JP2003510280A - Vasopressin agonist prescription and manufacturing method - Google Patents

Abstract

(57) SUMMARY The present invention is a novel formulation for a vasopressin agonist compound having the general structure (I) or a pharmaceutically acceptable salt thereof, and a process for preparing the same, comprising from about 1% to about 20% About 1% to about 18% of a surfactant component, about 50% to about 80% of one or more polyethylene glycol components, about 1% to about 20% of one or more sucrose fatty acid esters and / or There is provided a formulation comprising the components of polyvinylpyrrolidone and optionally one or more preservatives or antioxidants. Embedded image

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a novel formulation for a series of tricyclic vasopressin agonist compounds and pharmaceutically acceptable salts thereof, as well as a process for producing the formulation. The invention particularly relates to orally administered formulations of these compounds.

BACKGROUND OF THE INVENTION The art has shown many methods of making liquid or semi-solid encapsulated pharmaceutical formulations. In Bull. Tech./Gattefosse Rep. (1996), 89, 27-38, author Shah et al. Described hard gelatin capsule technology that is particularly useful for improving bioavailability of poorly soluble or poorly absorbed drugs. is doing. U.S. Pat. No. 4,620,974 (Hersh et al.) Has a nested nest with a lubricant comprising polyethylene glycol having a molecular weight of about 200 to about 900 formulated in a mixture with the composition at a concentration of about 0.5 to about 25 weight percent. A hard gelatin capsule comprising a two piece cap is taught.

WO 96/40071 (Lamberti) discloses a method and a device for producing minimum volume capsules. WO 96/41622 (Tanner et al.) Teaches a suspension suitable especially for encapsulating a solid phase of solid particles and a gelatin capsule containing a solid phase in which the solid phase can be suspended. U.S. Pat. No. 5,641,512 (Cimiluca) teaches an analgesic whose outer coat is encapsulated in a soft gelatin capsule containing a xanthine derivative such as caffeine. U.S. Pat. No. 4,578,391 (Kawata et al.) Describes at least one lipophilic or water-soluble antineoplastic agent, at least one oil and fat, and at least one solubilizing agent, crown ether, lecithin, polyethylene glycol, polypropylene glycol. , Vitamin E, polyoxyethylene alkyl ethers and sucrose esters of fatty acids in oily vehicles for antitumor agents.

EP 0 815 854 A1 is a substantially translucent semi-solid filling material for soft gelatin capsules, which is sufficiently transparent that the semi-solid material cannot be released from the capsule with a syringe at room temperature. Disclosed as viscous. U.S. Pat. No. 4,744,988 (Brox) is a soft gelatin capsule comprising a gelatin crust, polyethylene glycol and lower polyhydric alcohol softeners and fillers, and at least one active substance, wherein the crust is 4-40. Polyethylene glycol having an average molecular weight of 600, at least half the weight of the polyethylene glycol used, containing up to 20% by weight of glycerol and / or 1,2-propylene glycol. A capsule characterized in that it is taught. WO 95/19579 (Dhabhar) teaches a method of solubilizing poorly soluble drug substances in a mixture of polyethylene glycol and propylene glycol by using polyvinylpyrrolidone having a specific viscosity average molecular weight of about 5000 to about 25000.

SUMMARY OF THE INVENTION The present invention is directed to tricyclic vasopressin agonist compounds or pharmaceutically acceptable salts thereof (singularly or collectively also referred to herein as "active ingredients"). An orally administrable formulation, wherein the active ingredient has the structural formula:

[Chemical 7]

Wherein: A, B, E, G are independently CH or nitrogen; D is independently C—W or nitrogen; R ¹ is alkanoyl having 2 to 7 carbon atoms , CN, COOH, CONH ₂ ,

[Chemical 8] A group selected from or:

[0007]

[Chemical 9] Is a part selected from

R ² , R ³ and R ⁵ are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms,
Branched alkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or perfluoroalkyl having 1 to 6 carbon atoms; R ⁴ is hydrogen, linear alkyl having 1 to 6 carbon atoms A branched alkyl having 3 to 7 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, an alkoxyalkyl having 2 to 7 carbon atoms, or an alkanoyl having 2 to 7 carbon atoms, a carbon atom having 3 to 7 carbon atoms. An acyl substituent selected from the group consisting of alkenoyl, cycloalkanoyl having 3 to 7 carbon atoms, aroyl or arylalkanoyl;

X and Y are independently hydrogen, linear alkyl having 1 to 6 carbon atoms, carbon atom 3
~ 7 branched chain alkyls, cycloalkyls with 3 to 7 carbon atoms, perfluoroalkyls with 1 to 6 carbon atoms, alkoxyalkyls with 2 to 7 carbon atoms, halogens (including chlorine, bromine, fluorine and iodine). ), Alkoxy having 1 to 6 carbons, hydroxy, CF ₃ , or perfluoroalkyl having 2 to 6 carbons; W is hydrogen, halogen (preferably chloro, bromo or iodo), alkyl, carbon 2 to 7 Alkoxyalkyl, hydroxyalkyl having 1 to 6 carbons,
Or CH ₂ NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are independently hydrogen, linear alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 7 carbon atoms; or of CH ₂ NR ⁶ R ⁷ . Together with the nitrogen atom, R ⁶ and R ⁷ include, but are not limited to, the groups:

[Chemical 10] Form a 5- or 6-membered ring which may contain one or more additional heteroatoms such as; R ⁸ is straight-chain alkyl of 1 to 6 carbon atoms; R ⁹ is independently Hydrogen, trimethylsilyl or straight-chain alkyl having 1 to 6 carbon atoms] or a tricyclic vasopressin agonist compound or a pharmaceutically acceptable salt, ester or prodrug form thereof.

[0011]   Particularly preferred active ingredients of the formulations of the present invention have the formula:

[Chemical 11]

Wherein A and B are independently CH or nitrogen; D is C—W or nitrogen; R ¹ is alkanoyl having 2 to 7 carbon atoms or

[Chemical 12] A group selected from:

R ² , R ³ and R ⁵ are independently hydrogen, linear alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 7 carbon atoms, cyclo of 3 to 7 carbon atoms. Alkyl, or perfluoroalkyl having 1 to 6 carbons; R ⁴ , X, Y, W, R ⁶ , R ⁷ and R ⁸ are as defined above] or a pharmaceutically acceptable compound thereof. It is salt.

For the compounds mentioned above and herein, unless otherwise stated, aroyl groups are, for example, hydrogen, halogen, cyano, straight-chain alkyl of 1 to 6 carbon atoms,
Benzoyl which can be substituted independently carbon atoms 3-7 branched alkyl, with one or more substituents from the group of carbon 1-6 alkoxy, CF ₃ or phenyl, including naphthoyl. As used herein, heteroaroyl refers to a carbonyl (bonded directly to a carbon atom of a 5-membered heterocycle having 1 or 2 heteroatoms selected from nitrogen, oxygen, sulfur.
Free radical), for example 2-thienoyl. The heterocycle of the heteroaroyl group also includes, but is not limited to, the aryl moiety of furan, pyrrole, 2H-pyrrole, imidazole, pyrazole, isothiazole, isoxazole, thiophene,
It may include groups which are pyrazoline, imidazolidine or pyrazolidine groups. In the present specification, the heteroaryl group is independently one or more substituents derived from the group of hydrogen, halogen, cyano, linear alkyl having 1 to 6 carbon atoms or branched alkyl having 3 to 7 carbon atoms. Can be replaced.

In the present specification, the arylalkanoyl group refers to a carbonyl group or a free group directly bonded to an alkyl group having 1 to 6 carbon atoms whose terminal is substituted with an aryl group, for example, phenylacetic acid. Aryl groups are hydrogen, halogen, cyano,
Straight chain alkyl having 1 to 6 carbon atoms, branched alkyl having 3 to 7 carbon atoms, carbon 1
6 alkoxy, CF ₃ or phenyl or substituted group is halogen, cyano, 1 to 6 carbon atoms straight-chain alkyl, carbon atoms 3-7 branched alkyl, carbon 1-6 alkoxy, It can be independently substituted with one or more substituents from the group of substituted phenyls selected from CF ₃ . Halogen referred to herein may be selected from fluorine, chlorine, bromine or iodine unless otherwise specified.

The definition of the compound of formula (I) is R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ⁷ .
Or, where Y contains an asymmetric carbon, it will be understood by those skilled in the art to include all possible stereoisomers and mixtures thereof having the following activities: In particular, it is any optical isomer and diastereomer having the required activity; and racemic and resolved enantiomerically pure R and S stereoisomers; and other R and S stereoisomers. And a pharmaceutically acceptable salt thereof. Optical isomers may be obtained in pure form by standard separation techniques. In addition, all possible regioisomers of the compounds of formula (I) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X or Y have the following activities and their It is also understood to include mixtures. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art.

[0017]   Also, inter alia, preferred groups of active ingredients in the formulations of the present invention are:   a) General formula:

[Chemical 13] [Wherein A, B, W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and Y are as defined above]. Compound;

[0018]   b) General formula:

[Chemical 14] [Wherein A, B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , X and Y are as described above]; and

[0019]   c) General formula:

[Chemical 15] [Wherein A, B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , X and Y are as described above].

The above subgroups a) -c) are further: wherein A and B are independently CH or nitrogen; R ¹ is alkanoyl of 2 to 7 carbon atoms or

[Chemical 16] A group selected from:

R ² , R ³ and R ⁵ are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms,
Branched alkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or perfluoroalkyl having 1 to 6 carbon atoms; R ⁴ , X, Y, W, R ⁶ , R ⁷ and R ⁸ Is understood to include subgroups as described above or pharmaceutically acceptable salts thereof.

Particularly preferably among the compounds of group a) above, W is H, A and B are each CH and R ¹ is an alkanoyl group of 2 to 7 carbon atoms, Alternatively, the above-mentioned portions (a), (b), (e), (f), (g), (h), (i) or (
a compound which is a group selected from k). Pharmaceutically acceptable salts include lactic acid, citric acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid and likewise known acceptable salts. And salts derived from organic and inorganic acids, such as acid.

[0023]   In particular, a more preferred formulation of the present invention has, as the active ingredient, the structural formula:

[Chemical 17] [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl- (5H, 11H) -pyrrolo [2,1-c] [1,4] benzodiazepine-1 represented by
Formulations described herein having 0-yl) -methanone or a pharmaceutically acceptable salt thereof.

The formulations of the present invention are useful in the treatment of human or other mammalian diseases, conditions or disorders in which vasopressin agonist activity is desired. These therapies release factor VIII and von Willebrand factor into the circulation, release tissue plasminogen activator (t-PA) into the blood circulation, or affect renal retention of water and urine concentrations. It includes treatments for diseases, conditions or disorders in which it is desirable. Such treatments include, but are not limited to, treatment for bleeding and coagulation disorders in humans or other mammals, including diabetes insipidus, nocturnal enuresis, nocturnal polyuria, urinary incontinence, or hemophilia. Includes.

The methods of the invention in which these formulations are used include facilitating a temporary delay in voiding in a human or other mammal, which also, if desired, temporarily delays voiding. Inability to do so may be described as modulating or treating. It is understood that the method is separate from the treatment of the condition known as nocturnal enuresis and nocturnal polyuria and includes treatments that facilitate a temporary delay in urination that is not included in the treatment. For consistency of administration, the compositions of the invention are preferably in unit dosage form. Suitable unit dosage forms preferably include tablets or capsules,
Those skilled in the art will appreciate that the semi-solids or gels of the present invention are also easily manufactured and useful. Such unit dosage form is 0.1-1000 mg, preferably 2
It may contain -50 mg of the compound of the invention. An even more preferred unit dosage form contains 1-25 mg, more preferably 1-10 mg of a compound of the invention. The compounds of the invention may be administered orally in a dosage range of about 0.01 to 100 mg / kg, or preferably in a dosage range of 0.1 to 10 mg / kg. Such a composition is
It may be administered 1 to 6 times a day, more usually 1 to 4 times a day.

The compositions of the present invention may be formulated with other conventional carriers or fillers, excipients such as disintegrating agents, binders, lubricants, flavoring agents and the like. The formulations of the present invention comprise: a) about 1% to about 20% by weight of the active ingredient or a pharmaceutically acceptable salt thereof, preferably about 1% to about 16%, more preferably about 5%. ~ About 16% by weight of the active ingredient; b) about 1% to about 18% by weight of the surfactant component, preferably about 1% by weight.
About 5% by weight, more preferably about 5% to about 15% or about 5% to about 18%, most preferably about 5% to about 10% or about 8% to about 12%. Wt% surface active ingredient; c) about 50 wt% to about 80 wt% of one or more polyethylene glycols (PEG).
Component), preferably from about 55% to about 70% by weight of one or more polyethylene glycols; d) from about 1% to about 20%, preferably from about 5% to about 15% and more preferably. Is about 8% to about 12% by weight: i) one or more sucrose fatty acid esters; or ii) a K value of about 15-90, preferably a K of about 17 or more as defined in USP / NF. Polyvinylpyrrolidone (PVP) having a value; iii) one or more sucrose fatty acid esters and PVP as described above
Including a combination of.

The polyethylene glycol component is one or more PEG polymers, preferably PEG
200 to PEG 4000 commercial PEG polymers, ie, about 190 to about 48
It consists of a PEG polymer with an average molecular weight of 00. More preferably about 190
PEG having an average molecular weight of about 3450, most preferably about 400-1540
It is a polymer. Particularly preferred PEG polymers are PEG 400 having an average molecular weight of about 380 to about 420, P having an average molecular weight of about 950 to about 1050.
EG1000. The ratio of high molecular weight to low molecular weight PEG species in the PEG component is preferably about 2.5: 1 to about 1: 2.5, more preferably about 1: 1. For example, a preferred mixture of PEG polymers of this invention is PEG400 and PEG100.
It will include a 1: 1 mixture of 0's. It is preferred to select a mixture of PEG components that has a melting point at or near the physiological temperature of the mammal to receive the formulation. A final mixture of components having a viscosity range of about 140 to about 1500 centipoise at 37 ° C is preferred, more preferably in the range of 300 to about 800 centipoise at 37 ° C.

Surfactants that may be used in the formulations of the present invention include, but are not limited to, Polysorbate 20 (Polyoxyethylene 20 sorbitan monolaurate), Polysorbate 60, Polysorbate 40, Polysorbate 80, Span. (Span) 80 Sorbitan oleate (ICI Americans, Wilmington, Delawar
e)), polysorbate 81, polysorbate 85, polysorbate 120
, Martindale The Extra Pharmacopoeia 30th Edition, pages 1341-1342, eg, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid and ursodeoxycholic acid,
Includes pluronic or poloxamer, such as pluronic F68, pluronic L44, pluronic L101, a combination of one or more of the above. Polysorbate 80, either alone or in combination with one or more other surfactants, is preferred for use in the present invention.

Sucrose fatty acid esters useful in the present invention are commercially available art-recognized esters useful in orally administered pharmaceutical compositions including sucrose monoesters, diesters and triesters or mixtures thereof. Includes. Specific examples of esters useful in the present invention include sucrose monolaurate, sucrose monomyristate, sucrose monopalminate, sucrose monostearate, sucrose distearate, sucrose tristearate, sucrose trisate. Myristate, and sucrose tripalmitate, or a combination thereof.

In addition to these ingredients, other fortifying or protecting antioxidants or preservatives may be added to the compositions of the present invention, which may comprise up to about 4% by weight of the formulation. For example, ascorbyl palmitate, benzyl alcohol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) and the like may be used. Examples of these components in the formulations of the present invention include B at a concentration of about 0.3% to about 2.5% by weight.
HA and BHT at a concentration of about 0.005% to about 0.15% by weight, preferably a mixture of BHA and BHT within these ranges. A further embodiment comprises about 0.2% BHT.

Formulations of the present invention utilizing one or more of these antioxidants or preservatives comprise a) about 1% to about 20% by weight of the active ingredient or a pharmaceutically acceptable salt thereof, preferably about. 1% to about 16% by weight, more preferably about 5% to about 16% by weight of the active ingredient; b) about 1% to about 18% by weight of the surfactant component, preferably about 5%. % ~
About 15% by weight of the surfactant component, more preferably about 5% to about 10% or about 8% to about 12% by weight of the surfactant component; c) about 50% to about 80% by weight. 1 or more polyethylene glycol (PEG
Component), preferably from about 55% to about 70% by weight of one or more polyethylene glycols; d) from about 1% to about 20%, preferably from about 5% to about 15% by weight.
The above sucrose fatty acid ester or a K value of about 15 to 90, preferably
Polyvinylpyrrolidone (PVP) having a K value as defined in USP / NF of about 17 or greater; e) about 0.1% to about 4% by weight of one or more preservatives or antioxidants, for example,
About 0.3 wt% to about 2.5 wt% BHA and / or about 0.005 wt% to
Contains about 0.15% by weight BHT.

One preferred embodiment of the present invention is: a) about 5% to about 16% active ingredient; b) about 5% to about 15% surfactant ingredient; c) about 55% to about 70%. D) Polyvinylpyrrolidone (PVP) having a K value of about 15 to 90 of about 5% to about 15%, preferably a K value of about 17 or more as defined in USP / NF. ); E) A pharmaceutical composition comprising about 0.3% to about 2.5% (% w / w) BHA and about 0.005% to about 0.15% (% w / w) BHT. I will provide a.

Preferably, the formulations of the present invention are encapsulated after manufacture in a closed container such as a soft or hard gelatin capsule. The formulations of the present invention may be manufactured as liquid or semi-liquid formulations and incorporated into capsules. Similarly, the formulation may be prepared as a gel or solid prior to encapsulation using the acceptable range of ingredients and / or temperatures.

Detailed Description of the Invention Active compounds useful in the formulations of the present invention may be prepared by one of the general methods outlined below. As shown in Scheme I, the tricyclic benzodiazepines of formula (1) are added to pyridine or trialkylamines, for example, in the presence of a base such as triethylamine, in an aprotic solvent such as dichloromethane or tetrahydrofuran at -40 ° C.
At 50 ° C., an appropriately substituted acetylaroyl (heteroaroyl) of formula (2)
Treatment with a halide, preferably aroyl (heteroaroyl) chloride, gives the formula (
The acylated derivative of 3) is obtained. According to the method of Lin et al., J. Het. Chem, 14, 345 (1997), (3) was treated with a dialkyl of formula (4) in an aprotic organic solvent such as dichloromethane at 0 ° C to the reflux temperature of the solvent. Treatment with an amido dialkyl acetal gives the enone of formula (5). Treatment of (5) with acetic acid of formula (6) or a substituted hydrazine in acetic acid at ambient temperature to the reflux temperature of the solvent gives formula (I)
The target compound (wherein A, B, D, E, G, X, Y, R ² and R ⁴ are as described above, and R ¹ is (f), (g) of the above heterocycle or (J) is a heterocyclic moiety selected from the group).

[0035]

[Chemical 18]

The preferred substituted acetylaroyl (heteroaroyl) chloride of formula (2) of Scheme I is conveniently treated with the corresponding carboxylic acid with thionyl chloride at ambient temperature to the reflux temperature of the solvent. Or by treatment with oxalyl chloride at 0 ° C. to 40 ° C. in the presence of a catalytic amount of dimethylformamide in an aprotic solvent such as dichloromethane or tetrahydrofuran.

Preferred dialkylamide dialkyl acetals are either commercially available or known in the literature or, conveniently, the literature, Kantlehner.
, W. Chem. Ber. 105, 1340 (1972). A preferred tricyclic benzodiazepine of formula (1) is 10,11-dihydro-5H
-Pyrrolo [2,1-c] [1,4] benzodiazepines (Albright et al., US Pat. No. 5,536,718 issued Jul. 16, 1996) 10,11-dihydro-5H-pyrazole [5,1- c] [1,4] benzodiazepines (Cecchi, L. et al., J. Het. Chem., 20, 871 (1983)) and 10,11-dihydro-5H-tetrazole [5,1-c] [1,4. ] Benzodiazepines (Klaubert, DH, J. Het
Chem., 22, 333 (1985).

[0038]   Scheme I

[Chemical 19]

[0039]   An alternative method for the preparation of intermediates of formula (3) is illustrated in Scheme II below.   Scheme II

[Chemical 20]

Thus, the tricyclic benzodiazepines of formula (1) are added to -40 ° C. to 50 ° C. in an aprotic organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic base such as pyridine or trialkylamine, eg triethylamine. ℃
At a treatment with an appropriately substituted bromoaroyl (heteroaroyl) halide of formula (8), preferably aroyl (heteroaroyl) chloride, to give an acylated intermediate of formula (9). Then pyridine and bis (triphenylphosphine)
Basically, in the presence of a catalyst such as palladium (II) chloride and copper (I) iodide, in an organic base as a solvent such as triethylamine, in a pressure tube sealed at ambient temperature to 100 ° C. Martinez et al., J. Med. Chem., 35, 620 (19
According to the method of 92), the intermediate (9) is converted to trimethylsilyl or 1 to 1 carbon atoms.
It is attached to a mono-substituted terminal acetylene such as 6 straight chain alkyls. The resulting acetylene intermediate of formula (10) is then essentially prepared by Reed et al., J. Org. Chem., 5
2, 3491 (1987), at ambient temperature, hydrated by treatment with 1% sulfuric acid in an aprotic organic solvent such as tetrahydrofuran saturated with mercury (II) sulphate, to give the formula The desired acyl compound of (3) (wherein A, B
, D, E, G, X and Y are as described above, R ⁹ is hydrogen or carbon atom 1
~ 6 straight chain alkyl). Alternatively, compound ⁹ where R ⁹ is trimethyl is treated with tetrabutylbutylammonium fluoride in an ether solvent such as tetrahydrofuran to give compound (10) where R ⁹ is hydrogen.

A preferred acylating agent of formula (8) in Scheme II is conveniently of formula (8)
By treating the appropriately substituted aryl (heteroaryl) carboxylic acid of 7) with thionyl chloride at ambient temperature to the reflux temperature of the solvent or in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. Prepared by treating with oxalyl chloride in the presence of dimethylformamide at 0 ° C-40 ° C. The protected acetylene intermediates of Scheme II are either commercially available or known in the art or can be readily prepared by methods similar to those in the literature.

As shown in Scheme III, the intermediate acetyl compound (3) of Scheme I
Is in the presence of a catalytic amount of bis (triphenylphosphine) palladium (II) chloride in an aprotic organic solvent such as toluene at ambient temperature to the reflux temperature of the solvent, basically by Kosugi et al., Bull. Chem. Soc. Jpn., 60, 767 (1987) and a bromoaryl (heteroaryl) compound of formula (9) of Scheme II and an (α-ethoxyvinyl) trialkyltin, preferably (α It can also be prepared by Stille coupling with -ethoxyvinyl) tributyltin.

[0043]   Scheme III

[Chemical 21]

The preparation of the acetyl compound (3) is also described by Cabri et al., Tetrahedron Lett., 32, 17
53 (1991), using the aryl halide intermediate of formula (9),
This can be accomplished via palladium-catalyzed arylation of vinyl alkyl ethers such as vinyl butyl ether. The (α-alkoxyvinyl) trialkyltin intermediates of Scheme III are either commercially available or known in the art, or can be readily prepared by analogy to literature procedures.

When R ⁴ is hydrogen in Scheme I, the nitrogen of the heterocycle can be alkylated or acylated according to the reactions outlined in Scheme IV.

[0046]   Scheme IV

[Chemical formula 22]

Thus, a pyrazole compound of formula (I, R ⁴ is H) is treated with a strong compound such as sodium or potassium hydride in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at 0 ° C to 80 ° C. Alkylation by treatment with a base and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide), to give a compound (I, R ¹ = (f) or (g)) (wherein A, B, C, D, E, G, X, Y and R ² are as described above and R ⁴ is an alkyl or acyl group). Alternatively, compound (I) can be prepared by
An additional solvent when pyridine is used as a base in an aprotic organic solvent such as dichloromethane or tetrahydrofuran in the presence of an amine base such as pyridine or a trialkylamine, preferably triethylamine, at ℃ to ambient temperature. Acylation by treatment with a carboxylic acid halide, preferably a chloride, or a carboxylic acid anhydride without a compound of formula (I) (wherein A, B, C, D, E, G, X , Y and R ² are as described above, and R ⁴ is an alkyl or acyl moiety). Alkylation or acylation of a compound of formula (I, R ⁴ = H) allows R ^{2 to} be hydrogen and R ^{1 to} be as described above and each
A mixture of regioisomers is obtained which is a heterocyclic moiety selected from either the (f) or (g) groups of the heterocycle illustrated below.

[0048]

[Chemical formula 23]

A compound of general formula (I) of scheme I, wherein A and B are carbon, R ² is H and R ¹ is a heterocycle selected from the (g) groups of the above heterocycles. The cyclic moiety) can be prepared according to the general method outlined in Scheme V.

[0050]   Scheme V

[Chemical formula 24]

[Chemical 25]

[0051]   Thus, an appropriately substituted haloaryl (heteroaryl) of formula (11)
The carboxylic acid ester, preferably bromo (or iodo) methyl ester, is
Sus (triphenylphosphine) palladium (II) chloride and copper (I) iodide
In the presence of an organic base such as triethylamine as a solvent in the presence of a catalyst such as
At ambient temperature to 80 ° C, basically, Alami et al., Tetrahedron Lett.,
34, 6403 (1993) and Sanogashira et al., Tetrahedron Lett, 4467 (1975).
In accordance with the procedure, a dialkylaminopropyne, preferably 1-dimethylaminopropyne
Coupling with ropine gives the substituted acetylene intermediate of general formula (12). Then
Some at below ambient temperature in an aprotic organic solvent such as dichloromethane
Standard oxidation method (Albini, A., Synthesis, 263 (1993))
With oxidants or dioxirane reagents (Murray, R.W., Chem. Rev., 1187 (1989)
) Converts intermediate (12) to its N-oxide. Intermediate N
-Oxide is not isolated, but preferably with heating, water, either C₁-C ₈ Linear or branched alkyl alcohol, ethylene glycol, polyethylene
Glycol, 1,2-propylene diol, polypropylene glycol, glyce
Roll, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-tri
Fluoroethanol, benzyl alcohol, phenol or 1 known to those skilled in the art
From any equivalent solvent containing the above free hydroxyl (-OH) substituents
Including any solvent or combination of solvents that consists of, or contains
In-situ enone of general formula (13) by treatment with a hydroxyl solvent
Transpose to.

Solvent systems containing one or more co-solvents together with one or more solvents may be used in this method of rearrangement of N-oxides to the desired enaminones. As used herein, a co-solvent is defined as a diluent of a major solvent and is a hydrocarbon such as pentane, hexane or heptane; an aromatic hydrocarbon such as benzene, toluene or xylene; diethyl ether, tetrahydrofuran, dioxane or Ethers such as dimethoxyethane; chlorinated hydrocarbons such as dichloromethane, chloroform, dichloroethane or tetrachloroethane; or such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone and the like. Other common solvents can be selected.

Conversion of the amine N-oxide to the enaminone can be accomplished by introducing the amine N-oxide into a suitable hydroxy solvent, preferably at room temperature or at ambient temperature to the reflux temperature of the solvent. . In another example, the introduction of the amine N-oxide into the hydroxy solvent, preferably with stirring, is carried out at room temperature to the reflux temperature of the solvent in the presence of an acceptable catalyst such as a palladium (II) catalyst or a copper (I) catalyst. Can be achieved in.

The procedure provides a novel synthesis of enaminone compounds from propargylamine or its N-oxide in a hydroxy solvent that affects the final outcome of the reaction. This new method of enaminone synthesis provides a convenient alternative to existing methods and further expands the range of starting materials that can be converted to enaminone products.

The exact mechanism by which propargylamine N-oxide is converted to the enaminone product has not been accurately determined, but there are probably two known methods; the terminal [2,3] -terminal of propargylamine N-oxide. Sigma directional dislocation (Craig et al., Tetrahedr
on Lett., 4025, 1979; Hallstrom et al., Tetrahedron Lett., 667, 1980; Khuthie
r, AH et al., J. Chem., Soc. Chem. Commun., 9, 1979) and the conversion of certain isoxazoles to enaminones (Liguori et al., Tetrahedron, 44, 1255, 1988).

Substituted hydrazine of (13) (6) in acetic acid at ambient to reflux temperature
Treatment with ## STR15 ## gives a mixture of regioisomeric compounds of the general formulas (14) and (15) in variable proportions. The major product, an isomer of formula (14), is separated by chromatography and / or crystallization and then hydrolyzed to the desired carboxylic acid of formula (16).

Intermediate (16) is then converted to an acylating species, preferably an acid chloride (bromide or iodide) or a mixed anhydride of formula (17), by procedures similar to those described above. The acylating agent (17) is then used to formula (1) by any of the procedures described above.
A) the tricyclic benzodiazepine is acylated to provide the desired compound of formula (I) wherein A, B are CH and D, E, G, X, Y and R ⁴ are as described above,
R ² is hydrogen and R ¹ is a heterocyclic moiety selected from the (g) group of heterocycles illustrated below).

[0058]

[Chemical formula 26]

Similarly, treatment with an unsubstituted hydrazine of (13) (6, R ⁴ is H) in acetic acid at ambient temperature to the reflux temperature of the solvent provides the intermediate pyrazole ester of formula (18). In this case, the heterocycle nitrogen is alkylated or acylated as shown in Scheme VI, wherein R ² is hydrogen and R ¹ is a heterocyclic moiety selected from the (f) groups of the above heterocycles. A compound of formula (I) can be obtained.

[0060]   Scheme VI

[Chemical 27]

Thus, an intermediate ester of formula (18) is treated with a strong base such as sodium or potassium hydride and an alkyl halide at 0 ° C.-80 ° C. in an aprotic solvent such as dimethylformamide or tetrahydrofuran. Alkylation, preferably by treatment with an alkylating agent such as an alkyl chloride (bromide or iodide), affords regioisomeric mixtures of formulas (14) and (15) in variable ratios. The major product, the regioisomer of formula (15), is separated by chromatography and / or crystallization and then hydrolyzed to the desired carboxylic acid of formula (19), then by a procedure similar to the above. It is converted to an acylating agent, preferably an acyl chloride or mixed anhydride. The tricyclic benzodiazepine of formula (1) is then acylated with an acylating species of formula (20) to provide the desired compound of formula (I) (wherein A, B, D, E, G, X, Y and R ⁴ are as described above, R ² is hydrogen and R ¹ is a heterocyclic moiety selected from the (f) group of the above heterocycle).

[0062]

[Chemical 28]

Compounds of general formula (I), wherein R ¹ is a heterocyclic moiety selected from the (h) groups of the R ¹ heterocycle above are prepared as outlined in Scheme VII. it can.

[0064]   Scheme VII

[Chemical 29]

The appropriately substituted malondialdehyde of formula (21) is first treated with hydrazine in acetic acid at ambient temperature to the reflux temperature of the solvent and then the intermediate pyrazole in a basic aqueous solution at ambient temperature. To oxidize with potassium permanganate at the reflux temperature of the solvent to give the carboxylic acid intermediate of formula (22). The acid (22) is converted to an acylating agent, preferably an acid chloride (bromide or iodide) or mixed anhydride, by procedures analogous to those described above. Finally, the acylating agent of formula (23) is replaced by formula (1
) Of a compound of general formula (I) (wherein A
, B, D, E, G, X, Y and R ⁴ are as described above, and R ¹ is a heterocyclic moiety selected from the (h) group of the above heterocycle).

[0066]

[Chemical 30]

When R ⁴ is hydrogen in Scheme VII, the heterocyclic nitrogen can be alkylated or acylated according to the procedures described above. Preferred malondialdehydes of formula (21) and hydrazines of Scheme VII are commercially available or known in the art, or Knorr et al., J. Org. C.
hem., 49, 1288 (1984) and Coppola et al., J. Het. Chem., 11, 51 (1974) can be readily prepared by methods similar to those in the literature for known compounds.

Another method for preparing intermediate carboxylic acids of formula (22) of Scheme VII, where Y is as described above and R ⁴ is other than hydrogen, is outlined in Scheme VIII.

[0069]   Scheme VIII

[Chemical 31]

Basically, according to a procedure similar to that found in Farina et al., J. Org. Chem., 59, 5905 (1994), the organotin reagent of formula (25) was treated with tetrakis (triphenylphosphine) palladium. Ambient temperature to 15 in an organic aprotic solvent such as dimethylformamide in the presence of a catalyst such as (0) and copper (I) iodide.
Reaction at 0 ° C. with an appropriately substituted aryl (heteroaryl) halide of formula (28), preferably bromide or iodide, in a stille coupling reaction. The resulting ester of formula (26) is stirred at ambient temperature to the reflux temperature of the solvent.
Basic hydrolysis with sodium or lithium hydroxide in aqueous alcohol or tetrahydrofuran gives the desired carboxylic acid of formula (22).

