watanabe et al. | Synthesis of novel succinamide derivatives having the 5, 11-dihydro-6H-pyrido [2, 3-b][1, 4] benzodiazepin-6-one skeleton as potent and selective M2 muscarinic receptor antagonists. I | |
| JP2003502374A (en) | Dihydropyrazine derivatives as NPY antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |