CA1197242A - Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivatives - Google Patents
Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivativesInfo
- Publication number
- CA1197242A CA1197242A CA000422672A CA422672A CA1197242A CA 1197242 A CA1197242 A CA 1197242A CA 000422672 A CA000422672 A CA 000422672A CA 422672 A CA422672 A CA 422672A CA 1197242 A CA1197242 A CA 1197242A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- pyrrolo
- pyrimido
- carboxylic acid
- chloro
- 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.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Abstract
ABSTRACT
This invention discloses novel pyrimido[1,2-a] pyrrolo[2,1-c] [1,4]-benzodiazepine-3-carboxylic acid derivatives, processes for their preparation, pharmaceutical compositions thereof and methods for using the compounds.
The compounds of this invention are useful in the treatment of anaphylactic reactions and allergic conditions in a mammal.
This invention discloses novel pyrimido[1,2-a] pyrrolo[2,1-c] [1,4]-benzodiazepine-3-carboxylic acid derivatives, processes for their preparation, pharmaceutical compositions thereof and methods for using the compounds.
The compounds of this invention are useful in the treatment of anaphylactic reactions and allergic conditions in a mammal.
Description
\
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PYRIMIDO[1,2-a] PYRROLO[2,1-c] [1,4] BEN~;ODIAZEPINE-3-CARBOXYLIC
ACID DERIVATIVES
Background of ths Invention This invention relates to novel pyrimido[l,2-a] pyrrolo[2,1-c] 1~,4~ -benzodiazepine-3-earboxylic acid derivatiYes to processes for their preparation,to methods of using the derivatives and to pharmaceuticRl compositions of the d~ ~iv~.tives. The compounds of this inventi~n are useful in the ~eatment of anaphylac~c reacti~ns ~nd allergic conditions in mP.mm~lx.
The compounds of this invention have a novel pyrimido[l,2-a] pyrrol~
[2,1-cJ n,4~ b~n~odi~Yepine ring system. The c3osest related and known ring system is illustrated by the pipera~ino-wrrolo-b~zodiazepine derivatives des-cribed in Derwent Publications Ltd., Farmdoc 33701B for European Patent Appli-lQ cation Pub. No. 1585, p-hliXh~d May 2,1979. The compounds of this invention are distinguished from the known compounds by having a different ring system, different ~xli~u~:nts on the ring system and different pharmacological activity.SummaFy of the Invention The compounds of this invention~ are represented by formula I
0-C~OR
O =~ CI
Rl ~_~
in which Rl and R2 each is Iy~ Ogt711, halo or lower alkyl and R3 is lower alkyl.
A preferred group of compounds is represented by formula I in which one of Rl and R2 is hydrogen and the other of Rl and R2 is h~-lLogen, chloro or lower alkyl hRving one to three carbon atoms; and R3 is lower alkyl having one to three ca~bon atoms.
~7~
~7~
PYRIMIDO[1,2-a] PYRROLO[2,1-c] [1,4] BEN~;ODIAZEPINE-3-CARBOXYLIC
ACID DERIVATIVES
Background of ths Invention This invention relates to novel pyrimido[l,2-a] pyrrolo[2,1-c] 1~,4~ -benzodiazepine-3-earboxylic acid derivatiYes to processes for their preparation,to methods of using the derivatives and to pharmaceuticRl compositions of the d~ ~iv~.tives. The compounds of this inventi~n are useful in the ~eatment of anaphylac~c reacti~ns ~nd allergic conditions in mP.mm~lx.
The compounds of this invention have a novel pyrimido[l,2-a] pyrrol~
[2,1-cJ n,4~ b~n~odi~Yepine ring system. The c3osest related and known ring system is illustrated by the pipera~ino-wrrolo-b~zodiazepine derivatives des-cribed in Derwent Publications Ltd., Farmdoc 33701B for European Patent Appli-lQ cation Pub. No. 1585, p-hliXh~d May 2,1979. The compounds of this invention are distinguished from the known compounds by having a different ring system, different ~xli~u~:nts on the ring system and different pharmacological activity.SummaFy of the Invention The compounds of this invention~ are represented by formula I
0-C~OR
O =~ CI
Rl ~_~
in which Rl and R2 each is Iy~ Ogt711, halo or lower alkyl and R3 is lower alkyl.
A preferred group of compounds is represented by formula I in which one of Rl and R2 is hydrogen and the other of Rl and R2 is h~-lLogen, chloro or lower alkyl hRving one to three carbon atoms; and R3 is lower alkyl having one to three ca~bon atoms.
~7~
-2- AHP-8225 The compounds of this invention are useful for preventing or treating anaphylactic reactions or allergic ~onditions in a mn~m~l by administering to the m~mm~l an effectiYe anaphylactic ~lleviating or allergic allevi~ting amount of a compound of formula I.
The compounds of this invention form a pharmaceutical composition 5 which comprises a compound of form~a I and a pharmaceutically acceptable carrier.
The compounds of form~a I are prepared by cyclizing a compound of form~La II
R30- C-o N-H
~3 (II) in which Rl, R2 and R3 are as defined herein.
DetRiled Description of the Invention The term 'qower alkyl" as used herein means straight and branched 20 chain alkyl radicals containing from one to six carbon atoms, preferably on~sto three cQrbon atoms, and includes methyl, ethyl, propyl, l-methylethyl, butyl,l,l-dimethylethyl, pentyl Md the like, unless stated otherwise.
The term "halo" as used herein means halo rAdicals and includes fluoro, chloro, bromo and iodo, unless stated otherwise.
The term 'qower alkMol" as used herein means both straight and branched chain alk~nolq containing from one to four carbon atoms and inf lud~s methanol, ethanol, l-methylethanol, butanol and the like.
The term "alkoxide" as used herein means the anion derived from ~ lower allcanol, as defined herein.
The compounds of this invention of formula I are useful in the pre-vention or treatment of allergic reactions in a mammal.
7~
The compounds of this invention form a pharmaceutical composition 5 which comprises a compound of form~a I and a pharmaceutically acceptable carrier.
The compounds of form~a I are prepared by cyclizing a compound of form~La II
R30- C-o N-H
~3 (II) in which Rl, R2 and R3 are as defined herein.
DetRiled Description of the Invention The term 'qower alkyl" as used herein means straight and branched 20 chain alkyl radicals containing from one to six carbon atoms, preferably on~sto three cQrbon atoms, and includes methyl, ethyl, propyl, l-methylethyl, butyl,l,l-dimethylethyl, pentyl Md the like, unless stated otherwise.
The term "halo" as used herein means halo rAdicals and includes fluoro, chloro, bromo and iodo, unless stated otherwise.
The term 'qower alkMol" as used herein means both straight and branched chain alk~nolq containing from one to four carbon atoms and inf lud~s methanol, ethanol, l-methylethanol, butanol and the like.
The term "alkoxide" as used herein means the anion derived from ~ lower allcanol, as defined herein.
The compounds of this invention of formula I are useful in the pre-vention or treatment of allergic reactions in a mammal.
7~
-3- AHP-8a25 More specifically, the compounds of this invention are useful for the prophylactic treatment as well as for the management of anaphylacffc re-actions and ~topic allergic manifestations, or ~YAmrle, bronchiat asthma, hay fever, allergic rhinitis, allergic conj~~ ivilies, ood allergies, urticaria and the like, in a sensitiæed mflmm~l The prevention or treatment of altergic reactions in a mammat by administration of a compound of formula I is demonstrated by using known anti-~llergic tests in an appropriste ~nimat model.
Ln one such test for the determination of useful anti-allergic activity, the compounds of formula I are tested using the passive paw anaphylaxis (PPA) method, described by R.R. Martel Qnd J. Klicius, Int. Archs. Allergy Appl. Immun., 54, 205 (1977). In this method, reaginic antibody-induced hypersensitivity is produced in the rat hindpaw. IncreQsed vasculQr permeability is determined by measuring the increase in paw volume. An effective anti-allergic drug inhibits the increase in paw volume when compared to the untreated reaginic hyper-sensitive controls. In this test, the foltowing illustrative compounds o formula I are effective anti-allergic agents when administered at an intraperitoneat dose of 30 mg/kg of body weight: 4-oxo-lOH-pyrimido[1,2-a] pyrrolo[2,1-c] ~,4] -b~n70di~epine-3-carboxylic acid, ethyl ester causes a 53% inhibition at 15 minutes of the increase in paw volume; 8~methyl-4-oxo-lOH-pyrimido[l,~-a]pyr-rolo~291-c] ~,4] benzotlin~epine-3-carboxylic acid, ethyl ester causes a 56% in-hibition at 15 minutes of the increase in pnw volume; 8-chlolo 4 o2~10II ~ylilllido-~2-a] pyrrolo[2,1-c] ~,4] benzodiazepine-3-carboxylic acid, ethyl ester causes a 58% inhibition At 15 minutes of the increase in paw volume; and 7-chloro-4-oxo-lOH~pyrimidon,2~] wrrolo[2,1-c] ~,4] b~n~odi~7epine-3-c~rboxylic acid, ethyl ester causes a 19% inhibition at lS minutes of the increase in paw volume.When the compounds of formuta I of this invention are used for sup-pressing allergic manifestations of ~naphylactic reactions and atopic hypersen-SitiYity in a mnrllmnl, they are used alone or in combination with pharmacolo-gically acceptable carriers, the proportion oE which is determined by the solu-bility and the chemical nature of the compound, chosen route of administration and standard biological practice.
~at72~
Ln one such test for the determination of useful anti-allergic activity, the compounds of formula I are tested using the passive paw anaphylaxis (PPA) method, described by R.R. Martel Qnd J. Klicius, Int. Archs. Allergy Appl. Immun., 54, 205 (1977). In this method, reaginic antibody-induced hypersensitivity is produced in the rat hindpaw. IncreQsed vasculQr permeability is determined by measuring the increase in paw volume. An effective anti-allergic drug inhibits the increase in paw volume when compared to the untreated reaginic hyper-sensitive controls. In this test, the foltowing illustrative compounds o formula I are effective anti-allergic agents when administered at an intraperitoneat dose of 30 mg/kg of body weight: 4-oxo-lOH-pyrimido[1,2-a] pyrrolo[2,1-c] ~,4] -b~n70di~epine-3-carboxylic acid, ethyl ester causes a 53% inhibition at 15 minutes of the increase in paw volume; 8~methyl-4-oxo-lOH-pyrimido[l,~-a]pyr-rolo~291-c] ~,4] benzotlin~epine-3-carboxylic acid, ethyl ester causes a 56% in-hibition at 15 minutes of the increase in pnw volume; 8-chlolo 4 o2~10II ~ylilllido-~2-a] pyrrolo[2,1-c] ~,4] benzodiazepine-3-carboxylic acid, ethyl ester causes a 58% inhibition At 15 minutes of the increase in paw volume; and 7-chloro-4-oxo-lOH~pyrimidon,2~] wrrolo[2,1-c] ~,4] b~n~odi~7epine-3-c~rboxylic acid, ethyl ester causes a 19% inhibition at lS minutes of the increase in paw volume.When the compounds of formuta I of this invention are used for sup-pressing allergic manifestations of ~naphylactic reactions and atopic hypersen-SitiYity in a mnrllmnl, they are used alone or in combination with pharmacolo-gically acceptable carriers, the proportion oE which is determined by the solu-bility and the chemical nature of the compound, chosen route of administration and standard biological practice.
~at72~
-4- AHP-8225 For example, they are e(-lmini~tered orQlly in solid form i.e. capsule or tablet. They can also be administered orally in the form of suspensions or solutions or they may be injected parenterally. They can be administered p&r enterelly by the nasal routel for instance, as drops or aerosol; or by inhalation from an aerosol.
In addition, the compounds of this invention can be administered in conjuncffon with common anti-allergic agents, for example, known compounds effeoting anti-histaminic, analgesie, central nervous system d~pressnnt, anti-hypertensive, immunosupressive, anti-bradykinin, anti-serotonin or endocrinol~
gical responses.
The tablet compositions for oral ~mini~ration contain the active ingredient in admixture with non-toxic pharmaceutical excipie~ts known to be suitable in the manufacture of tablets. Suitable pharmaceutical excipients are~
for example, starch, milk sugar, certain types of cl~y and so forth. The tabletscan be uncoated or they can be coated by known techniques so QS to delay dis-integration and nbsorption in the gastrointestinal trQct and thereby provide a sustained action over a longer period.
The aqueous suspensions of the compounds of formula I for oral ad-ministration contain the active ingredient in adrnixture with one or more non-toxic pharmaceutical excipients known to be suitable in the m~nufacture of aqueous suspensions. Suitable excipients are, for example~ methylcellulose, sodium ~1-ginate, gum acaciQ, lecithin and so forth. The aqueous suspensions can also contain one or more preser v~tives~ one or more coloring agents, one or more ~lavoring agents and one or more sweetening agents.
Non~aqueous suspensions for oral administration can be formulRted by suspending ~he active ingredient in ethyl alcohol, in a vegetable oil, for ex-ample, arachis oil, olive oil, sesame oil, or coconut oil, or in R mineral oil, for example liquid paraffin, and the suspension may contain a thickening agent, for example beeswax or hard paraffirl. These compositions can also contflin a sweet-ening agent, ilavoiing ngent and antioxidant.
~or administration to Q mammal by parenteral injection, it is pre-ferred to use the compounds of formlda I in solution in a sterile agueous vehicle
In addition, the compounds of this invention can be administered in conjuncffon with common anti-allergic agents, for example, known compounds effeoting anti-histaminic, analgesie, central nervous system d~pressnnt, anti-hypertensive, immunosupressive, anti-bradykinin, anti-serotonin or endocrinol~
gical responses.
The tablet compositions for oral ~mini~ration contain the active ingredient in admixture with non-toxic pharmaceutical excipie~ts known to be suitable in the manufacture of tablets. Suitable pharmaceutical excipients are~
for example, starch, milk sugar, certain types of cl~y and so forth. The tabletscan be uncoated or they can be coated by known techniques so QS to delay dis-integration and nbsorption in the gastrointestinal trQct and thereby provide a sustained action over a longer period.
The aqueous suspensions of the compounds of formula I for oral ad-ministration contain the active ingredient in adrnixture with one or more non-toxic pharmaceutical excipients known to be suitable in the m~nufacture of aqueous suspensions. Suitable excipients are, for example~ methylcellulose, sodium ~1-ginate, gum acaciQ, lecithin and so forth. The aqueous suspensions can also contain one or more preser v~tives~ one or more coloring agents, one or more ~lavoring agents and one or more sweetening agents.
Non~aqueous suspensions for oral administration can be formulRted by suspending ~he active ingredient in ethyl alcohol, in a vegetable oil, for ex-ample, arachis oil, olive oil, sesame oil, or coconut oil, or in R mineral oil, for example liquid paraffin, and the suspension may contain a thickening agent, for example beeswax or hard paraffirl. These compositions can also contflin a sweet-ening agent, ilavoiing ngent and antioxidant.
~or administration to Q mammal by parenteral injection, it is pre-ferred to use the compounds of formlda I in solution in a sterile agueous vehicle
-5- AHP-8225 which may also contain other solutes, such as buffers or preservatives, as well as sufficient quantities of pharmaceutically ~cceptable salts or of glucose to make the solution isotonic.
The compounds of formula I can also be administered as nasal powders or insufflations. For such purposel the compounds are administered in finely 5 divided solid form together with a pharmaceuffcally acceptable solid carrier, for example, a finely divided polyethylene glycol (e.g. "Carbowax 1540") or finely divided lactose. Such compositions may also contain other excipients in finely divided solid form. "Carbowax" is a trademark.
For Rdministering the compounds of this invention by inhalation 10 from an aerosol, the compound of formula I is dissolved in water or eth~nol and mixed with Q volatile propellant, for example, dichlorotetrafluoroethane and dichlorodifluoromethane, and placed in a pressurized container having a metering valve to release a predetermined amount of material.
The dosage of the compounds of formula I as anti-allergic agents 15 will vary with the form of administration and the particular compound chosen.Furthermore, it will vary with the particular host as well as the age, weight and condition of the host under treatment as well as with the nature and extent of the symptoms. Gener~lly, treatment is initiated with small dosages substan-tially less than the optimum dose of the compound. Thereafter, the dosage 20 is increased by small increments until the optimum effect under circumstancesis reached. In general, the compounds of this invention are most desirably ad-ministered at a concentration level that will generally afford effective resultswithout causing any harmeul or deleterious side effects. For example, an ef-fective anti-allergic amount of n compound of formula I usually ranges from 25 about 0.1 mg to about 500 mg per kg of body weight per day in single or divided doses, although Q~ aforementioned, variations will occur. However, a dosage level that is in the range from about 0.5 mg to about 200 mg per kg of body weight per day in single or divided dose is employed most desirably in order to achieve effective results.
The following reaction scheme illustrates a method for preparing the compounds of formul~
~l 7~
N2 k~ R2~N 2 CN
R ~` H N~ Rl~_N~
( I IIl ~ IV) R2 ~ NH2 CN ~2~ NH2 R1~--N)3 R ~_ ~3 +
10 (Yl (~1l) OAlk. CQoR3 H COOR
(VI I) With reference to the above re~ction scheme, most of the compounds of formulae IY, ~ ~nd ~I are described by W.B~ Wright et ~1., J. Med. Chem., 23, 462 (1980) or they cRn be prepared in an analogous manner. ~or example, qrnd~nQntion of the compound of formula I~ in which Rl and R2 are as defined herein wlth 2-pyrroloc~rbonitrile in the pres~nce of sodium hydride in dimethyl-formamide at about -30 to 40 C gives the corresponding compound of formula IV in which R and R ' are RS defined herein. HydrogenRtion of the compound of formuIa IV in the presence of 10% pall~dium on charcoal catalyst in methanol gives the corresponding compound of form~a V in which Rl and R2 are ~s defined herein. Cycliz~tlon of the compound of formula V with benzyl trimethyIammonium 3~ hydroxide in toluene at ~bout 100 to 115 C a~fords the corresponding compound of formulQ VI in which Rl and R2 are QS defined herein.