An organotin reagent of formula (25), where the R group is preferably an alkyl group, is then conveniently added to an alkyllithium such as n-butyllithium, sec-butyllithium or The procedure found in Martina et al., Syntehsis, 8, 613 (1991) in the presence of a metallizing agent such as tert-butyllithium in an aprotic organic solvent such as diethyl ether at -40 ° C or ambient temperature. Prepared by metallization of 4-bromo N-alkylpyrazoles of formula (24) with a trialkyltin halide, preferably tributyltin chloride (or bromide), according to a procedure analogous to.

The preferred N-alkyl substituted 4-bromopyrazoles of formula (24) may be conveniently prepared in the presence of a strong base such as lithium hydride, sodium or potassium hydride.
Prepared from 4-bromopyrazole by alkylation with an alkyl halide, preferably an alkyl chloride (bromide or iodide) at 0 ° C.-80 ° C. in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran. Alternatively, a phase transfer catalyst such as benzyldimethyltetradecyl ammonium chloride or benzyl trimethyl ammonium chloride (Jones, RA Aldrichimica ACTA, 9 (3),
35, 1976), and alkylation of 4-bromopyrazole can be carried out with the above alkylating agent and a strong alkaline base such as lithium hydroxide, sodium or potassium hydroxide.

Basically Street et al., J. Med. Chem., 36, 1529 (1993) and Coffen et al., J. Org.
Chem., 49, 296 (1984), the preferred aryl (heteroaryl) iodides of formula (28) are conveniently prepared by diazotization of the corresponding substituted anilines of formula (27), then , By reacting the corresponding diazonium salt with iodine and potassium iodide in an aqueous acidic medium.

[0074]   Another method for preparing compounds of general formula (I) is outlined in Scheme IX.   Scheme IX

[Chemical 32]

The tricyclic benzodiazepines of formula (1) are prepared in the presence of a base such as triethylamine or dipropylethylamine in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at −40 ° C. to the reflux temperature of the solvent. ,
An appropriately substituted haloaroyl (heteroaroyl) halide of formula (29),
Treatment with preferably fluoroaroyl or fluoro (or chloro) heteroaroyl chloride gives the acylated derivative (30).

Alternatively, the acylated species may be prepared according to Inanaga et al., Bull. Chem. Soc. Jpn. 52, 1989 (197
It can be a mixed anhydride of the above carboxylic acids as prepared by the reaction of 2,4,6-trichlorobenzoyl chloride in a solvent such as dichloromethane according to procedure 9). In the presence of an organic base such as 4-dimethylaminopyridine in a solvent such as dichloromethane, the compound of the general formula (0) to the reflux temperature of the solvent (
Treatment of the mixed anhydride of 29) with a tricyclic benzodiazepine of formula (1) gives the intermediate acylated derivative (30) of scheme IX.

[0077]   Then, the compound of formula (30) is treated with dimethylformamide or tetrahydrofuran.
In a polar aprotic organic solvent such as amine at ambient temperature to the reflux temperature of the solvent,
A suitably substituted heterocyclic lithium, sodium or potassium salt of formula (31)
Compound of general formula (I) (wherein A, B, D, E, G, X, Y, R ^Two , R^ThreeAnd R⁵Is as described above, and R¹Is a (a) of the above heterocycle, (
selected from the group consisting of b), (c), (d), (l), (n) or (o)
Is a heterocyclic moiety).

[0078]

[Chemical 33]

Condensation of intermediates of formula (30) with intermediate salts of formula (31) gives variable ratios of regioisomers of general formula (I), which can be chromatographed and / or crystallized. To separate by. Preferred substituted fluoroaroyl and fluoro (or chloro) of formula (29)
Heteroalloyyl chlorides are either commercially available or known in the art or can be readily prepared by methods analogous to those in the literature for known compounds.

The heterocyclic lithium, sodium or potassium salt of formula (31) is obtained by converting the heterocycle into lithium hydride in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at -40 ° C to ambient temperature. Sodium hydride,
Prepared by treatment with a strong base such as potassium hydride or a metal alkoxide. Alternatively, the compounds of general formula (I) described in Scheme IX can be prepared according to the methods outlined in Scheme X.

[0081]   Scheme X

[Chemical 34]

Accordingly, an appropriately substituted fluoroaryl or fluoro (or chloro) heteroarylcarboxylic acid of formula (32) is treated with oxalyl chloride (or) in an alcohol solvent such as methanol in the presence of a catalytic amount of dimethylformamide. Esterification using methods known in the art such as treatment with thionyl chloride) or by condensation with methanol in the presence of an acid catalyst such as paratoluenesulfonic acid at ambient to reflux temperature.

The resulting ester of formula (33) is treated in a polar aprotic organic solvent such as dimethylformamide at ambient temperature to 150 ° C. at an appropriately substituted heterocyclic lithium, sodium or formula (31) Reaction with the potassium salt yields formula (34
) Intermediate ester. Condensation of (33) with (31) gives variable ratios of regioisomers of formula (34), which are separated by chromatography and / or crystallization. Subsequent hydrolysis of the intermediate ester of formula (34) with an aqueous base such as sodium hydroxide or lithium hydroxide in methanol or tetrahydrofuran gives the carboxylic acid of formula (35).

The intermediate carboxylic acid (35) is then converted to an acylating agent, preferably the acid chloride or mixed anhydride of general formula (36), using any of the techniques described above. Subsequent reaction of the tricyclic benzodiazepines of formula (1) with an intermediate acylating agent of formula (36) according to any of the procedures described above provides the compounds of formula (I) of scheme IX
To obtain the desired compound of. Alternatively, the substituted carboxylic acid of formula (35) described in Scheme X can be prepared according to the method outlined in Scheme XI.

[0085]   Scheme XI

[Chemical 35]

Thus, a fluoroaryl or fluoro (chloro) heteroaryl nitrile of formula (37) is substituted with a substituted heterocycle of formula (31) in a non-polar aprotic solvent such as dimethylformamide at ambient temperature to 150 ° C. Is reacted with a lithium, sodium or potassium salt of to obtain an intermediate of the general formula (38). (37
) And (31) to give variable ratios of regioisomers of formula (38),
It is separated by chromatography and / or crystallization. Formula (38,
Y is other than CF ₃ ) hydrolysis of the intermediate nitrile at ambient temperature to 60 ° C.
Is preferentially performed using an inorganic acid such as sulfuric acid.

Alternatively, the hydrolysis of the nitrile (38) is carried out in the presence of a strong alkaline base such as sodium hydroxide in a phase transfer catalyst such as benzyldimethyltetradecylammonium chloride (Jones, RA Aldrichimica Acta, 9 (3 ), 35, 1976), with or without heating, in ethanol. The resulting carboxylic acid of formula (35) is then converted to the desired compound of formula (I) in Scheme IX by a procedure analogous to that described above.

Alternatively, the substituted carboxylic acid of formula (35) of Scheme X is converted to Scheme XII
Basically, Katrizky et al., Syntehsis, 949 (1989
), The nitrile of formula (38) (wherein A and B are CH and R ¹ is other than alkanoyl, alkynyl, (b) or (d) having 2 to 7 carbon atoms) in dimethyl. Treatment with basic hydrogen peroxide in sulfoxide and then treating the resulting amide of formula (38) according to the procedure of Hanes et al., Tetrahedron, 51, 7403 (1995), preferably with dilute sulfuric acid and sodium nitrite. It can be prepared by a continuous process of hydrolysis.

[0089]   Scheme XII

[Chemical 36] R ¹ is other than (b) or (d).

A preferred method of preparing the intermediate-substituted carboxylic acid of formula (35) of Scheme X, wherein R ¹ is a heterocycle moiety selected from group (a) of R ¹ heterocycle above, is schemed Outlined in XIII.

[0091]   Scheme XIII

[Chemical 37]

According to the method of Street et al., J. Med. Chem., 36, 1529 (1993), formula (40)
By diazotization of the appropriately substituted aniline of ## STR1 ## and then reduction of the resulting diazonium salt of formula (41) with tin (II) chloride in concentrated hydrochloric acid.
The intermediate hydrazine hydrochloride is obtained. (42) and an aldehyde derivative of formula (47) in a solvent such as aqueous methanol at ambient temperature to 100 ° C., wherein R ² is as described above, R ³ and R ⁵ are H, P Is a dialkyl acetal, for example acetylacetaldehyde dimethyl acetal) or formula (47)
Of the compound of formula (34) after crystallization by subsequent condensation with a ketone of ## STR3 ## wherein R ² , R ³ and R ⁵ are as described above and P is ═O or (O-alkyl) _2.
, R ¹ is (a) and R ⁵ is H) to give the desired intermediate ester, which is then converted to a compound of formula (I) as outlined in Scheme X above.

[0093]

[Chemical 38]

When Y is OCH ₃ , the compounds of general formula (I) of scheme I can be conveniently dimethylated as outlined in scheme XIV.

[0095]   Scheme XIV

[Chemical Formula 39]

[0096]   Therefore, the compound (I) (in this case, in an organic solvent such as dichloromethane)
Here Y is OCH_ThreeBy the reaction of boron tribromide with the corresponding formula (I)
Phenol (where Y is OH, A, B, D, E, G, X, R^TwoAnd R ^Three Is as described above, and R¹Is a heterocyclic (a) group illustrated above and below.
Is a heterocyclic moiety selected from).

[Chemical 40]

Compounds where R ¹ contains 3 heteroatoms are prepared according to Scheme XV. Scheme XV

[Chemical 41]

Therefore, the tricyclic benzodiazepines of formula (1) are treated at 40 ° C. in the presence of a base in an aprotic organic solvent such as dichloromethane or tetrahydrofuran.
An appropriately substituted cyanoaroyl (heteroaroyl) of formula (43) at -80 ° C
Treatment with a halide, preferably aroyl (heteroaroyl) chloride, gives the formula (
46, an intermediate nitrile of scheme XVI) is obtained, which is then hydrolyzed with an inorganic acid such as sulfuric acid at ambient temperature to 50 ° C. to the amide intermediate of general formula (44). Treatment of the amide (44) with a dialkylamide dialkyl acetal of formula (4) at 0 ° C. to 80 ° C. in an aprotic organic solvent such as dichloromethane or tetrahydrofuran gives intermediates of formula (45). Treatment of (45) with a hydroxyamine of formula (6) or hydrazine in acetic acid at ambient to reflux temperature provides the desired target compound of formula (I) (wherein A, B, D, E, G).
, X, Y, R ² and R ⁴ are as described above, and R ¹ is (e
), (I) or (k) is a heterocyclic moiety selected from groups).

[0099]

[Chemical 42]

Another preferred method for preparing intermediate amides of formula (44) (see Scheme XV, where A and B are CH and D is other than CH) is Scheme XVI
And consists essentially of the treatment of the nitrile of formula (46) with basic hydrogen peroxide in dimethylsulfoxide according to the procedure of Katritzky et al., Synthesis, 949 (1989).

[0101]   Scheme XVI

[Chemical 43]

A preferred method for preparing compounds of general formula (I) wherein R ¹ contains 4 heteroatoms and R ⁴ is hydrogen is outlined in Scheme XVII.

[0103]   Scheme XVII

[Chemical 44]

Treatment of the nitrile intermediate of formula (46) of Scheme XVI with sodium azide and ammonium chloride in an aprotic organic solvent such as dimethylformamide at ambient temperature to reflux temperature of the solvent provides a compound of formula (I ) Desired compound (where A, B, D, E, G, X and Y are as described above, R ⁴ is hydrogen and R ¹ is from the (m) group of the above heterocycle. Which is the heterocyclic moiety of choice).

[0105]

[Chemical formula 45]

Compounds of general formula (I), where D is CW and W is hydrogen, can undergo a Mannich condensation, as shown in Scheme XVIII. Scheme XVIII

[Chemical formula 46]

Thus, a compound of formula (I, D is CH) and an aqueous formaldehyde or paraformaldehyde, a substituted amine of formula (47), at ambient to reflux temperature, in an alcohol solvent such as methanol. And the corresponding Mannich base of general formula (I) (wherein A, B, D, E, G, X
, Y, R ² , R ³ , R ⁵ , R ⁶ and R ⁷ are as described above, D is CW, W is a dialkylaminoalkyl residue, preferably dimethylaminomethyl residue, R ¹ Is (a), (c), (e), (f), (g), (of the above heterocycle
h), (i), (j), (k), (l), (m), (n) and (o) which is a heterocyclic moiety selected from the groups).

Similarly, compounds of general formula (I), wherein D is CH, are prepared according to Scheme XI
It can undergo halogenation as indicated by X. Scheme XIX

[Chemical 47]

[0109]   Therefore, in a polar aprotic organic solvent such as dichloromethane, -80 ° C.
To formula (I, D is CH) and N-chloro (bromo or iodo) s at ambient temperature
By reaction with an N-halosuccinimide such as succinimide, a compound of general formula (I)
Corresponding halogenated derivative (wherein A, B, E, G, X, R^Two, R^ThreeAnd R ⁵ Is as described above, D is CW, and W is chlorine (bromine or iodine).
Una halogen, R¹Is (a), (c), (e), (f) of the above heterocycle
, (G), (h), (i), (j), (k), (l), (m), (n) and (
o) is a heterocyclic moiety selected from the group).

The compounds of interest of the present invention were tested for biological activity according to the following procedure. Normal male vasopressin V ₂ agonists effect weighing 350-500g of a test compound in rats loaded with water conscious or female normotensive Sprague - Dawley (Spragu
e-Dawley) rats (Charles River Laboratories, Inc., Kingston, NY) were fed a standard rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of the study, the rats were individually placed in metabolic cages equipped with a device for separating feces and urine and a collection container for urine. Test compound or control substance 10 ml /
It was given at an oral dose of 10 mg / kg in a kg dose. The vehicle used was 20% dimethylsulfoxide (DMSO) in 2.5% pre-boiled corn starch. Thirty minutes after the administration of the test compound, the rats were given 30 ml / kg of water in the stomach using a feeding needle. During the test period, rats were not fed water or food. Urine was collected 4 hours after test compound administration. Urine volume was measured at the end of 4 hours. Fiske One-Ten Osmometer (Fiske Associates, Norwo
od, MA, 02062) or Advanced CRYOMATIC Osmometer, Model 3C2 (Ad
venced Instruments, Norwood, MA) was used to determine osmolality in urine.
Measurements of Na ⁺ , K ⁺ and Cl ⁻ ions were performed on a Beckman SYNCHRON EL-ISE Electrolysis System Analyzer using ion-specific electrodes. The osmolality of urine should increase proportionally. Two rats were used for each compound in the screening test. A third rat was used if the difference in urine volume between the two rats was greater than 50%.

Normal Conscious Homozygotes for Central Diabetes Insipidus Brattleboro La
Vasopressin V ₂ Agonist Effects of Test Compounds in Rats Male or Female Homozygous Brattleboro Rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) Weighing 250-350 g Standard Rodent Diet (Purina
Rodent Lab. Chow 5001) and water ad libitum. On the day of the study, the rats were individually placed in metabolic cages equipped with a device for separating feces and urine and a collection container for urine. Test compound or control substance 1-10 m at a volume of 10 ml / kg
It was given at an oral dose of g / kg. The vehicle used was 20% dimethyl sulfoxide (DMSO) in 2.5% pre-boiled corn starch.
During the test period, the rats were given water ad libitum. Urine was collected 6 hours after test compound administration. Urine volume was measured at the end of 6 hours. Fiske One-Ten Osmometer (F
Urine osmolality was determined using the Iske Associates, Norwood, MA, 02062) or Advanced CRYOMATIC osmometer model 3C2 (Advenced Instruments, Norwood, MA). Na ⁺ , K ⁺ and Cl ⁻ ions are measured by Beckman SYNC
HRON EL-ISE electrolysis system analyzer was performed using ion-specific electrodes. The animal model was mainly used for the evaluation of the strength and duration of action of active compounds. The results of the study are shown in Table I.

[0112]

[Table 1]

[Table 2]

[Table 3] unless ^a otherwise, unless percent reduction ^a stated in urine volume relative to controls at 10mg / kg, 10mg / kg in the control of percent rat model changes ^c used in osmolarity: Sprague - Dawley (CD) or Brattleboro (BB)

The following examples are presented to illustrate rather than limit the scope of the invention. Example 1 (4-Fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Oxalyl chloride (2.0 g). Was added to a suspension of 4-fluoro-2-trifluoromethylbenzoic acid (2.0 g) in dichloromethane (25 ml). Two drops of dimethylformamide were added and the mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated to dryness to give the crude acid chloride. This was redissolved in dichloromethane and filtered. Evaporation of the material gave a liquid which was then redissolved in hexane, filtered and evaporated to give the acid chloride as a pale yellow viscous liquid which was used without further purification.

The acid chloride (2.26 g) in dichloromethane (25 ml) was cooled in an ice bath of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (1.66 g). ), Dichloromethane (10 ml) and diisopropylethylamine (1.30 g) was added portionwise. After leaving at room temperature for 18 hours,
The reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (2.57g,
Mp 154-155 [deg.] C).

Example 2 [4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl] (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-
10-yl) -methanone 60% hydrogenated sodium in oil (0.15 g) was washed with hexane and dry dimethylformamide (25 ml) was added, followed by 3-methylpyrazole (0.25 g).
) Was added. After the hydrogen evolution was completed, (4-fluoro-2-trifluoromethyl-phenyl) (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g ) Was added. The reaction mixture is placed in a sand bath for 11
Heat at 0 ° C. for 15 hours. The reaction mixture was poured onto ice and saturated saline solution was added. The precipitate was collected by filtration. The crude reaction product was dissolved in dichloromethane, filtered through a short column of sodium magnesium silicate hydrate and eluted with several more volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly. After cooling, the crystals were collected by filtration to give a crude product (0.77g). Further purification by additional filtration of sodium magnesium silicate hydrate through a short column, followed by addition of hexane afforded the title compound as a crystalline solid (0.66 g, mp 194-195 ° C).

Example 3 [4- (4-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10-yl) -methanone In the method of Example 2, (4-fluoro-2-trifluoromethyl-phenyl) (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone (0.8g), 60% sodium hydride in oil (0.15g)
, 4-methylpyrazole (0.20 g) and dimethylformamide (25 ml)
) Was used to give the product as a colorless amorphous solid (0.47 g). MS, m / z
: 437.3 (M + H) ⁺ , 873.2 (2M + H) ⁺

Example 4 (4-pyrazol-1-yl-2-trifluoromethyl-phenyl)-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone In the method of Example 2, (4-fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g
), Pyrazole (0.25 g) and dimethylformamide (35 ml) to give the product as a colorless amorphous solid (0.62 g). MS, m / z: 423
． 2 (M + H) ⁺ , 445.2 (2M + H) ⁺ , 845.3 (2M + H) ⁺

Example 5 [4- (3-Cyclopropyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepines -10-yl) -methanone In the method of Example 2, (4-fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1.
0-yl) -methanone (1.42 g), 60% sodium hydride in oil (0.20
The product was obtained as a crystalline solid (1.22 g) using g), 3-cyclopropylpyrazole (0.43 g) and dimethylformamide (50 ml). Melting point 163-164 ° C

Example 6 [4- (4-Methyl-imidazol-1-yl) -2-trifluoromethyl-
Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone In the method of Example 2, (4-fluoro-2-trifluoromethyl-phenyl)- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g
), 4-methylimidazole (0.25 g) and dimethylformamide (25
ml) was used to give the title compound as an amorphous solid (0.66 g). MS, m
/ Z ^: 437.2 (M + H) ⁺ , 873.2 (2M + H) ⁺

Example 7 (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-(4- [1,2,4] Triazol-1-yl-2-trifluoromethyl-phenyl) -methanone In the method of Example 2, (4-fluoro-2-trifluoromethyl-phenyl)- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g
), 1,2,4-triazole (0.20 g) and dimethylformamide (2
5 ml) to give the title compound as a colorless amorphous solid (0.36 g). M
S, m / z: 424.2 (M + H) ⁺ , 847.3 (2M + H) ⁺

Example 8 (2-Chloro-4-fluorophenyl)-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone Oxalyl chloride (2.60 g) was added to 2-chloro-4-fluorobenzoic acid (3.4).
4 g) was added to a suspension in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred at room temperature for 18 hours. The resulting solution is evaporated and
Crude 2-chloro-4-fluorobenzoyl chloride was obtained as a viscous oil (3.72 g).
.

Crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added to 11,11-dihydro-5H-pyrrolo [2,1-c] [].
1,4] benzodiazepine (2.76 g), diisopropylethylamine (2.
47 g) and dichloromethane (50 ml) were added portionwise to a stirred ice-cold solution. After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (3.85g, mp 110-112 ° C).

Example 9 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (isomer A) and [2-chloro-4- (5-methyl-pyrazol-1-yl). -Phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (Isomer B) Method 1: 60% sodium hydride in oil (0 ml) in dimethylformamide (25 ml). To 0.3 g, defatted with hexane) was added 3-methylpyrazole (0.55
g) was added. When the hydrogen evolution subsided, (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone (1.70 g) was added. The reaction mixture was heated in a sand bath for 18 hours (starting temperature 125 ° C). The reaction mixture was then poured onto ice and further diluted with saturated saline solution. The precipitated solid was collected by filtration. The crude product was dissolved in dichloromethane, dried over anhydrous sodium sulfate, then filtered through a short column of sodium magnesium silicate hydrate, eluting with several additional volumes of dichloromethane. The combined eluates were refluxed on a hot plate and hexane was added slowly until an opaque solution was observed. Cooled to give an amorphous solid.
The material was subjected to a second column of sodium magnesium silicate hydrate and evaporation of the solvent in vacuo gave a mixture of regioisomers 9A and 9B as an amorphous glassy material in a ratio of about 9: 1. (1.11 g). MS, m / z: 403.2 (M
+ H) ⁺

Method 2: To a precooled stirred suspension of 60% sodium hydride (3.00 g) washed with hexane in dry dimethylformamide (250 ml) at 0 ° C. under nitrogen at 3-methylpyrazole (5). .50 g) was added dropwise. The mixture was warmed to room temperature. After the gas generation was completed, (2-chloro-4-fluorophenyl)-(5
H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)
-Methanone (17.0 g) was added as a solid and the mixture was heated to 130 <0> C for 1 hour. The reaction mixture was poured into ice water and the precipitate was collected by filtration and air dried. The precipitate was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered through a short column of silica gel and eluted with ethyl acetate. The combined filtrate was evaporated in vacuo to a foam residue (18.5g). Gradient mixture of ethyl acetate-hexane (1
Purification and separation of the regioisomers by low pressure column chromatography on silica gel, eluting with 0:90 to 25:75) gave two purified regioisomers.

Isomer A, [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(5H, 11H) -pyrrolo [2,1-c] [1,4] benzodiazepine- 10-yl) -methanone (13.5 g), a colorless amorphous solid; MS (EI), m
/ Z: 402 (M) ⁺ sample (0.5g) was crystallized from diethyl ether and then recrystallized from ethanol to give regioisomer A as a colorless crystalline solid (0.275g, mp 141). -143 ° C).

Isomer B, [2-chloro-4- (5-methyl-pyrazol-1-yl) -phenyl]-(5H, 11H) -pyrrolo [2,1-c] [1,4] benzodiazepine- 10-yl) -methanone (1.93 g), a colorless amorphous solid. A sample was crystallized from diethyl ether and then recrystallized from methanol to give regioisomer B as colorless needles (1.4 g). Melting point 160-163
° C; MS (EI), m / z: 402 (M) +, MS (+ FAB), m / z: 40
3 (M + H) ⁺

Example 10 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Step a) 2-chloro-4- (3-methylpyrazol-1-yl) benzonitrile: dimethylformamide Sodium hydride in (50 ml) (60% in oil
2.0 g) in a cooled (0 ° C.) suspension 3-methylpyrazole (3.39 g)
Was divided and added. After the evolution of hydrogen gas was complete, 2-chloro-4-fluorobenzonitrile (5.17 g) was added and the mixture was stirred at room temperature for 18 hours. The mixture was added on ice, diluted with brine and the resulting precipitate was collected by filtration. The crude product was dissolved in dichloromethane, filtered through a column of anhydrous sodium magnesium silicate and crystallized by addition of hexane. The product was obtained by recrystallization from ethanol (4.42 g, mp 148-150 ° C).

Step b) 2-Chloro-4- (3-methylpyrazol-1-yl) benzamide: 2-chloro-4 from step a in dimethylsulfoxide (20 ml) containing potassium carbonate (0.40 g). A suspension of-(3-methylpyrazol-1-yl) benzonitrile (4.35g) was cooled in an ice bath. Hydrogen peroxide (30%
2.4 ml) was added and the mixture was warmed at room temperature for 1 h. The resulting precipitate was collected by filtration and recrystallized from ethanol to give the product as fine needles (2.44 g, mp 159-160 ° C). MS, m / z: 235.9.
(M + H) ⁺

Step c) 2-Chloro-4- (3-methylpyrazol-1-yl) benzoic acid: 2-chloro-4- (3-from Step b in aqueous 75% sulfuric acid (25 ml).
A solution of methylpyrazol-1-yl) benzamide (1.09g) was cooled in an ice bath and sodium nitrite (1.73g) was added. The mixture was warmed to room temperature for 1 hour and poured onto ice. The precipitate was collected by filtration and used directly in the next reaction.

Step d) [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(5H-10,11-dihydro-pyrrolo [2,1-c] [1,4] Benzodiazepin-10-yl) -methanone: 2-chloro-4- (3-methylpyrazol-1-yl) benzoic acid from step c (0.69 g), dichloromethane (25 ml), oxalyl chloride (1.0 g) and A drop of dimethylformamide was stirred at room temperature for 18 hours. Concentrate the mixture,
Dissolve in dichloromethane (25 ml) and diisopropylethylamine (0.7
6 g) was added to a mixture of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodiazepine (0.51 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated and the resulting material was crystallized from diethyl ether to give the product (0.67 g, mp 137-138 ° C).
). MS, m / z: 403.2 (M + H) ⁺ , 805.8 (2M + H) ^+.

Example 11 [2-Chloro-4- (4-methyl-pyrazol-1-yl) -phenyl- (5
H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)
-Methanone In the method of method 1 of Example 9, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.3 g, defatted with hexane), 4-Methylpyrazole (0.48 g) and dimethylformamide (25 ml) were used to give the title compound as an amorphous solid (0.74 g).
. MS, m / z: 403.2 (M + H) ⁺ , 425.2 (M + Na) ⁺ , 805.
． 3 (2M + H) ⁺

Example 12 [2-Chloro-4- (4-methyl-imidazol-1-yl) -phenyl]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone In the method of Example 1, method 1, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.3 g, defatted with hexane), 4-Methylimidazole (0.48 g) and dimethylformamide (25 ml) were used to give the title compound as an amorphous solid (0.38 g).
). MS, m / z: 403.3 (M + H) ^+.

Example 13 [2-Chloro-4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10-yl) -methanone In the method of method 1 of Example 9, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (0.8 g), 60% sodium hydride in oil (0.25 g, defatted with hexane), 3-Trifluoromethylpyrazole (0.61 g) and dimethylformamide (25 ml) were used to give the title compound as an amorphous solid. MS, m / z: 457.2 (M + H) ⁺

Example 14 [2-Chloro-4- (1,2,4-triazol-1-yl) -phenyl]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone In the method of Example 1, method 1, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.7 g), 60% sodium hydride in oil (0.5 g, defatted with hexane), 1,2,4-Triazole (0.70 g) and dimethylformamide (50 ml) were used to give the title compound as an amorphous solid (0.51).
g). MS, m / z: 390.3 (M + H) ⁺ , 779.3 (2M + H) ^+.

Example 15 (2-Chloro-4-pyrrol-1-yl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Example In the method 1 of 9 above, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.7 g), 60% sodium hydride in oil (0.3 g, defatted with hexane), Pyrrole (0.42 g) and dimethylformamide (25 m
1) was used to give the title compound as an amorphous solid (0.60 g). MS, m /
z: 388.2 (M + H) ⁺

Example 16 (2-Chloro-4-pyrazol-1-yl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Example In the method 1 of 9 above, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.2 g, defatted with hexane), Pyrazole (0.20 g) and dimethylformamide (25
ml) was used to give the title compound as an amorphous solid. MS, m / z: 389.
2 (M + H) ⁺ , 777.1 (2M + H) ⁺

Example 17 [2-Chloro-4- (1H-imidazol-1-yl) -phenyl)-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone In the method of Example 9, Method 1, (2-chloro-4-fluorophenyl)-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (2.0 g), 60% sodium hydride in oil (0.50 g, defatted with hexane), Imidazole (0.50 g) and dimethylformamide (
25 ml) to give the title compound as a tan amorphous solid (0.57 g)
). MS, m / z: 389 (M + H) ⁺

Example 18 [2-Chloro-4- (3-methylpyrazol-1-yl) -phenyl]-(3
-Methyl-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-
10-yl) -methanone Step a) 1- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoroethanone: dichloromethane (75 ml) Trifluoroacetic anhydride in dichloromethane in an ice-cold solution of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodiazepine (5.62 g) and diisopropylethylamine (4.0 g) in (7.0 g) was added dropwise. The mixture was stirred at room temperature for 18 hours, washed with water and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the product as fine needles (7
． 70 g, melting point 134-135 ° C). MS, m / z: 281 (M + H) ⁺

Step b) 1- (3-Dimethylaminomethyl-5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -2,2,2-trifluoroethanone 1- (5H, 11H-pyrrolo [derived from step a in a mixed solution of tetrahydrofuran (50 ml) and methanol (50 ml)] 2,1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoroethanone (2.80)
g), bis-dimethylaminomethane (2.04 g), paraformaldehyde (2
． A mixture of 70 g) and acetic acid (1.20 g) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, water was added and the aqueous mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue crystallized from hexane to give the product as a colorless solid (2.05g, mp 109-110 ° C).
MS, m / z: 338.3 (M + H) ^+.

Step c) Trimethyl iodide- (10-trifluoroacetyl-10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepin-3-yl-
Methyl) -ammonium: 1- (3-dimethylaminomethyl-5H, 11H-pyrrolo [2, from step b)
1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoroethanone (1.83 g) and iodomethane (1.0 g) in dichloromethane (
The mixture was stirred at room temperature for 18 hours. Diethyl ether was added and the resulting precipitate was collected by filtration to give the product as a colorless solid (2.54g,
Melting point 140-155 [deg.] C (decomposition)).

Step d) 10,11-dihydro-3-methyl-5H-pyrrolo [2,1-c] [
1,4] Benzodiazepine: Sodium borohydride (2.6 g) was divided into two portions to obtain trimethyl iodide- (10-trifluoroacetyl-10,11-dihydro-5H-pyrrolo [2,1] derived from step c. -C] [1,4] Benzodiazepin-3-yl-methyl) -ammonium (2.60 g) was added to a refluxing mixture in ethanol. After 4 hours, the mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue crystallized from hexane to give the product (1.14 g, mp 150-151 ° C). MS, m / z: 199
． 1 (M + H) ⁺

Step e) [2-chloro-4- (3-methylpyrazol-1-yl) -phenyl]-(3-methyl-5H, 11H-pyrrolo [2,1-c] [1,4]- Benzodiazepin-10-yl) -methanone: 2-chloro-4- (3-methylpyrazol-1-yl) -benzoic acid (0.18 g), oxalyl chloride (0.18 g) and 1 drop of dimethyl from step d. A mixture of formamide in dichloromethane (10 ml) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, the residue redissolved in dichloromethane and reconcentrated in vacuo to give 2-chloro-4- (3-methylpyrazol-1-yl) -benzoyl chloride. A slurry of the acid chloride in dichloromethane (25 ml) was added to 10,11-dihydro-3-methyl-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g). ) In dichloromethane (25 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours, washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to give the product as colorless crystals (0.115g, mp 178-180 ° C). MS, m / z: 417.3 (M
+ H) ⁺ , 833.3 (2M + H) ⁺

Example 19 (2-Chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 2-chloro-4- (trifluoromethyl) pyrimidine-5-carbonyl (
2.57 g) of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4]
-Benzodiazepine (1.84 g) and diisopropylethylamine (1.3
7 g) was slowly added to an ice-cold solution in dichloromethane (50 ml). After stirring for 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (3.22g
, Melting point 221-223 [deg.] C).

Example 20 [2- (3-Methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl]-(5H, 11H-pyrrolo [2,1-c] [1, 4] Benzodiazepin-10-yl) -methanone 60% sodium in oil (0.1 ml) in dimethylformamide (25 ml).
5-Methylpyrazole (0.25 g) was added to 5 g, defatted with hexane).
When the hydrogen evolution subsided, (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)- Methanone (0.98 g) was added. The reaction mixture was heated in a sand bath (internal temperature 110 ° C.) for 18 hours. The mixture was then poured onto ice and further diluted with saturated saline solution. The precipitate was filtered, redissolved in dichloromethane and dried over anhydrous sodium sulfate. Purification was aided by filtration through a short column of sodium magnesium silicate hydrate and further elution with several volumes of dichloromethane. The combined eluates were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the solid was collected by filtration to give the title compound as colorless crystals (0.54g, mp 202-204 ° C).