~7;2~
-7~ AHP 8225 The compound of formula VI in which Rl and R2 are a5 defined herein is condensed with a compound of formula VII in which R3 is as defined herein at about 50 to 100 C for about 15 rninutes to 5 hours to obtain the col~e~ ding compound of formlda ~ in which Rl, R2 and R3 are as defined herein. An inert organic solvent ~an be used as a reaction medium or, preferably9 an excess 5 of the compound of formula VII can also act as a solvent for the cond~n~ation re~ction.
Cyclization of the compound of formula II in which Rl, R2 and R3 are as defined herein gives the corresponding compound of formula I in which Rl, R2 and R3 arP as defined herein. The cyclization can be achieved by reacting10 the compound of formula II with a catalytic amount of sodium or potassium aL"oxide, preferubly about 0.1 to 0.5 molar equivalents of sodium aL'coxide in a lower aL'canol at about 20 to 50 C for about 30 minutes to 5 hours. In a pr~
ferred method of cyclization, the compound of formula Il is dissolved in an inert organic solvent, preferably a eutectic mixture of biphenyl and diphenyl-15 eneoxide, and the solution is heated at about 250 to 300 C for about 30 minutesto 3 hours.
The following ~mpl~ illustrate further this invenl:ion.
ll-Amino-7-methyl-SH-pyrrolol2,1-c] ~,4] ben7o ~ epine (VI: Rl = Me and R2 20 = H) Sodium hydride (50% d~spersion, 15.50 g, 323 mmoles) was added in small portions to a solution of 2-wrrolecarbonitrile (~9.0 g, 315 mmoles) in dry dimethylformamide (DMF) (800 mL) stirred under nilloge.l below -30 C
during 20 min. After no more hyd~O~ - evolved, a solutior! of 5-methyl-2-nitro-25 benzyl chloride (50.0 g, 270 mmoles) in DMF (200 mL) WRS added dropwise tothe reaction mixture. The internal temperQture of the reaction mixture was allowed to rise to room temperature over a period of 1 hour. The dark solution was then poured onto ice-water containin~ dilute hydrochloric acid. The crude tan solid was collècted by filtration and crystallized from diethyl ether-hexane30 to give 1-(S-methyl-2-nitrobenzyl)-2-pyrrolecarbonitrile as an off-white solid (53.37 g), mp 97-98 C.
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The latter compound (S0.0 g, 207 mmoles) was dissolved in methanol (1 liter) and stirred at room temperatwe with 10% Pd/charcoal catalyst (5.00 g) under ]ly~ogt:nation conditions. The catalyst WQS then recovered by filtration through a cake of diatomaeeon~ earth and the soluffon was concentrated. The crude residue was purified by filtration and the material thus obtained was finally rec. ~ ~lallized from cyclohexane to yield 1-(5-methyl-2-aminobenzyl~
2-pyrroleeArbonitrile as off-white crystals (30.7 g), mp 111-112 C.
The latter compound (1.00 g, 4.73 mmoles) was stirred in boiling toluene (15 mL) in the presence of benzyl trimethylammonium hydroxide (40%
in meth~nol, 0.6 mL) for 3 hr. The mixture was cooled in ice-water to afford white crystals, mp 218-al9 C (460 mg). Recryst~llliPation from ethyl acetate-hexane afforded the title compound; mp 224-225 C and IR (mineral oil) 3420, 3290, 3060,1645,1575 and 1520 cm 1.
In the same manner, but repl~ ing 5-methyl-2-nitrobenzyl chloride with an equivalent amount of 2-nitrobenzyl chloride, 5-c~dor~2-nitrobenzyl chloride or 4-chloro-2-nitrobenzyl chloride, the following compounds of formu!a VI were obtained, respectively: ll-amino-5H-pyrrolo~2,1-c] [1,4] benYorli~7epine, mp 177-178 C; ll-amino-7-chloro-5H-pyrrolo[2,1-c] ~1,4] b~o lif~Y.epine, mp 205-206 C; and ll-amino-8-chloro-SH-pyrrolo[2,1-c] 11,4] bPn~ Yepine, mp 244-245 C.
~XAM PLE 2 [(7~methyl-5H-pyrrolo[2,1-c] 1~,4] benzodiazepin-ll-yl)amino] methylene Propan~
dioic Acid, Diethyl Ester (II: Rl = Me, R2 = H and R3 = Et) ll-Amino-7-methyl-5H-pyrrolol2,1-c] r;l 14] benzodiazepine (1.00 g7 4.73 mmoles, described in ExRmple 1) w~ stirred in diethyl ethoxymethylene-25 malonate (7.9 mL) on a steam bath for 30 min. Hexane was added to the cold mixture to afford a yellow precipitnte which was collected by filtration and dried. Recrystnlliyation from ethyl acetate-hexane gave the title cornpound as a yellow green powder (1.03 g): mp 139-140 C; Anal. Calcd for C21H23N3O4:
C, 66.13% H, 6.08% N, 11.02% and Found: C, 66.09% H, 6.02% N, 11.04%; ~R
30 (mineral oil) 3295,1690,16S0, 1610,1578 ~nd 1520 cm 1; and NMR (CDC13) ô
1.35 (6H, t), 2~3 (3H, s)~ 4.25 (~H, q), 4.88 (2H, s), 6.7 (6H, m), 9.15 (lH, d) and 10.9 (lH, d).
97~4~2 AHP-8a25 In the same rnanner, but replacing ll-amino-7-methyl-5H-pyrrol~
~2,1-c] [1,4~ ben~.o lip~epine with nnother compound of form~a VI described in Ex~mple 1, the following compounds of formula II were obtained, r~spectively:
~(5H-pyrrolo[2,1-c] [1,41 benzodiazepin-11-yl3amino3 methylene propanedioic acid, diethyl ester: mp 129-130 C (crystallized ~rom diethyl ether-hexane); Anal.