Example 21 [2- (4-Methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl]-(5H, 11H-pyrrolo [2,1-c] [1, 4] Benzodiazepin-10-yl) -methanone In the method of Example 9, method 1, (2-chloro-4-trifluoromethyl-
Pyrimidin-5-yl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (0.98 g), 60% sodium hydride in oil (0.15 g) ), 4-methylpyrazole (0.42 g) and dimethylformamide (25 ml) to give the title compound as a crystalline solid (0.
73 g, melting point 214-217 ° C).

Example 22 1- [4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone 4-acetylbenzoic acid (5.0 g) And thionyl chloride (10 ml) was heated on a steam bath under argon for 0.75 h and the volatiles were removed under reduced pressure. Toluene was added and the volatiles were removed again to give the crude acid chloride as a red-orange oil. The compound tended to clot and was used as such for further transfer.

The acid chloride (4.56 g) was added to 10,11 in dichloromethane (25 ml).
-Dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodiazepine (3.
68 g) and diisopropylethylamine (3.25 g) in dichloromethane (
100 ml) in ice-cold solution was added in portions. After stirring for 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of sodium magnesium silicate hydrate, eluting with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (1.75g, mp 135-137 ° C).
.

Example 23 3-Dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1
, 4] Benzodiazepine-10-carbonyl) -phenyl] -2-propene-1
-One 1- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone (1.40 g), t-butoxy-bis-dimethylamino. Methane (5.0 ml) and dichloromethane (10 ml
The reaction mixture of 1) was stirred for 18 hours. The red-orange precipitate was filtered to give the title compound (1.22g, mp 203-205 ° C). Additional product was isolated from the reaction mixture by concentration (0.18g).

Example 24 [4- (1H-Pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 3- Dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1
, 4] Benzodiazepine-10-carbonyl) -phenyl] -2-prop-1-
A reaction mixture of on (1.0 g), anhydrous hydrazine (0.20 g) and glacial acetic acid (20 ml) was refluxed for 7 hours and evaporated to dryness. The crude residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solution was filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. Concentrate the combined organic phases on a hot plate,
Hexane was added slowly until crystallization occurred. After cooling, crystals were collected by filtration. The column method was repeated to give the title compound (0.65 g, mp 219-22.
1 ° C).

Example 25 [4- (1-Methyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
Methanone To a mixture of 60% sodium hydride in oil (0.35 g, defatted with hexane) and dimethylformamide (20 ml) was added [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo. [2,1-c] [1,4] Benzodiazepin-10-yl) -methanone (0.98 g) was added and after a few minutes iodomethane (0.50 g) was added. The reaction mixture was stirred at room temperature for 18 hours, then
It was poured into water and extracted with dichloromethane. After drying, the organic layer was filtered through a short column of sodium magnesium silicate hydrate and extracted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (
0.70 g, melting point 194-195 ° C).

Example 26 [4- (1-Ethyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
Methanone In the method of Example 25, [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.27 g)
), Dimethylformamide (25 ml) and ethyl iodide (0.87 g) to give the title compound as a crystalline solid (0.69 g, mp 180-183 ° C).
).

Example 27 [4- (1-Propyl-1H-pyrazol-3-yl) -phenyl]-(5H
, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)
-Methanone In the method of Example 25, [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (0.98 g), 60% sodium hydride in oil (0.30
g), dimethylformamide (25 ml) and 1-iodopropane (0.60
g) was used to give the title compound as a crystalline solid (0.32 g, mp 159-).
161 ° C).

Example 28 [4- (1-Butyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
Methanone In the method of Example 25, [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (0.98 g), 60% sodium hydride in oil (0.30
g), dimethylformamide (25 ml) and 1-iodobutane (0.60 g
Was used to give the title compound as a crystalline solid (0.32 g, mp 122-1).
23 ° C).

Example 29 [4- (1-Methoxymethyl-1H-pyrazol-3-yl) -phenyl]-
(5H, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-
Yl) -methanone In the method of Example 25, [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.15 g)
), Dimethylformamide (25 ml) and iodomethyl methyl ether (0
． 50 g) was used to give the title compound as an amorphous solid (0.26 g). MS
, M / z: 399.2 (M + H) ⁺ , 797.2 (2M + H) ⁺

Example 30 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -ethanone [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (0.
To a solution of 50 g) in dry pyridine (10 ml) was added acetic anhydride (0.20 g). After stirring for 18 hours at room temperature, the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The solution was filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. The eluate was concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.46g, mp 192-194 ° C).

Example 31 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -propane -1-one In the method of Example 30, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.16 g) and propionic anhydride (0.10 g) were used to give the title compound as a crystalline solid (0.17 g, mp 150-). 152 ° C).

Example 32 [4- (1-Cyclopropanecarbonyl-1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10- Yl) -methanone [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl) -methanone (1
． 0 g) in a solution of dry pyridine (10 ml) in cyclopropanecarbonyl chloride (
0.44 g) was added. After stirring at room temperature for 18 hours, the reaction mixture was poured into water,
The precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The solution was filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. The eluate was concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound as a crystalline solid (0.88g
, Melting point 197-199 [deg.] C).

Example 33 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -butane -1-one In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.71 g) and butyryl chloride (0.32 g) were used to give the title compound as a solid (0.5
4 g, melting point 105-110 ° C). MS, m / z: 424 (M) +

Example 34 (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-{4- [1- (thiophen-2-carbonyl) -1H-pyrazole-3
-Yl} phenyl} -methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.5 g) and thiophene-2-carbonyl chloride (0.25 g) were used to give the title compound as a crystalline solid (0.41 g, Mp 195-197 ° C). MS, m / z: 464
(M) +

Example 35 {4- [1- (5-Fluoro-2-methyl-benzoyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [ 1, 4]
Benzodiazepin-10-yl) -methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.35 g) and 2-methyl-5-fluorobenzoyl chloride (0.22 g) were used to give the title compound as an amorphous light yellow solid. (0.11 g). MS, m / z: 490 (M)
+

Example 36 {4- [1- (2-Methyl-benzoyl) -1H-pyrazol-3-yl]-
Phenyl}-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
Using c] [1,4] benzodiazepin-10-yl) -methanone (0.71 g) and o-toluyl chloride (0.39 g) gave the title compound as a crystalline solid (0.59 g, mp 170). -173 ° C). MS, m / z; 472 (M) +

Example 37 {4- [1- (2-chloro-4-fluoro-benzoyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [ 1, 4]
Benzodiazepin-10-yl} methanone 2-chloro-4-fluorobenzoyl chloride (0.82 g) was cooled in an ice bath [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo. [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0
g) and diisopropylamine (0.55 g) in dichloromethane (25 ml)
The solution was added in portions. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of sodium magnesium silicate hydrate and further eluted with several volumes of dichloromethane. The eluate was evaporated to dryness to give the product as a solid (1.06 g, mp 150-157 ° C). MS, m / z; 510 (M
) +

Example 38 {4- [1- (2,4-Dichloro-benzoyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [1, 4] Benzodiazepin-10-yl} methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.71 g) and 2,4-dichlorobenzoyl chloride (0.52 g) were used to give the title compound as a crystalline solid (0.66 g). , Melting point 180-182 [deg.] C). MS, m / z; 52
8 (M) +

Example 39 2- (2,4-Dichloro-phenyl) -1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -Phenyl] -pyrazol-1-yl} -ethanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.71 g) and 2,4-dichlorophenylacetyl chloride (0.56 g) were used to give the title compound as a crystalline solid (0.20 g). , Melting point 130-140 ° C., resolidifying, melting point 180-182 ° C.).

Example 40 {4- [1- (biphenyl-2-carbonyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin-10-yl) methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.71 g) and 2-biphenylcarbonyl chloride (0.65 g) were used to give the title compound as an amorphous solid (0.49 g). MS, m / z; 534 (M) +

Example 41 {4- [1- (4′-Trifluoromethyl-biphenyl-2-carbonyl)-
1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1
-C] [1,4] benzodiazepin-10-yl} -methanone In the method of Example 32, [4- (1
H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.71 g) and 4′-trifluoromethyl-2-biphenylcarbonyl chloride (0.71 g) to give the title compound as an amorphous solid. (0.59 g). MS, m / z; 6
02 (M) +

Example 42 3-Dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1
, 4] Benzodiazepine-10-carbonyl) -phenyl] -2-butene-1-
A mixture of 1- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone (2.0 g) and dimethylacetamide dimethyl acetal (15 ml). Was refluxed for 15 hours in an inert atmosphere and volatiles were removed under reduced pressure. The crude solid was dissolved in dichloromethane and filtered through a short column of sodium magnesium silicate hydrate, then eluted with several volumes of dichloromethane. The combined eluates were concentrated and hexane was added slowly until crystallization. The cooled solution was filtered to recover the title compound as a crystalline solid (1.03g, mp 183-185 ° C).

Example 43 [4- (5-Methyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
Methanone anhydrous hydrazine (0.10 g) was added to 3-dimethylamino-1- [4- (5H, 1
1H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl)
-Phenyl] -2-buten-1-one (0.50 g) was added to a solution in glacial acetic acid (25 ml). The reaction mixture was refluxed for 18 hours and then concentrated under vacuum. The solid was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a steam bath and hexane was added slowly to give an opaque solution.
After cooling, the amorphous solid was collected by filtration to give the product (0.33g). MS,
m / z; 368 (M) +

Example 44 4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-Carbonyl) -benzonitrile 4-cyanobenzoic acid (5.0 g) and thionyl chloride (5.0 ml) were heated on a steam bath for 1 hour and all volatiles were removed under reduced pressure. Add hexane,
The crude crystalline acid chloride (5.30 g) was collected by filtration and used without further purification. To a reaction mixture of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodiazepine (3.68 g), dichloromethane (100 ml) and diisopropylethylamine (2.80 g), 4-cyanobezoyl chloride was added. (2.97
g) was added. After standing at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. Concentrate the combined organic phases on a hot plate,
Hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (5.05g, mp 184-186 ° C).

Example 45 4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-Carbonyl) -benzamide 4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile of Example 44 (0.5 g) was added to concentrated sulfuric acid (5 ml).
) And the mixture was stirred at room temperature for 18 hours to give a light yellow solution. The solution was poured onto ice and made basic by the addition of concentrated ammonium hydroxide. The solid obtained was filtered, dissolved in dichloromethane, filtered through a short column of sodium magnesium silicate hydrate and further eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (5.05g, mp 22
6-228 ° C).

Example 46 N- (Dimethylaminomethylene) -4- (5H, 11H-pyrrolo [2,1-c
] [1,4] Benzodiazepine-10-carbonyl) -benzamide 4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide of Example 45 (1.25 g) ) And dimethylformamide dimethyl acetal (20 ml) were refluxed for 4 hours and volatiles were removed in vacuo to give a solid. The solid was dissolved in dichloromethane, filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a steam bath and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (1.40 g, mp 232-234 ° C).

Example 47 N- (1-Dimethylaminoethylene) -4- (5H, 11H-pyrrolo [2,1]
-C] [1,4] benzodiazepine-10-carbonyl) -benzamide The 4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide of Example 45 (1 A mixture of .24 g) and dimethylacetamide dimethyl acetal (5.0 ml) was heated on a steam bath for 4 hours. A crystalline solid precipitated upon cooling for 18 hours, which was collected by filtration. The solid was washed with hexane to give the product (1.54 g, mp 210-212 ° C.
). MS, m / z; 400 (M) +

Example 48 (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-[4- (2H- [1,2,4] Triazol-3-yl) -phenyl]
-Methanone N- (dimethylaminomethylene) -4- (5H, 11H-pyrrolo- [2,1-c] [1,4] -benzodiazepine-10-carbonyl) benzamide of Example 46 (1.0 g), ice A mixture of acetic acid (15 ml) and anhydrous hydrazine (0.16 g) was refluxed for 15 hours and volatiles were removed in vacuo. Saturated aqueous sodium bicarbonate solution was added and the resulting solid was collected by filtration. The solid was refluxed for 4 hours and the volatiles were removed in vacuo to give a solid. The solid was dissolved in dichloromethane, filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a steam bath and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.39g, mp 225-227 ° C). MS, m / z; 355
(M) +

Example 49 [4- (2-Methyl-2H- [1,2,4] triazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4 ] -Benzodiazepin-10-yl) -methanone Example 46 in a manner similar to Example 48 in glacial acetic acid (75 ml).
N- (dimethylaminomethylene) -4- (5H, 11H-pyrrolo [2,1-c
] [1,4] Benzodiazepine-10-carbonyl) -benzamide (1.56
g) and methylhydrazine (0.32 g) were used to give the title compound as a solid (0.10 g, mp 155-158 ° C). MS, m / z; 369 (M) +

Example 50 [4- (5-Methyl-2H- [1,2,4] triazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4 ] Benzodiazepine-
10-yl) -methanone Example 47 in a similar manner to Example 48 in glacial acetic acid (75 ml).
N- (1-dimethylaminoethylene) -4- (5H, 11H-pyrrolo [2,1
-C] [1,4] benzodiazepine-10-carbonyl) -benzamide (1.
00g) and anhydrous hydrazine (0.25g) to give the title compound as an amorphous solid (0.20g). MS, m / z; 369 (M) +

Example 51 [4- (2,5-Dimethyl-2H- [1,2,4] triazol-3-yl)
-Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone In the method of Example 48, N- of Example 47 in glacial acetic acid (75 ml).
(1-Dimethylaminoethylene) -4- (5H, 11H-pyrrolo [2,1-c]
[1,4] Benzodiazepine-10-carbonyl) -benzamide (1.18 g
) And methylhydrazine (0.30 g) to give the title compound as a solid (0.33 g, mp 193-195 ° C). MS, m / z; 383 (M) +

Example 52 [4- (3-Methyl [1,2,4] oxadiazol-5-yl) -phenyl]-(5H, 11H-pyrrolo- [2,1-c] [1,4 ] -Benzodiazepine-
10-yl) -methanone N- (1-dimethylaminoethylene) -4- (5H) of Example 47 in glacial acetic acid (50 ml) containing hydroxylamine hydrochloride (0.40 g) and potassium acetate (1.0 g). A solution of, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -benzamide (1.15 g) was refluxed for 2 hours. All volatiles were removed under reduced pressure and saturated aqueous sodium bicarbonate solution was added.
The mixture was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate.
The solution was filtered through a short column of sodium magnesium silicate hydrate and further eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a steam bath and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.38g, mp 177-179 ° C). MS, m / z; 3
71.3 (M) +, 741.3 (2M) +

Example 53 1-Methyl-4- (4-methylphenyl) -1H-pyrazole 2- (4-methylphenyl) -malondialdehyde (3.05 g), absolute ethanol (40 ml) and methylhydrazine (1 0.09 g) mixture at room temperature
Stir for 8 hours and remove volatiles at room temperature. Water was added and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solution was filtered through a short column of sodium magnesium silicate hydrate and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a steam bath and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (2.91 g
, Melting point 107-108 ° C).

Example 54 4- (1-Methyl-1H-pyrazol-4-yl) -benzoic acid 1-Methyl-4- (4-methylphenyl) -1H-pyrazole (1.70 g)
, Potassium permanganate (9.70 g) and 1N sodium hydroxide (100 m
The mixture of l) was refluxed for 18 hours. The suspension was filtered through diatomaceous earth and cooled.
The aqueous solution was extracted with dichloromethane and it was discarded. The aqueous solution was acidified to pH 5.5. The precipitate obtained was difficult to filter and was extracted with dichloromethane. After evaporating the solvent, the obtained solid was recrystallized from acetone to give the title compound (0.60 g, melting point 274-275 ° C). MS, m / z; 202 (M) +

Example 55 [4- (1-Methyl-1H-pyrazol-4-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
Methanone Oxalyl chloride (0.30 g) was added to 4- (1-methyl-1H-pyrazole-4-
Yl) -benzoic acid (0.46 g) was added to a suspension in dichloromethane (25 ml). Two drops of dimethylformamide were added and the mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated to dryness to give the crude acid chloride (0.57g), which was used without further purification.

The acid chloride was converted to 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4]-.
Benzodiazepine (0.37 g) and diisopropylethylamine (0.58
g) was added to a solution in dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.38g, mp 200-
201 ° C). MS, m / z; 368 (M) +

Example 56 6- (1-Methyl-1H-pyrazol-4-yl) -pyridine-3-carboxylic acid 6- (1-formyl-2-hydroxyvinyl) pyridine-3-carboxylic acid (1
． A suspension of 93 g) (Eastman Chemicals) in absolute ethanol (50 ml) and methylhydrazine (0.50 g) were stirred at room temperature for 18 hours. The reaction mixture was filtered to give the product (1.30 g). The filtrate was evaporated to give a solid which was recrystallized from ethyl acetate to give an analytical sample of the title compound (0.55 g, mp 262-).
264 ° C).

Example 57 [6- (1-Methyl-1H-pyrazol-4-yl) -pyridin-3-yl]
-(5H, 11H-Pyrrolo [2,1-c] [1,4] -benzodiazepine-10
-Yl) -methanone 6- (1-methyl-1H-pyrazol-4-yl) pyridine-3-carboxylic acid (0.48 g) in thionyl chloride (5.0 ml) was stirred at room temperature for 2 hours. . The volatiles were removed under reduced pressure to give 6- (1-methyl-1H-pyrazole-chloride) chloride.
4-yl) Pyridin-3-carbonyl was obtained as a solid and used without further purification.

A solution of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.37 g) and diisopropylethylamine (0.61 g) in dichloromethane (25 ml) was cooled to 0 ° C. And 6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-carbonyl chloride in dichloromethane (25 ml)
The medium solution was added in portions. After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.31g, mp 173-175 ° C). MS, m
/ Z; 370.3 (M ⁺ H) ⁺

Example 58 [4- (pyrazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [2
, 1-c] [1,4] Benzodiazepin-10-yl) -methanone 4- (pyrazol-1-yl) benzoic acid (1.56 g) in dichloromethane (2
To a suspension in 5 ml) was added oxalyl chloride (1.04 g) and 1 drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours to give a clear solution. Volatiles were removed under reduced pressure to give 4- (pyrazol-1-yl) benzoyl chloride as a pale yellow solid (1.58 g), which was used without further purification.

4- (pyrazol-1-yl) benzoyl chloride (0.75 g) was added to 10,11-
Dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.61
g) and diisopropylethylamine (0.47 g) in dichloromethane (25
ml) in solution. After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.90 g, mp 179-181 ° C).

Example 59 [4- (3-Methyl-pyrazol-1-yl) -phenyl]-(5H, 11H
-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 4- (3-methylpyrazol-1-yl) benzoic acid (1.84 g) suspension in dichloromethane (25 ml). To oxalyl chloride (1.16 g) and 1 drop of dimethylformamide were added. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure. Dichloromethane was added, the solution was filtered and the solvent was evaporated under reduced pressure to give 4- (3-methylpyrazol-1-yl) benzoyl chloride as a yellow oil (1.76 g), which was used without further purification. used.

4- (3-Methylpyrazol-1-yl) benzoyl chloride was converted into 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.55 g).
And diisopropylethylamine (0.44 g) in dichloromethane (25 ml
) Medium ice-cold solution. After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the title compound was obtained as an amorphous solid (0.90g). MS, m / z; 369 (M + H) ⁺

Example 60 [4- (4-Methyl-pyrazol-1-yl) -phenyl]-(5H, 11H
-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 4- (4-methylpyrazol-1-yl) benzoic acid (0.75 g) suspension in dichloromethane (15 ml) To oxalyl chloride (0.50 g) and 1 drop of dimethylformamide were added. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. The solvent was evaporated in vacuo to give 4- (4-methylpyrazol-1-yl) benzoyl chloride (0.77g), which was used without further purification.

4- (4-methylpyrazol-1-yl) benzoyl chloride (0.72 g) was added to 1 part.
0,11-Dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.60 g) and diisopropylethylamine (0.48 g) were added to an ice-cold solution in dichloromethane (25 ml). After stirring for 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.75g, mp 179-181 ° C).
). MS, m / z; 369 (M + H) ⁺

Example 61 [4- (3,5-Dimethyl-pyrazol-1-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] -benzodiazepin-10-yl)-
To a suspension of methanone 4- (3,5-dimethylpyrazol-1-yl) benzoic acid (1.34 g) in dichloromethane (25 ml) was added oxalyl chloride (1.0 g) and 1 drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatiles were removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. The solvent was evaporated in vacuo to give 4- (3,5-methylpyrazol-1-yl) benzoyl chloride (0.80 g), which was used without further purification.

4- (3,5-Dimethylpyrazol-1-yl) benzoyl chloride (0.75 g
) Was added to an ice-cold solution of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.55 g) and diisopropylethylamine (0.42 g) in dichloromethane (25 ml). After stirring for 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the title compound was obtained as an amorphous solid (0.79g). MS, m / z; 383 (
M + H) ⁺

Example 62 (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-[4- (3-Trifluoromethyl-pyrazol-1-yl) -phenyl] -methanone 4- (3-trifluoromethylpyrazol-1-yl) benzoic acid (1.45 g
) In thionyl chloride (5.0 ml) was heated to reflux for 3 hours. The volatiles were removed under reduced pressure, the residue was dissolved in dichloromethane and filtered through diatomaceous earth.
The solvent was evaporated in vacuo and 4- (3-trifluoromethylpyrazole-1-
(Yl) benzoyl was obtained (1.45 g) and used without further purification.

[0194]   10,11-Dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodia
Zucine of zepine (0.88g) and diisopropylethylamine (0.66g)
4- (3-Trifluoromethylpyrazole chloride chloride in solution in loromethane (50 ml)
-1-yl) Benzoyl (1.40 g) was added. After stirring for 18 hours at room temperature, the reaction mixture
The mixture was washed with water and saturated aqueous sodium bicarbonate. No dichloromethane solution
A short column of sodium magnesium silicate hydrate, dried over sodium sulfate.
And then eluted with several volumes of dichloromethane. The combined organic phases
Concentrate on a hot plate and slowly add hexane until crystallization occurs. cooling
Afterwards, the crystals were collected by filtration to give the title compound (1.70 g, mp 166-
167 ° C). MS, m / z; 423.3 (M + H).⁺, 845.4 (2M + H) ⁺

Example 63 [4- (imidazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [
2,1-c] [1,4] benzodiazepin-10-yl) -methanone 4- (imidazol-1-yl) benzoic acid (0.90 g) thionyl chloride (2
． (0 ml) was heated on a steam bath under argon for 1 hour. The volatiles were evaporated under reduced pressure to give a residue, which was crystallized by addition of hexane to give 4- (imidazol-1-yl) benzoyl chloride as the hydrochloride salt (1.17 g).
, Melting point 242-247 [deg.] C).

10,11-Dihydro-5H-pyrrolo [2,1-c] [1,4] -benzodiazepine (0.75 g), diisopropylethylamine (1.20 g) and 4-
4- (Imidazol-1-yl) benzoyl chloride (1.12 g) was added to a solution of dimethylaminopyridine (0.1 g) in dichloromethane (50 ml). After stirring for 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the crystals were collected by filtration to give the title compound (0.57g, mp 171-172 ° C). MS, m / z; 354 (M + H) ⁺

Example 64 [4- (4-Methyl-imidazol-1-yl) -phenyl]-(5H, 11
H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 4- (4-methylimidazol-1-yl) benzoic acid (0.80 g) suspended in dichloromethane (25 ml) To the solution was added oxalyl chloride (0.50 g) and 1 drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and volatiles were removed under reduced pressure to give 4- (4-methylimidazol-1-yl) benzoyl chloride (1.02 g), which was used without further purification. did.

4- (4-Methylimidazol-1-yl) benzoyl chloride (0.99 g) was added to 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0.64 g). And diisopropylethylamine (0.60 g) in ice-cold solution in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium magnesium silicate hydrate, and eluted with several volumes of dichloromethane. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling, the title compound was obtained as a solid (0.52g, mp 140-145 ° C). MS,
m / z; 369 (M + H) ⁺

Example 65 4-Bromo-2-chloro-benzoic acid methyl ester Thionyl chloride (1.64 ml) was added to 4-bromo-2-chlorobenzoic acid (6.92).
g) was added dropwise to the suspension in methanol and heated to 60 ° C. for 2 hours. The solvent was removed in vacuo, the residue redissolved in ethyl acetate and washed successively with 0.5N sodium hydroxide (2x), water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the title compound (7.8g). ¹ H NMR (300 MH
z), (DMSO-d ₆ ) δ: 3.87 (s, 3H), 7.68-7.9 (m,
3H)

Example 66 2-Chloro-4- (3-dimethylamino-propyn-1-yl) benzoic acid methyl ester 4-Bromo-2-chlorobenzoic acid methyl ester (18.69 g) in triethylamine (110 ml). 1-Dimethylamino-2-propyne (12
． 1 ml), bis (triphenylphosphine) palladium (II) chloride (1.
26 g) and copper (I) iodide (0.136 g) were added. The mixture was slowly heated to 60 ° C. and the temperature was maintained for 1 hour. The reaction was cooled to room temperature, filtered through diatomaceous earth and the collected solid washed with ethyl acetate. The solvent was removed in vacuo and the resulting residue was redissolved in ethyl acetate and washed with water (3x). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (225g) eluting with 40% ethyl acetate / hexane. After removing the solvent in vacuo, the title compound was obtained as a viscous oil (17.7g). MS (+ FAB), m / z: 252 (
M + H) ⁺

Example 67 2-Chloro-4- (3-dimethylamino-2-propen-1-on-1-yl) -benzoic acid methyl ester 3-chloroperoxybenzoic acid (10.76 g) was reacted slowly. Temperature is -20 ℃
2-chloro-4- (3-dimethylamino-propyn-1-yl) -benzoic acid methyl ester (15.07 g) was added to a solution in dichloromethane (40 ml) at a rate maintained at. The mixture was stirred for 10-15 minutes. The obtained N-oxide was 10
Purified by chromatography on Activity Grade I basic alumina (215 g) eluting with% methanol / dichloromethane. 1 solvent
Evaporated in vacuo at 2-18 ° C. The resulting residue was dissolved in methanol (100 ml) and heated at 60-65 ° C with stirring for 18 hours. After removing the solvent in vacuum,
The product was purified by column chromatography on silica gel (190g) eluting with 70% ethyl acetate / hexane. Trituration with diethyl ether containing some hexane gave the title compound as a solid (5.
68 g, melting point 92-96 ° C).

Example 68 2-Chloro-4- (1H-pyrazol-3-yl) -benzoic acid methyl ester 2-chloro-4- (3-dimethylamino-2-propen-1-on-1-yl) Hydrazine monohydrochloride (7.0 g) was added to a suspension of benzoic acid methyl ester (13.67 g) in ethanol (53 ml). Mix the mixture in an oil bath at 75-80 ° C.
Heated for 1 hour. The solvent was removed in vacuum. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the title compound as a crude solid (12g). 130 purified samples
It had a melting point of -131 ° C.

Example 69 2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester Hexane washed sodium hydride (3.05 g, 60% dispersion) in dimethylformamide. To a suspension in (6 ml) under nitrogen was added a solution of 2-chloro-4- (1H-pyrazol-3-yl) -benzoic acid methyl ester (12.0 g) in dimethylformamide (30 ml) over 15 minutes. It was The mixture was stirred at room temperature for 30 minutes. Iodomethane (9.5 ml) was added dropwise over 15 minutes. The mixture was stirred at room temperature for 45 minutes. Additional iodomethane (5.16 ml) was added and the reaction stirred for a further 75 minutes. The reaction was diluted with a little water and concentrated in vacuo. The residue was diluted with water (500 ml) and extracted with a small amount of ethyl acetate (5x). The combined organic phases were evaporated in vacuo to give a crude product (13.48g). 15% of crude product
Purified by column chromatography on silica gel (195 g) eluting with ethyl acetate / hexane to give the pure 1-methyl regioisomer (4.29 g), then a mixture of 1-methyl and 2-methyl regioisomers ( 4.6 g) was obtained. The isomer mixture was triturated 3 times with hexanes to give an additional sample of the pure 1-methyl regioisomer (2.55 g, mp 66.5-67 ° C). MS (+ FAB)
, M / z; 251 (M + H) ⁺

Example 70 2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid 2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid To a solution of methyl ester (6.85 g) in methanol (32 ml) was added 2.5N sodium hydroxide solution (15.3 ml). The reaction was heated to 50 ° C. for 1 hour.
The solvent was removed in vacuo, the residue was dissolved in water (250 ml), cooled in an ice bath,
Acidified with 2N hydrochloric acid (24 ml). The resulting precipitate was filtered and dried to give a colorless solid (6.3g, melting point 232-233 ° C). MS (+ FAB), m / z:
236 (M + H) ⁺

Example 71 [2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10
-Yl) -methanone Well powdered 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid (6.3g) and dimethylformamide (2.16ml) under nitrogen in tetrahydrofuran. Suspended in a mixture of (70 ml) and dichloromethane (15 ml). Oxalyl chloride (2.43 ml) in dichloromethane (5 ml
) Was added dropwise and the reaction was stirred for 1 hour. The obtained 2-chloro-4- (chloride)
A suspension of 1-methyl-1H-pyrazol-3-yl) benzoyl was used without further purification.

To a suspension of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (4.93 g) in dichloromethane (15 ml) was added diisopropylethylamine (7 ml). A freshly prepared suspension of acid chloride was added over 15 minutes under a positive nitrogen flow. The slightly warm reaction mixture is heated under nitrogen to 50
Stir for minutes. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water, 5% sodium bicarbonate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the crude product (10.95g). The crude product was purified by column chromatography on silica gel (200 g) packed with ram with 25% ethyl acetate / hexane. Almost non-polar impurities were eluted with 25-30% ethyl acetate / hexane.
The product was eluted with 30-40% ethyl acetate / hexane to give a pure sample (7.4
2 g), after seeding, was triturated with diethyl ether containing some hexane for 24 hours. Filtration afforded the title compound as a crystalline solid (6.88g, mp 148.5-150 ° C). MS (EI), m / z: 402 (
M) ⁺

Example 72 2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester methyl-2-chloro-4- (3-dimethylamino-2-propene-1- on)
The title compound was prepared in the same manner as in Example 68 using benzoate (0.8g) and methylhydrazine (0.319ml). The main product, the 2-methyl regioisomer, was isolated by column chromatography on silica gel. ¹ H
NMR (300MHz), (DMSO- d 6) δ: 3.87 (s, 3H), 3.
89 (s, 3H), 6.58 (d, 1H), 7.5 (d, 1H) 7.62-7.
93 (m, 3H)

Example 73 2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid 2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid Methyl ester (0.464g) and 2.5N sodium hydroxide (1.04ml)
The title compound was prepared in the same manner as in Example 70. ¹ H NMR (3
00 MHz), (DMSO-d ₆ ) δ: 3.89 (s, 3H), 6.56 (d,
1H), 7.49 (d, 1H), 7.59-7.90 (m, 3H)

Example 74 [2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10
-Yl) -methanone The title compound was prepared in the same manner as Example 71. 2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid (3.98 g) was used to produce the corresponding acid chloride to produce 10,11-dihydro-5H-pyrrolo [2. , 1-c] [1,
4] Acylation with benzodiazepine (0.293g) gave the title compound as a foam. Mp 78-79 [deg.] C; MS (EI), m / z: 402 (M) ^<+>.

Example 75 2-Chloro-4-cyanobenzoic acid methyl ester 2-Chloro-4-aminobenzoic acid methyl ester (13.95 g) was added to water (65
ml) and concentrated hydrochloric acid (15.7 ml). After stirring at room temperature for 10 minutes, the suspension was cooled to 0 ° C. A solution of sodium nitrite (5.71 g) in water (37 ml) was added slowly over 20 minutes while maintaining the reaction temperature at 0 ° C.
After stirring for 35 minutes at 0 ° C., the reaction mixture was partially neutralized by addition of solid sodium carbonate (3.16 g) to give a cold solution of the diazonium salt.

Pre-cooled copper (I) cyanide (8.4 g) and sodium cyanide (9.
To a solution of 19 g) in water (112 ml) was added 45-5 of the above diazonium salt solution.
Added slowly over 0 minutes. The diazonium salt solution was maintained at 0 ° C during the addition. The resulting mixture was stirred at room temperature for 18 hours. The precipitate was filtered, air dried, dissolved in ethyl acetate (250 ml) and filtered to remove insoluble material. The organic phase was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to give the crude product as a brown solid (13.2 g). The crude product was purified by column chromatography on silica gel (250g) eluting with 5-10% ethyl acetate / hexane to give the title compound as a solid (10.9g, mp 90-92 ° C). MS (EI), m
/ Z: 195 (M) ⁺

Example 76 2-Chloro-4-cyanobenzoic acid To a stirred solution of 2-chloro-4-cyanobenzoic acid methyl ester (24.3 g) in methanol (150 ml) was added 2.5N sodium hydroxide (54. 5 ml) was added. After stirring for 45 minutes at room temperature, the solvent was removed in vacuo. Dissolve the residue in water,
It was cooled in an ice bath and acidified with 2N hydrochloric acid (14 ml). The resulting precipitate was filtered and dried in vacuo to give the title compound as a solid (22.55g, mp 154-158 ° C).