Calcd for C20H21N304: C, 65.38% H, 5.76% N, 11.44% and Found: C, 65.28%
H, 5.79% N, 11.36%; IR ~mineral oil) 3285,1690 and 1650 cm ; and NMR (CDC13)~
1.35 (6H, t), ~.25 (4H, m), 4.92 (2H, S)9 6.9 (7~, m), 9.15 (lH, d), 111 (lH, d); [(7-chloro-5~I-pyrrolo[a,l-c] n,4] b~n~o liP7epin-ll-yl)amino] methylene propanedioic acid7 diethyl ester: mp 191-192 C (crystallized ~om ethyl acetate-hexane);
Anal. Calcd for C20H20N304Cl: C, 59.78% H, 5.02% H, 10.46% and Found:
C, 59.42% H, 5.02% N, 10.37%; IR (mineral oil3 3280,1723 and 1655 cm 1; and MMR (CDC13) ~ 1.34 and 1.36 (6H, triplets), 4.25 and 4.28 (4H, guartets)3 4.87 (2H, s), 6.2û (IH, dd), 6.65 (lH, dd), 6.80 (lH, m), 7.15 (3H, m), 9.02 and ~.17 (lH, s); [(8-chloro-51I-pyrrolo[2,1-c] ~,4] ~Pr~ 7epin-ll-yl)amino] methylene propane-dioic acid, diethyl ester: mp 172-173 C (crystallized from methylene chloride-hexane); Anal. C:slcd for C20H20N30~LCl: C, 59.78% H, 5.02% N, 10.46% and Yound: C, 59.40% H, 5.06% N, 10.31%; and NMR (CDC13) ~ 1.35 (6H, t), 4.3 (4H, m), 4.g (2H, s) 6.7 (6H, m), 9.1 (lH, d), 11.0 (lH, d).
8-Methyl-4-oxo-lOH-pyrimido~,2-a] pyrrolo~2,1-c] ~,4] benzodiazepine-3-car-boxylic Acid, Ethyl Ester (I: Rl = Me, Ra = H and R3 = Et [(7-Methyl-5H-pyrrolo[2,1-c] ~,4] benzodiazepin-ll-yl)amino] methylene propanedioic ncid, diethyl e~ster (2.50 g, 6.55 mmoles, described in Exarnple 2) in a eutectic mixture of biphenyl nnd diphenyleneoxide, sold under the trad~
mark '~owtherm A", (20 mL) was stirred at 268-278~ C for 1 hr. The dark sol-ution was cooled nnd hexane was added in excess to yield a solid materi~l (2.a4 g) which was purified by filtration through a column of silica gel with a solvent of methylene chlorlde-ethyl acetate (7:1). The main fraction was oonc.3l~t~ated and the resultlng solid was rec.yalallized from ethyl acetate-hexane to yield the title compollnd (1.84 g): mp 207-208 C; Anal. Calcd for C19H17N303: C, 68.05% El, 5.11% N, 12.53% and Found: C, 68.15% H, 5.19% N, 12.46%; IR (C~IC13) 1735 and 1700 cm 1; and NMR (CDC13) ô 1.37 t3H, t), 2.35 (3H, s), 4.35 (2H, q)14.9 and 5.15 (2H, d), 6.2 (lH, m), 7.15 (5EI, m) and 8.7 (lH, s).
7~
In the same manner, but replacing the diester of formula II with an equivalerlt amount of another compound of formula ~ described in ~xample 2, the fo~lowing compounds of ~ormula I are obtained, respectively: ~oxo-lûH-pyrimido~,2-a] pyrrolo[2,1-c] ~,4] bPn7,0~ epine-3-carboxylic ~cid9 ethyl ester;8-chloro-~-oxo-lOH-pyrimido[1,2-a] pyrrolo[2,1-c] ~,4] benzodiazepine-3-carbo~ylic acid, ethyl ester: mp 209-210 C (crystallized from ethyl acetate-hexane); IR
(mineral oil) 1741,1730,1675 and 1660 cm 1; Anal. Calcd for C18H14ClN303:
C, 60.76% H, 3.~7% N, 11.81% and Found: C, 60.74% H, 4.05% N, 11.77%; and NMR (CDC13) ~ 1.35 (3H, t), 4.35 (2H, q), 4.75 and 5.15 t2H, d), 6.2 (lH, m), 7.25 (SH, m), 8.66 (lH, s); and 7-chlor~4-ox~10~-pyrimido~,2-a] pyrrolo[2,1-c~-~,4] bPn~ 7epin~3-carboxylic acid, ethyl esters mp 247-248~ C (crystallized from ~oluene-he~ane); IR (minersl oil3 1710 and 1675 cm 1; NM~ (CDC13) 1.35 (3H, t), 4.35 (2H, q), 4.75 flnd 5.15 (2H, d), 7~3 (7H, m).
4-Oxo-lOH-pyrimido~,2-al pyrrolo[2,1-c] ~,4] ben~;o~ epin~3-carboxylic Acid, lethyl Ester (I: Rl and R2 = H and R3 = Et) [(5H-Pyrrolo[2,1-c] ~,4] b~n7orli~7,epin~11-yl)amino] methylene pro-p~nerlioic acid, diethyl ester (6.90 g, 18.7 mmol, described in Example 2) was dissolved in dry ethanol (100 mL) by warming up the mixturel A catalytic quantity of sodium ethoxide (freshly prepared from sodium in ethanol) was added to the solution which was allowed to stir at room temperature for one hour. The yellow material was collected by filtr~tion, dried and ret;~ Lallized from acetonitrileto yield the title compound ~s yellow crystals (5.20 g): mp 211-212 C; IR (mineral oil) 1735 and 1690 cm 1; NMR (DMSO-d6) ~ 1.25 (3H, t), 4.2 (2H, q), 5.12 and 5.37 (2H, doublets) and 7.3 (8H, m); and Anal. Calcd for C18H15N303: C, 87.28%
H, 4.71% N, 13.08% ~nd Found: C, 66.67% H, 4.69% N, 12.94%.
The compounds of formula I can also be administered as nasal powders or insufflations. For such purposel the compounds are administered in finely 5 divided solid form together with a pharmaceuffcally acceptable solid carrier, for example, a finely divided polyethylene glycol (e.g. "Carbowax 1540") or finely divided lactose. Such compositions may also contain other excipients in finely divided solid form. "Carbowax" is a trademark.
For Rdministering the compounds of this invention by inhalation 10 from an aerosol, the compound of formula I is dissolved in water or eth~nol and mixed with Q volatile propellant, for example, dichlorotetrafluoroethane and dichlorodifluoromethane, and placed in a pressurized container having a metering valve to release a predetermined amount of material.