Example 77 3-Chloro-4- (5-H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile 2-chloro-4-cyanobenzoic acid (9.1 g) of dichloromethane (40 ml)
A solution of oxalyl chloride (4.6 ml) in dichloromethane (10 ml) was added dropwise at 0 ° C. to a cooled suspension in a mixture of and dimethylformamide (3.88 ml). The stirred reaction was warmed to room temperature over 1 hour. A cloudy solution of 2-chloro-4-cyanobenzoyl chloride was used without further purification.

Nitrogen was added to a stirred suspension of 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml). Underneath, a cloudy solution of 2-chloro-4-cyanobenzoyl chloride was added. After 1 hour at room temperature, the mixture was diluted with dichloromethane and washed successively with water, 5% sodium bicarbonate and 50% saturated brine.
After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give a crude product (18.
0 g). Purification by column chromatography on silica gel (250g) eluting with 20% ethyl acetate / hexane then 25% ethyl acetate / hexane gave the title compound as a pale yellow foam (13.56g). MS (EI), m /
z: 347 (M) ⁺

Example 78 3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzoic acid 3-chloro-4- (5H, 11H- To a suspension of pyrrolo- [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -benzonitrile (90.72g) in ethanol was added 10N sodium hydroxide (1.02ml) and the mixture was added. 2
Heated to reflux for hours. The solvent was removed in vacuo, the residue was dissolved in water and 2N hydrochloric acid (4.
Acidified with 7 ml). The obtained precipitate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the foam was triturated with diethyl ether for 18 hours and filtered to give the crude product (0.69g). The crude product was purified by treatment with activated carbon in methanol. Crystallization from methanol / ether gave the title compound as a purified solid (0.29 g, mp 1
98-199 ° C). MS, m / z: 366 (M) ⁺

Example 79 3-Chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide Concentrated sulfuric acid (70 ml) was added to 3-chloro-4-. (5H, 11H-pyrrolo- [2,1-
c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile (12
． 85 g). The mixture was stirred at 60 ° C. for 3 hours and then at room temperature for 18 hours. The reaction mixture was poured onto ice and 30% ammonium hydroxide (
Neutralized with 184 ml). The resulting suspension was extracted with ethyl acetate. The aqueous mixture was filtered and re-extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulphate and the solvent removed in vacuo. The residue is diethyl ether (50-60 ml)
And triturated with a mixture of a small amount of ethyl acetate. By filtering the precipitate,
The title compound was obtained as a crystalline solid (10.44 g, mp 211-212 ° C).
MS (EI), m / z: 365 (M) ⁺

Example 80 N- (1-Dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -benzamide 3 A suspension of -chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide (5.48g) and dimethylacetamide dimethyl acetal (10.97ml). Was heated at 90 ° C. for 20 minutes. Excess reagent was removed under reduced pressure and the title compound was used without further purification. MS (EI), m / z: 434 (M) ⁺

Example 81 [2-Chloro-4- (5-methyl-2H- [1,2,4] triazole-3-
Iyl) phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -methanone N- (1-dimethylaminoethylene) -3-chloro-4- (5H, To a solution of 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -benzamide (3.01 g) in acetic acid (4 ml) was added anhydrous hydrazine (0.43).
5 ml) in acetic acid (4 ml) was added. The reaction mixture was stirred at 85-90 ° C for 45 minutes. After removal of acetic acid in vacuo, the reaction mixture was diluted with water (35-40 ml), neutralized to pH 7.0 with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the crude product (2.68g). Purification of the crude product by column chromatography on silica gel (45g) eluting with 70% ethyl acetate / hexanes gave the purified product (2.5g) which after trituration with diethyl ether gave the title compound as a solid. (2g, melting point 211-212 [deg.] C). MS (EI
), M / z: 403 (M) ⁺

Example 82 N- (Dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide 3-chloro- Example 80 Using 4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide (1.83g) and dimethylformamide dimethylacetal (5.3ml). The title compound was prepared in the same manner. MS (EI), m / z: 420 (M) ⁺

Example 83 [2-Chloro-4- (2H-1,2,4-triazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepine-1
0-yl) -methanone N- (dimethylaminomethylene) -3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide (2.53 g) ) And hydrazine (0.38 ml) were used to prepare the title compound in the same manner as in Example 81. Melting point 174-177 [deg.] C., MS (EI), m / z
: 389 (M) ⁺

Example 84 [2-Chloro-4- (2-methyl-2H- [1,2,4] triazole-3-
Iyl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -methanone N- (dimethylaminomethylene) -3-chloro-4- (5H, 11H Prepare the title compound in the same manner as in Example 48 using -pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide (0.572g) and methylhydrazine (0.149ml). did. Melting point 141-143 ° C, MS (EI
), M / z: 403 (M) ⁺

Example 85 4-[(2,5-Dimethyl-2H- [1,2,4] triazol-3-yl)
-2-Chloro-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4]
Benzodiazepine-10-carbonyl) -methanone N- (1-dimethylaminomethylene) -3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide The title compound was prepared in the same manner as in Example 48 using (0.51 g) and methylhydrazine (0.125 ml). Melting point 197-199 ° C, MS (E
I), m / z: 417 (M) ⁺

Example 86 [2-Chloro-4- (1H-tetrazol-5-yl) -phenyl]-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone 3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -benzonitrile (0.348g) in a solution in dimethylformamide (2ml), Sodium azide (0.078g) and ammonium chloride (0.065g) were added. The mixture was heated to 100 ° C. for 18 hours. Most of the dimethylformamide was removed in vacuo. The residue is water (about 8 ml)
, Basified to pH 9.0 with 2.5 N sodium hydroxide (0.6 ml) and extracted with ethyl acetate. The aqueous extract was acidified with 2N hydrochloric acid (1.1 ml), re-extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the crude product as an oil (0.350 g). . The oily product was triturated with diethyl ether, filtered through acid treated silica gel and eluted with 40% ethyl acetate / hexane to give a purer sample. This was further triturated with diethyl ether and filtered to give a sample (0.88g, mp 218-220 ° C).
MS (+ FAB) 391 (M + H) ⁺

Example 87 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
3-Dimethylaminomethyl-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone [2-chloro-4- (3-methyl-pyrazol-1-yl)- Phenyl]-(
5H, 11H-pyrrolo- [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.61 g), N, N, N ′, N′-tetramethyldiamino-
To a stirred solution of methane (0.82g) and glacial acetic acid (0.48g) in methanol (25ml) was added a solution of 37% aqueous formaldehyde (4ml). The mixture was warmed to 40 ° C. for 10 minutes. After stirring for 1 hour at room temperature, the reaction was concentrated in vacuo, redissolved in dichloromethane and successively extracted with aqueous sodium bicarbonate and water (4x). The organic phase was dried over anhydrous sodium sulfate, filtered through a plug of silica gel and eluted with ethyl acetate. Evaporation of the solvent in vacuo gave an oil which was triturated with hexane to give the title compound as a colorless powder (0.
36 g, melting point 100-102 ° C). MS (+ FAB), m / z: 482 (M + N
a) ⁺ , 460 (M + H) ⁺

[0225]   Example 88   (3-Bromo-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiaze
Pin-10-yl)-[2-chloro-4- (3-methyl-pyrazol-1-yl
) -Phenyl] -methanone   [2-Chloro-4- (3-methyl-pi) in dichloromethane (25 ml)
Razol-1-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [
1,4] Benzodiazepin-10-yl) -methanone (1.61 g) stirred
To the pre-cooled solution, add solid N-bromosuccinimide (0.712) at -78 ° C.
g) was added over 10 minutes. The reaction was warmed to -40 ° C for 30 minutes.
. The mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate (2 x 100 m
l) and water (100 ml) successively extracted. Dry the organic phase over anhydrous sodium sulfate.
Dried, filtered through a plug of silica gel and evaporated in vacuo to give a residue. The
Crystallization from ethyl ether gave the title compound as a colorless solid (1.4
7 g, melting point 148-149 ° C (decomposition)). MS (EI), m / z: 480 (M) ⁺

Example 89 (4-Bromo-2-chlorophenyl)-(5H, 11H-pyrrolo [2,1-c
] [1,4] Benzodiazepin-10-yl) -methanone dimethylformamide (1 drop) was added to 4-bromo-2-chlorobenzoic acid (2.20).
g) was added to a solution of anhydrous tetrahydrofuran (20 ml). Oxalyl chloride (
1.46 g) was added and the mixture was heated to reflux. The resulting solution was cooled to ambient temperature and then evaporated to dryness to give crude 4-bromo-2-chlorobenzoyl chloride as a golden viscous liquid which was used without further purification.

10,11-Dihydro-5H-pyrrolo [2,1-c] [1, cooled in an ice bath
4] -Benzodiazepine (1.44 g) and triethylamine (0.95 g)
To a mixture of 4 in dichloromethane (40 ml) was added dropwise a solution of 4-bromo-2-chlorobenzoyl chloride (2.42 g) in dichloromethane (20 ml). The cooling bath was removed and after stirring for 22 hours the reaction mixture was treated with water, saturated aqueous sodium bicarbonate, 0.
It was washed successively with 5N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness in vacuo to give an off-white foam. Purification by flash chromatography on silica gel, eluting with hexane-ethyl acetate (2: 1) gave a white foam (3.02g, mp 77-80).
C). MS, m / z: 400 (M) ⁺

Example 90 [2-Bromo-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Step a) 4-Fluoro-2-bromobenzoyl chloride: Dimethylformamide (2 drops) 4-fluoro-. 2-Bromobenzoic acid (4.9
1 g) was added to a solution in anhydrous tetrahydrofuran (55 ml). Oxalyl chloride (3.41 g) was added and the mixture was heated to reflux. The resulting solution is cooled to room temperature,
Evaporation in vacuo gave the crude acid chloride as a golden viscous liquid which was used without further purification.

Step b) (4-Fluoro-2-bromophenyl)-(5H, 11H-pyrrolo [
2,1-c] [1,4] benzodiazepin-10-yl) -methanone: A solution of 4-fluoro-2-bromobenzoyl chloride (5.32 g) from step a in dichloromethane (35 ml) was 10,11-. Dihydro-5H-pyrrolo [2,1
-C] [1,4] -benzodiazepine (3.44 g) and triethylamine (
A solution of 2.27 g) in dichloromethane (80 ml) was added dropwise and cooled in an ice bath. The cooling bath was removed and after stirring for 16 hours the reaction mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale purple foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) gave the intermediate (4-fluoro-2-bromophenyl)-(5H, 11H-pyrrolo [2,1-c] [1. , 4] Benzodiazepine-10
-Yl) -methanone was obtained as a tan foam (6.91 g, MS, m / z: 38).
4 (M) ⁺ ). The material was used in the next step without further purification.

Step c) [2-Bromo-4- (3-methyl-pyrazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone: A dispersion of 60% sodium hydride in oil (0.20 g) was washed with hexane and then suspended in dimethylformamide (15 ml). 3-Methylpyrazole (0.41 g) was added to the suspension. When the hydrogen gas generation was completed, (4-fluoro-2-bromophenyl)-(5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (1.74 g) was added. The reaction mixture was heated to 130 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 5
Poured into 0% saturated aqueous sodium chloride solution and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a brown oil. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) gave a colorless solid (0.75g). Recrystallization from methanol gave an off-white crystalline solid (0.53 g,
Melting point 141-142.5 ° C). MS, m / z: 446 (M) ⁺

Example 91 (2,4-Difluoro-phenyl)-(5H, 11H-pyrrolo [2,1-c]
[1,4] benzodiazepin-10-yl) -methanone Step a) 2,4-difluorobenzoyl chloride: 2,4-difluorobenzoic acid (3 containing 2,3 drops of dimethylformamide).
． A suspension of 6 g) in dichloromethane (40 ml) under nitrogen was treated with oxalyl chloride (
2.4 ml) was added. After the gas evolution had subsided, the reaction mixture was refluxed for another 15 minutes. The solution was evaporated to dryness in vacuo and the residue used without further purification.

Step b) (2,4-difluorophenyl)-(5H, 11H-pyrrolo [2,1
-C] [1,4] benzodiazepin-10-yl) -methanone: To a solution of the crude 2,4-difluorobenzoyl chloride chloride from step a in dichloromethane under nitrogen, solid 10,11-dihydro-5H-pyrrolo. [2,1-c] [1,
4] benzodiazepine amine (2.0 g) and diisopropylethylamine (
3.4 ml) was added. The reaction mixture turned yellow-orange. 10 at room temperature
After stirring for an hour, the reaction mixture was washed with water, 1N hydrochloric acid, 1N sodium hydroxide and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The crude product was silica gel (Merck-60 with 20% ethyl acetate-hexane).
) Was purified by column chromatography above to give the title compound as a white foam (2.9 g). MS (EI, m / z): 324 (M) ⁺

Example 92 [2-Fluoro-4- (3-methyl-pyrazol-1-yl) -phenyl]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone A suspension of 60% sodium hydride (0.31 g) washed with hexane in dry dimethylformamide was nitrogen. Under room temperature, 3-methylpyrazole (0.62 ml)
Was added dropwise. Stirring was continued until gas evolution subsided (10 minutes). (2,4-Difluorophenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (2.4-difluorophenyl) -derived from step b of Example 91.
5 g) was added in one portion and stirring continued until a clear solution was obtained. 1 in a preheated oil bath
The mixture was heated at 30 ° C. for 1 hour. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (Merck-60) eluting with 20% ethyl acetate-hexane to give the title product as a foam, which was crystallized from ethanol / hexane by sonication. (0.82 g, melting point 1
92-193 ° C). MS (EI) m / z: 386 (M) ⁺

Example 93 Methyl 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoate Step a) Methyl 4-fluoro-2-trifluoromethylbenzoate: 4-Fluoro-2- Trifluoromethylbenzoic acid (25.6 g) and 2,3
A drop of a suspension of dimethylformamide in dichloromethane (250 ml) was treated under nitrogen with the dropwise addition of oxalyl chloride (11.3 ml). After the gas evolution had subsided, the reaction mixture was refluxed for another 15 minutes. The reaction was cooled and methanol (5
0 ml) was added. After stirring for 2 hours, the reaction was concentrated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound as a golden oil (18.
0 g). MS, (EI) m / z: 222 (M) ⁺ aqueous layer was acidified with 2N hydrochloric acid to give a colorless solid which was collected by filtration to give the starting benzoic acid (7.5g).

Step b) Methyl 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoate: 60% sodium hydride (3.85 g) in dry dimethylformamide (150 ml) washed with hexane. The suspension is suspended under nitrogen at room temperature in 3-methylpyrazole (7
． Treated by the dropwise addition of a solution of 75 ml) in dimethylformamide (50 ml). Stirring was continued until gas evolution subsided (10 minutes). A solution of methyl 4-fluoro-2-trifluoromethylbenzoate from step a (17.8 g) in dimethylformamide (50 ml) was added dropwise to the clear solution. After stirring at room temperature for 30 minutes, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. Organic extract (3x
) Was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (Merck 60) using a dichloromethane-hexane gradient (50% -75%) to give the title compound as a colorless solid (13.6 g, mp 59-61). C). MS (EI, m / z): 284 (M
) ⁺

Example 94 4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethylbenzoic acid 4- (3-Methyl-pyrazol-1-yl) -2 from Example 93, step b. −
Methyl trifluoromethylbenzoate (1.19 g) was dissolved in methanol (10 ml) and a solution of 2.5N sodium hydroxide (3.3 ml) was added. The reaction was heated at reflux for 90 minutes, cooled to room temperature, concentrated in vacuo to dryness. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a colorless solid (1.14g).
MS (FAB) m / z: 271 (M + H) ⁺

Example 95 [4- (3-Methylpyrazol-1-yl) -2-trifluoromethylphenyl]-(5H, 11H-pyrazolo [5,1-c] [1,4] benzodiazepine-
10-yl) -methanone A solution of 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoic acid from Example 94 in tetrahydrofuran (5 ml) was added to dimethylformamide (0.020 ml), then Treated with oxalyl chloride (0.090 ml). The solution was stirred at room temperature until gas evolution ceased, then the solution was heated to reflux for 10 minutes. The sample was cooled to room temperature and concentrated to a solid which was converted to tetrahydrofuran (2
5H-10,11-dihydropyrazolo [5,1-
c] [1,4] benzodiazepine (0.143 g) and triethylamine (0
． 150 ml) in tetrahydrofuran (20 ml) was added. The solution was stirred at room temperature overnight. A precipitate formed. The sample was diluted with dichloromethane to dissolve the precipitate, then the sample was concentrated in vacuo to about 1/3 of its original volume. The sample was partitioned between dichloromethane and saturated aqueous ammonium chloride. The sample was extracted with dichloromethane and the organic layers were pooled, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The oil was flash chromatographed on silica gel using a gradient of 40% ethyl acetate / hexane to 100% ethyl acetate to give the title compound as a foam (0.30g). A portion of the material was recrystallized from acetone / hexane to give a thick plate. Melting point 100-102 [deg.] C., MS m / z: 437 (M) ^<+>.