The dosage of the compounds of formula I as anti-allergic agents 15 will vary with the form of administration and the particular compound chosen.Furthermore, it will vary with the particular host as well as the age, weight and condition of the host under treatment as well as with the nature and extent of the symptoms. Gener~lly, treatment is initiated with small dosages substan-tially less than the optimum dose of the compound. Thereafter, the dosage 20 is increased by small increments until the optimum effect under circumstancesis reached. In general, the compounds of this invention are most desirably ad-ministered at a concentration level that will generally afford effective resultswithout causing any harmeul or deleterious side effects. For example, an ef-fective anti-allergic amount of n compound of formula I usually ranges from 25 about 0.1 mg to about 500 mg per kg of body weight per day in single or divided doses, although Q~ aforementioned, variations will occur. However, a dosage level that is in the range from about 0.5 mg to about 200 mg per kg of body weight per day in single or divided dose is employed most desirably in order to achieve effective results.
The following reaction scheme illustrates a method for preparing the compounds of formul~
~l 7~
N2 k~ R2~N 2 CN
R ~` H N~ Rl~_N~
( I IIl ~ IV) R2 ~ NH2 CN ~2~ NH2 R1~--N)3 R ~_ ~3 +
10 (Yl (~1l) OAlk. CQoR3 H COOR
(VI I) With reference to the above re~ction scheme, most of the compounds of formulae IY, ~ ~nd ~I are described by W.B~ Wright et ~1., J. Med. Chem., 23, 462 (1980) or they cRn be prepared in an analogous manner. ~or example, qrnd~nQntion of the compound of formula I~ in which Rl and R2 are as defined herein wlth 2-pyrroloc~rbonitrile in the pres~nce of sodium hydride in dimethyl-formamide at about -30 to 40 C gives the corresponding compound of formula IV in which R and R ' are RS defined herein. HydrogenRtion of the compound of formuIa IV in the presence of 10% pall~dium on charcoal catalyst in methanol gives the corresponding compound of form~a V in which Rl and R2 are ~s defined herein. Cycliz~tlon of the compound of formula V with benzyl trimethyIammonium 3~ hydroxide in toluene at ~bout 100 to 115 C a~fords the corresponding compound of formulQ VI in which Rl and R2 are QS defined herein.
~7;2~
-7~ AHP 8225 The compound of formula VI in which Rl and R2 are a5 defined herein is condensed with a compound of formula VII in which R3 is as defined herein at about 50 to 100 C for about 15 rninutes to 5 hours to obtain the col~e~ ding compound of formlda ~ in which Rl, R2 and R3 are as defined herein. An inert organic solvent ~an be used as a reaction medium or, preferably9 an excess 5 of the compound of formula VII can also act as a solvent for the cond~n~ation re~ction.
Cyclization of the compound of formula II in which Rl, R2 and R3 are as defined herein gives the corresponding compound of formula I in which Rl, R2 and R3 arP as defined herein. The cyclization can be achieved by reacting10 the compound of formula II with a catalytic amount of sodium or potassium aL"oxide, preferubly about 0.1 to 0.5 molar equivalents of sodium aL'coxide in a lower aL'canol at about 20 to 50 C for about 30 minutes to 5 hours. In a pr~
ferred method of cyclization, the compound of formula Il is dissolved in an inert organic solvent, preferably a eutectic mixture of biphenyl and diphenyl-15 eneoxide, and the solution is heated at about 250 to 300 C for about 30 minutesto 3 hours.
The following ~mpl~ illustrate further this invenl:ion.
ll-Amino-7-methyl-SH-pyrrolol2,1-c] ~,4] ben7o ~ epine (VI: Rl = Me and R2 20 = H) Sodium hydride (50% d~spersion, 15.50 g, 323 mmoles) was added in small portions to a solution of 2-wrrolecarbonitrile (~9.0 g, 315 mmoles) in dry dimethylformamide (DMF) (800 mL) stirred under nilloge.l below -30 C
during 20 min. After no more hyd~O~ - evolved, a solutior! of 5-methyl-2-nitro-25 benzyl chloride (50.0 g, 270 mmoles) in DMF (200 mL) WRS added dropwise tothe reaction mixture. The internal temperQture of the reaction mixture was allowed to rise to room temperature over a period of 1 hour. The dark solution was then poured onto ice-water containin~ dilute hydrochloric acid. The crude tan solid was collècted by filtration and crystallized from diethyl ether-hexane30 to give 1-(S-methyl-2-nitrobenzyl)-2-pyrrolecarbonitrile as an off-white solid (53.37 g), mp 97-98 C.
7'~
The latter compound (S0.0 g, 207 mmoles) was dissolved in methanol (1 liter) and stirred at room temperatwe with 10% Pd/charcoal catalyst (5.00 g) under ]ly~ogt:nation conditions. The catalyst WQS then recovered by filtration through a cake of diatomaeeon~ earth and the soluffon was concentrated. The crude residue was purified by filtration and the material thus obtained was finally rec. ~ ~lallized from cyclohexane to yield 1-(5-methyl-2-aminobenzyl~
2-pyrroleeArbonitrile as off-white crystals (30.7 g), mp 111-112 C.
The latter compound (1.00 g, 4.73 mmoles) was stirred in boiling toluene (15 mL) in the presence of benzyl trimethylammonium hydroxide (40%
in meth~nol, 0.6 mL) for 3 hr. The mixture was cooled in ice-water to afford white crystals, mp 218-al9 C (460 mg). Recryst~llliPation from ethyl acetate-hexane afforded the title compound; mp 224-225 C and IR (mineral oil) 3420, 3290, 3060,1645,1575 and 1520 cm 1.
In the same manner, but repl~ ing 5-methyl-2-nitrobenzyl chloride with an equivalent amount of 2-nitrobenzyl chloride, 5-c~dor~2-nitrobenzyl chloride or 4-chloro-2-nitrobenzyl chloride, the following compounds of formu!a VI were obtained, respectively: ll-amino-5H-pyrrolo~2,1-c] [1,4] benYorli~7epine, mp 177-178 C; ll-amino-7-chloro-5H-pyrrolo[2,1-c] ~1,4] b~o lif~Y.epine, mp 205-206 C; and ll-amino-8-chloro-SH-pyrrolo[2,1-c] 11,4] bPn~ Yepine, mp 244-245 C.
~XAM PLE 2 [(7~methyl-5H-pyrrolo[2,1-c] 1~,4] benzodiazepin-ll-yl)amino] methylene Propan~
dioic Acid, Diethyl Ester (II: Rl = Me, R2 = H and R3 = Et) ll-Amino-7-methyl-5H-pyrrolol2,1-c] r;l 14] benzodiazepine (1.00 g7 4.73 mmoles, described in ExRmple 1) w~ stirred in diethyl ethoxymethylene-25 malonate (7.9 mL) on a steam bath for 30 min. Hexane was added to the cold mixture to afford a yellow precipitnte which was collected by filtration and dried. Recrystnlliyation from ethyl acetate-hexane gave the title cornpound as a yellow green powder (1.03 g): mp 139-140 C; Anal. Calcd for C21H23N3O4:
C, 66.13% H, 6.08% N, 11.02% and Found: C, 66.09% H, 6.02% N, 11.04%; ~R
30 (mineral oil) 3295,1690,16S0, 1610,1578 ~nd 1520 cm 1; and NMR (CDC13) ô
1.35 (6H, t), 2~3 (3H, s)~ 4.25 (~H, q), 4.88 (2H, s), 6.7 (6H, m), 9.15 (lH, d) and 10.9 (lH, d).
97~4~2 AHP-8a25 In the same rnanner, but replacing ll-amino-7-methyl-5H-pyrrol~
~2,1-c] [1,4~ ben~.o lip~epine with nnother compound of form~a VI described in Ex~mple 1, the following compounds of formula II were obtained, r~spectively:
~(5H-pyrrolo[2,1-c] [1,41 benzodiazepin-11-yl3amino3 methylene propanedioic acid, diethyl ester: mp 129-130 C (crystallized ~rom diethyl ether-hexane); Anal.
Calcd for C20H21N304: C, 65.38% H, 5.76% N, 11.44% and Found: C, 65.28%
H, 5.79% N, 11.36%; IR ~mineral oil) 3285,1690 and 1650 cm ; and NMR (CDC13)~
1.35 (6H, t), ~.25 (4H, m), 4.92 (2H, S)9 6.9 (7~, m), 9.15 (lH, d), 111 (lH, d); [(7-chloro-5~I-pyrrolo[a,l-c] n,4] b~n~o liP7epin-ll-yl)amino] methylene propanedioic acid7 diethyl ester: mp 191-192 C (crystallized ~om ethyl acetate-hexane);
Anal. Calcd for C20H20N304Cl: C, 59.78% H, 5.02% H, 10.46% and Found:
C, 59.42% H, 5.02% N, 10.37%; IR (mineral oil3 3280,1723 and 1655 cm 1; and MMR (CDC13) ~ 1.34 and 1.36 (6H, triplets), 4.25 and 4.28 (4H, guartets)3 4.87 (2H, s), 6.2û (IH, dd), 6.65 (lH, dd), 6.80 (lH, m), 7.15 (3H, m), 9.02 and ~.17 (lH, s); [(8-chloro-51I-pyrrolo[2,1-c] ~,4] ~Pr~ 7epin-ll-yl)amino] methylene propane-dioic acid, diethyl ester: mp 172-173 C (crystallized from methylene chloride-hexane); Anal. C:slcd for C20H20N30~LCl: C, 59.78% H, 5.02% N, 10.46% and Yound: C, 59.40% H, 5.06% N, 10.31%; and NMR (CDC13) ~ 1.35 (6H, t), 4.3 (4H, m), 4.g (2H, s) 6.7 (6H, m), 9.1 (lH, d), 11.0 (lH, d).
8-Methyl-4-oxo-lOH-pyrimido~,2-a] pyrrolo~2,1-c] ~,4] benzodiazepine-3-car-boxylic Acid, Ethyl Ester (I: Rl = Me, Ra = H and R3 = Et [(7-Methyl-5H-pyrrolo[2,1-c] ~,4] benzodiazepin-ll-yl)amino] methylene propanedioic ncid, diethyl e~ster (2.50 g, 6.55 mmoles, described in Exarnple 2) in a eutectic mixture of biphenyl nnd diphenyleneoxide, sold under the trad~
mark '~owtherm A", (20 mL) was stirred at 268-278~ C for 1 hr. The dark sol-ution was cooled nnd hexane was added in excess to yield a solid materi~l (2.a4 g) which was purified by filtration through a column of silica gel with a solvent of methylene chlorlde-ethyl acetate (7:1). The main fraction was oonc.3l~t~ated and the resultlng solid was rec.yalallized from ethyl acetate-hexane to yield the title compollnd (1.84 g): mp 207-208 C; Anal. Calcd for C19H17N303: C, 68.05% El, 5.11% N, 12.53% and Found: C, 68.15% H, 5.19% N, 12.46%; IR (C~IC13) 1735 and 1700 cm 1; and NMR (CDC13) ô 1.37 t3H, t), 2.35 (3H, s), 4.35 (2H, q)14.9 and 5.15 (2H, d), 6.2 (lH, m), 7.15 (5EI, m) and 8.7 (lH, s).
7~
In the same manner, but replacing the diester of formula II with an equivalerlt amount of another compound of formula ~ described in ~xample 2, the fo~lowing compounds of ~ormula I are obtained, respectively: ~oxo-lûH-pyrimido~,2-a] pyrrolo[2,1-c] ~,4] bPn7,0~ epine-3-carboxylic ~cid9 ethyl ester;8-chloro-~-oxo-lOH-pyrimido[1,2-a] pyrrolo[2,1-c] ~,4] benzodiazepine-3-carbo~ylic acid, ethyl ester: mp 209-210 C (crystallized from ethyl acetate-hexane); IR
(mineral oil) 1741,1730,1675 and 1660 cm 1; Anal. Calcd for C18H14ClN303:
C, 60.76% H, 3.~7% N, 11.81% and Found: C, 60.74% H, 4.05% N, 11.77%; and NMR (CDC13) ~ 1.35 (3H, t), 4.35 (2H, q), 4.75 and 5.15 t2H, d), 6.2 (lH, m), 7.25 (SH, m), 8.66 (lH, s); and 7-chlor~4-ox~10~-pyrimido~,2-a] pyrrolo[2,1-c~-~,4] bPn~ 7epin~3-carboxylic acid, ethyl esters mp 247-248~ C (crystallized from ~oluene-he~ane); IR (minersl oil3 1710 and 1675 cm 1; NM~ (CDC13) 1.35 (3H, t), 4.35 (2H, q), 4.75 flnd 5.15 (2H, d), 7~3 (7H, m).
4-Oxo-lOH-pyrimido~,2-al pyrrolo[2,1-c] ~,4] ben~;o~ epin~3-carboxylic Acid, lethyl Ester (I: Rl and R2 = H and R3 = Et) [(5H-Pyrrolo[2,1-c] ~,4] b~n7orli~7,epin~11-yl)amino] methylene pro-p~nerlioic acid, diethyl ester (6.90 g, 18.7 mmol, described in Example 2) was dissolved in dry ethanol (100 mL) by warming up the mixturel A catalytic quantity of sodium ethoxide (freshly prepared from sodium in ethanol) was added to the solution which was allowed to stir at room temperature for one hour. The yellow material was collected by filtr~tion, dried and ret;~ Lallized from acetonitrileto yield the title compound ~s yellow crystals (5.20 g): mp 211-212 C; IR (mineral oil) 1735 and 1690 cm 1; NMR (DMSO-d6) ~ 1.25 (3H, t), 4.2 (2H, q), 5.12 and 5.37 (2H, doublets) and 7.3 (8H, m); and Anal. Calcd for C18H15N303: C, 87.28%
H, 4.71% N, 13.08% ~nd Found: C, 66.67% H, 4.69% N, 12.94%.
Claims (14)
1. A process for preparing a compound of formula I
(I) in which R1 and R2 each is hydrogen, halo or lower alkyl and R3 is lower alkyl, which comprises cyclizing a compound of formula II
(II) in which R1, R2 and R3 are as defined herein.
(I) in which R1 and R2 each is hydrogen, halo or lower alkyl and R3 is lower alkyl, which comprises cyclizing a compound of formula II
(II) in which R1, R2 and R3 are as defined herein.
2. The process of claim 1 wherein the cyclization is conducted at about 250 to 300°C in an inert solvent.
3. The process of claim 1 wherein the cyclization is conducted in the presence of sodium or potassium alkoxide in a lower alkanol.
4. The process of claim 1 which comprises cyclizing a compound of formula II wherein one of R1 and R2 is hydrogen and the other of R1 and R2 is hydrogen, chloro or lower alkyl having one to three carbon atoms; and R3 is lower alkyl having one to three carbon atoms to give a compound of formula I
in which R1, R2 and R3 are as defined herein.
in which R1, R2 and R3 are as defined herein.
5. The process which comprises cyclizing the compound [(5H-pyrrolo[2,1-c][1,4] benzodiazepine-11-y1) amino] methylene propanedioic acid, diethyl ester to give the compound 4-oxo-10H-pyrimido [1,2-a]-pyrrolo [2,1-c][1,4] benzodiazepine-3-carboxylic acid, ethyl ester.
6. The process which comprises cyclizing the compound [(7-methyl-5H-pyrrolo[2,1-c][1,4] benzodiaze-pine-11-y1)amino] methylene propanedioic acid diethyl ester to give the compound 8-methyl-4-oxo-10H-pyrimido [1,2-a]pyrrolo[2,1-c][1,4] benzodiazepine-3-carboxylic acid, ethyl ester.
7. The process which comprises cyclizing the compound [(8-chloro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-11-y1)amino] methylene propanedioic acid, diethyl ester to give the compound 8-chloro-4-oxo-10H-pyrimido-[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid, ethyl ester.
8. The process which comprises cyclizing the compound [(7-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-y1)amino] methylene propanedioic acid, diethyl ester to give the compound 7-chloro-4-oxo-10H-pyrimido-[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid, ethyl ester.
9. A compound of the formula in which R1 and R2 each is hydrogen, halo or lower alkyl and R is lower alkyl, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
10. A compound of claim 9 wherein one of R1 and R2 is hydrogen and the other of R1 and R2 is hydrogen, chloro or lower alkyl having one to three carbon atoms; and R3 is lower alkyl having one to three carbon atoms, whenever prepared by the process of claim 4 or its obvious chemical equivalents.
11. The compound of claim 10, which is 4-oxo-10H-pyrimido[1,2-a]-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid, ethyl ester, whenever prepared by the process of claim 5 or its obvious chemical equivalents.
12. The compound of claim 10, which is 8-methyl-4-oxo-10H-pyrimido-[1,2-a]pyrrolo[2,1-c][1,4]benzo-diazepine-3-carboxylic acid, ethyl ester, whenever prepared by the process of claim 6 or its obvious chemical equivalents.
13. The compound of claim 10, which is 8-chloro-4-oxo-10H-pyrimido-[1,2-a]pyrrolo[2,1-c][1,4]benzodia-zepine-3-carboxylic acid, ethyl ester, whenever prepared by the process of claim 7 or its obvious chemical equi-valents.
14. The compound of claim 10, which is 7-chloro-4-oxo-10H-pyrimido-[1,2-a] pyrrolo[2,1-c][1,4]benzo-diazepine-3-carboxylic acid, ethyl ester, whenever prepared by the process of claim 8 or its obvious chemical equivalents.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422672A CA1197242A (en) | 1983-03-02 | 1983-03-02 | Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422672A CA1197242A (en) | 1983-03-02 | 1983-03-02 | Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivatives |
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| CA1197242A true CA1197242A (en) | 1985-11-26 |
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1983
- 1983-03-02 CA CA000422672A patent/CA1197242A/en not_active Expired
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| US10246460B2 (en) | 2013-12-05 | 2019-04-02 | Hoffmann-La Roche Inc. | Synthesis of trans-8-chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10B-tetraaza-benzo[E]azulene and crytalline forms thereof |
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