Example 96 2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester and 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) Benzoic acid methyl ester A suspension of potassium hydride (0.424 g) in dimethylformamide (5 ml) washed with hexane was treated with 3-methylpyrazole (0.85 ml) in one portion with stirring. After completion of gas evolution, 2-chloro-4-fluorobenzoic acid methyl ester (2.0 g, 10.6) was added to the clear solution and heated at 130 ° C for 15 minutes.
The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave a yellow oil (2.2g). (Note: 20% hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product.) The desired regioisomer 2-chloro-4- (3-methyl-1H-pyrazol-1-yl). The benzoic acid methyl ester was isolated from the other isomers (described below) by flash column chromatography on silica gel (Merck 60) eluting with dichloromethane-hexane 2: 1 to give the title compound as a colorless solid (1. 55 g). MS (EI) m / z: 2
50/252 (M) ⁺ 5-positional isomer, ie 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester, further eluted with dichloromethane-hexane 2: 1. Isolate from flash column chromatography on silica gel (Merck60) as above to give the product as a colorless solid (0.20).
g). MS (EI), m / z: 250/252 (M) ⁺

Example 97 2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid 2-Chloro-4- (3-methyl-1H-pyrazole-1-) from Example 96 A solution of (yl) -benzoic acid methyl ester (1.42 g) and 6 ml of 1M aqueous lithium hydroxide in tetrahydrofuran (20 ml) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. By evaporating the solvent in vacuo,
The title compound was obtained as a colorless solid (1.05g, mp 192-193 ° C). MS
(EI), m / z: 236/238 (M) ⁺

Example 98 (2,6-dichloropyridin-3-yl) (5H, 11H-pyrrolo [2,1-
c] [1,4] benzodiazepin-10-yl) -methanone 2,6-dichloronicotinic acid (3.84 g), oxalyl chloride (2.0 g) and 1 drop of dimethylformamide in dichloromethane (25 ml) at room temperature. It was stirred for 18 hours. The solution was concentrated in vacuo to give 2,6-dichloronicotinyl chloride (
3.50 g) was obtained, which in dichloromethane (25 ml) was 10,11
-Dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (2.1
5 g) and diisopropylethylamine (2.03 g) in dichloromethane (5
0 ml) in ice-cold solution. The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phases were concentrated on a hot plate and hexane was added slowly until crystallization occurred. After cooling
The crystals were collected by filtration to give the title compound as an amorphous solid (2.65 g,
Melting point 115-130 ° C). MS, m / z: 358.1 (M + H) ⁺

Example 99 (2-Chloro-6-pyrazol-1-yl-pyridin-3-yl)-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml)
) Pyrazole (0.15 g) was added dropwise to the suspension. After the hydrogen gas generation was completed, (2,6-dichloropyridin-3-yl) (5H, 11H-pyrrolo [2,1-
c] [1,4] Benzodiazepin-10-yl) -methanone (0.67 g) was added and the reaction mixture was heated in a sand bath at 110 ° C. for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to give the title compound as a colorless solid (0.18g, mp 133-135 ° C). MS, m /
z: 390.8 (M + H) ⁺ , 779.1 (2M + H) ⁺

Example 100 [2-Chloro-6- (3-methylpyrazol-1-yl) -pyridin-3-yl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepines -1
0-yl) -methanone 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml)
) Was added dropwise to 3-methylpyrazole (0.15 g). After the hydrogen gas generation was completed, (2,6-dichloropyridin-3-yl) (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (0.6
7 g) was added and the reaction mixture was heated in a sand bath at 110 ° C. for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The crude product was purified by preparative hplc (Dynamax c60 silica cartridge) eluting with 40% ethyl acetate in hexanes to give colorless crystals (0.21 g, mp 171-172 ° C). MS, m / z: 404.2 (M +
H) ⁺ , 807.1 (2M + H) ⁺

Example 101 [2-Chloro-6- (4-methylpyrazol-1-yl) -pyridin-3-yl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepines -1
0-yl) -methanone 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml)
) Was added dropwise to 3-methylpyrazole (0.45 g). After the hydrogen gas evolution was completed, (2,6-dichloropyridin-3-yl) (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.7
9 g) was added and the reaction mixture was heated in a sand bath at 110 ° C. for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The crude product was purified by preparative hplc (Dynamax c60 silica cartridge) eluting with 40% ethyl acetate in hexane to give colorless crystals (0.26 g, mp 155-156 ° C). MS, m / z: 404.2 (M +
H) ⁺ , 807.0 (2M + H) ⁺

Example 102 [2-Chloro-4- (3-methyl-1,2,4-triazol-1-yl)-
Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone 60% sodium hydride in oil (0.3g) in dimethylformamide (50ml).
) Was added dropwise to 3-methyl-1,2,4-triazole (0.45 g). After completion of hydrogen gas generation, 2-chloro-4-fluorophenyl- (5H, 1
1H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.70 g) was added and the reaction mixture was heated in a sand bath at 110 ° C. for 18 hours.
The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as colorless crystals (1.25g, mp 191-193 ° C). MS, m / z: 404.1 (M + H) ^+.

Example 103 [4- (3-Methyl-1,2,4-triazol-1-yl) -2-trifluoromethyl-phenyl] (5H, 11H-pyrrolo [2,1-c] [1 , 4] Benzodiazepin-10-yl) -methanone 60% sodium hydride in oil (0.3 g) in dimethylformamide (50 ml)
) Was added dropwise to 3-methyl-1,2,4-triazole (0.45 g). After completion of hydrogen gas evolution, 4-fluoro-2-trifluoromethyl-phenyl- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone (1.76 g) was added and the reaction mixture was heated at 110 ° C in a sand bath at 18 ° C.
Heated for hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as colorless crystals (0
． 81 g, melting point 148-150 ° C). MS, m / z: 438.2 (M + H) ⁺ ,
875.8 (2M + H) ⁺

Example 104 4-hydrazino-2-methoxybenzoic acid methyl ester hydrochloride (1: 1), hydrate (2: 1) 4-amino-2-methoxybenzoic acid methyl ester cooled to -10 ° C. (21
． 74 g) of a stirred suspension of concentrated hydrochloric acid (110 ml) in sodium nitrite (8.5 g) in water (45 ml) at the rate necessary to keep the reaction temperature below 0 ° C.
) Was pre-cooled. After the addition was complete, the reaction mixture was stirred at -2 ° C for 10 minutes. The cloudy orange solution was added dropwise at −10 ° C. to a vigorously stirred precooled solution of tin (II) chloride dihydrate (101 g) in concentrated hydrochloric acid (67 ml). The rate of addition was adjusted to maintain the reaction temperature below -5 ° C. After the addition was complete, the cream suspension was warmed to room temperature and the solid was filtered. The solid was washed with diethyl ether and dried over anhydrous sodium sulfate to give a crude product (5
2g). The crude product (20g) was partitioned between aqueous 2.5N sodium hydroxide and dichloromethane. The organic phase was filtered through diatomaceous earth, washed with brine and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent in vacuo gave a cream colored solid (7.1 g) which was treated with an equal volume of anhydrous hydrogen chloride solution in diethyl ether to give the title compound as the monohydrochloride salt. . Melting point 76-79 ° C, M
S, m / z: 197 (M + H) ⁺

Example 105 2-Methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid methyl ester 4-hydrazino-2-methoxybenzoic acid methyl ester hydrochloride salt from Example 104 (0.88 g) ) And 1 drop of concentrated hydrochloric acid in a stirred solution of 1: 1 water / methanol (10 ml), acetylacetaldehyde dimethyl acetal (0.53 g
) Was added. The reaction was heated to 90 ° C. for 5 minutes. Concentrate the reaction in vacuo to 1N
Partitioned between sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed, washed with brine, dried over anhydrous magnesium sulfate and filtered.
Evaporation of the solvent in vacuo gave a brown oil which was combined with the previous lot (0.54g) and recrystallized three times from diisopropyl ether to give 2-methoxy-4- (
3-Methyl-pyrazol-1-yl) -benzoic acid methyl ester was obtained (0.5
g, melting point 167-169 ° C). MS, m / z: 246 (M) ⁺

Example 106 2-Methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid 2-Methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid from Example 105 Tetrahydrofuran (2.5 ml) of acid methyl ester (0.5 g)
The medium solution was treated with 1N lithium hydroxide (2.13 ml) at room temperature. After 14 hours the solvent was removed in vacuo and the title compound was precipitated by addition of 1N hydrochloric acid at 0 ° C. After drying under vacuum, the title compound was obtained as a solid (0.42g). MS, m /
z: 232 (M) ⁺

Example 107 [2-Methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] (
5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Oxalyl chloride (0.17 ml) was added to 2-methoxy-4- (3-of Example 106).
Methyl-pyrazol-1-yl) -benzoic acid (0.41 g) and dimethylformamide (0.004 ml) were added to a stirred solution in anhydrous tetrahydrofuran (10 ml). The reaction was heated at 35 ° C. for 10 minutes. The resulting solution was evaporated in vacuo to give crude 2-methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid carbonyl chloride. After co-evaporation with dichloromethane, the acid chloride was dissolved in dichloromethane (10 ml) and 10,11-dihydro-5H-pyrrolo [2,1-
c] [1,4] -Benzodiazepine (0.31 g) was added. Diisopropylethylamine (0.37 ml) was added and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water then 1N hydrochloric acid. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. The solid residue was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate (2/1) to give the title compound as a colorless solid (0.35g
, Melting point 92-94 ° C).

Example 108 (3-Dimethylaminomethyl-5H, 11H-pyrrolo [2,1-c] [1,4
] Benzodiazepin-10-yl) [2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] -methanone [2-methoxy-4- (3-methyl-pyrazole-1) from Example 107. -Yl) -phenyl] (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (0.57g) in a stirred solution of warm methanol (10ml) in N, N. , N, N'-tetramethyl-diaminomethane (0.392 ml
) And acetic acid (0.164 ml) were added. Aqueous 37% formalin solution (2.9
ml) was added and the reaction was stirred for 15 minutes. The mixture was concentrated in vacuo and partitioned between dichloromethane and sodium hydrogen carbonate. The organic phase was removed, washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica eluting with chloroform / methanol (50/1) to give a solid. Recrystallization of the solid from acetone gave the title compound as a colorless solid. Melting point 196-198
℃

Example 109 [2-Hydroxy-4- (3-methyl-pyrazol-1-yl] (5H, 11
H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone [2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl (5H , 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone was dissolved in dichloromethane (20 ml) and -7
Cooled to 8 ° C. Boron tribromide (6.2 ml) was added and the reaction was stirred at 0 ° C for 5 minutes. Ammonium hydroxide (15 ml) was added and the mixture was extracted with dichloromethane.
The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solid was removed by filtration and the solvent removed in vacuo. The residue was mixed with hexane / ethyl acetate (3/1
Purification by flash column chromatography on silica pressure eluting with 2/1) then gave the title compound as a colorless solid. Melting point 134-136 ° C

Example 110 2-Chloro-4-iodo-benzoic acid methyl ester 4-Amino-2-methoxy-benzoic acid methyl ester (22.97g) in concentrated hydrochloric acid (110ml) to an internal temperature of -10 ° C. Cooled and stirred as a suspension. A pre-cooled solution of sodium nitrite (98.71 g) in water (45 ml) was added to the mixture at such a rate to keep the reaction temperature below 0 ° C. 0
After stirring at 25 ° C for 25 minutes, the reaction was potassium iodide (24.44g) and iodine (18g) in water (50ml) at such a rate as to maintain a reaction temperature below -4 ° C.
． It was treated with a solution of 37 g). Ethyl acetate (100 ml) was added during the addition and the dark mixture was stirred at 0 ° C. for 1 hour. The organic layer was diluted with ethyl acetate and washed well with saturated sodium thiosulfate solution. The resulting orange solution was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give an oil which was purified by suction filtration on silica gel eluting with hexane / ethyl acetate (50/1). The resulting refined oil was solidified by cooling to give the title compound (33
． 71 g). MS, m / z: 296 (M) ⁺

Example 111 4-Bromo-1-methyl-1H-pyrazole 60% sodium hydride (11.6) in prewashed (tetrahydrofuran) oil.
To a suspension of 7 g) in tetrahydrofuran (200 ml) was added dropwise a solution of 4-bromopyrazole (39.77 g) in tetrahydrofuran (50 ml). The solution was stirred at room temperature for 2 hours. Iodomethane (33 ml) in excess tetrahydrofuran (50 ml) was added at such a rate as to maintain a slight temperature rise. The reaction was stirred for an additional 2 hours. The solvent was removed in vacuo and the residue was stirred in diethyl ether. The precipitate was removed by suction filtration and washed with diethyl ether.
The combined organic phases were evaporated in vacuo to give the title compound as an oil (42.22g
). MS, m / z: 160 (M) ⁺

Example 112 1-Methyl-4-tributylstannyl-1H-pyrazole Precooled with 1.6 Mn-butyllithium (100 ml) in anhydrous diethyl ether (100 ml) in hexane (<-10 ° C. internal temperature. ) To the solution under argon was added a solution of 4-bromo-1-methyl-1H-pyrazole (23.42 g) from Example 111 in diethyl ether (50 ml) at such a rate that the temperature was maintained. The reaction was stirred for an additional 20 minutes and then tributyltin chloride (4
3.4 ml) was added in diethyl ether (50 ml). Reaction temperature is 2
Raised to 0 ° C. The reaction was diluted with diethyl ether and insoluble material was removed by suction filtration. Evaporation of the solvent in vacuo gave the title compound as an oil (56g, MS, m / z: 373 "M + H] ⁺ ). Distillation under high vacuum at 170 ° C using a kugelrohr apparatus. The remaining amount of tin residue was removed from the oil.

Example 113 2-Chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid methyl ester 2-Chloro-4-iodo-benzoic acid methyl ester from Example 110 (25
． 4g), 1-methyl-4-tributylstannyl-1H-pyrazole (31.
77 g), tetrakis (triphenylphosphine) palladium (0) (1.8 g
) And catalytic copper (I) iodide in argon-degassed dimethylformamide solution (
70 ml) was heated at 80 ° C. for 7 hours. The solvent was removed in vacuo and the residue was adsorbed on silica gel. Purification by suction filtration through a pad of silica gel eluting successively with hexane then hexane / ethyl acetate (2/1) gave a solid residue after evaporation of the solvent which was recrystallized from diisopropyl ether to give the title compound. Was obtained (7.82 g). MS, m / z 250 (M) ⁺

Example 114 2-Chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid 2-Chloro-4- (1-methyl-1H-pyrazole-4-) from Example 113.
To a solution of (yl) -benzoic acid methyl ester (6.25 g) in methanol (80 ml) was added 1N sodium hydroxide (30 ml). The reaction was heated under reflux for 1 hour. The solvent volume was reduced to 3/4 in vacuo and the residue was treated with 2N hydrochloric acid at 0 ° C. The precipitate was filtered and dried in vacuo to give the title compound (5.84g
). MS, m / z: 237 [M + H] ⁺

Example 115 [2-Chloro-4- (1-methyl-1H-pyrazol-4-yl) phenyl)
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Oxalyl chloride (0.49 ml) was added to 2-chloro-4- (1) from Example 114.
-Methyl-1H-pyrazol-4-yl) -benzoic acid (0.41 g) and dimethylformamide (0.012 ml) were added to a solution in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35 ° C. for 10 minutes. The resulting solution was evaporated to dryness in vacuo to give crude 2-chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid carbonyl chloride. After coevaporation with anhydrous methylene chloride, the acid chloride was dissolved in dichloromethane (20 ml) and then 10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine (0. 888g)
And diisopropylethylamine (1.06 ml) were added. The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water then 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Dichloromethane was filtered, concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica pressure eluting with hexane / ethyl acetate (2/1) to give the title compound as a colorless solid (1.4g, mp 105-).
109 ° C).

Example 116 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
4H, 10H-Pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl) -methanone 2-chloro-4- (3-methyl-pyrazole-1) chloride from Example 18 step e.
-Yl) -benzoyl (0.214g) in a solution of dichloromethane (10ml), 5H-10,11-dihydropyrazolo [5,1-c] [1,4] benzodiazepine (0.153g) and diisopropylethylamine ( 0.173 ml) was added. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water then 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The dichloromethane solution was filtered, concentrated in vacuo to dryness.
The residue was purified by flash column chromatography on silica pressure eluting with hexane / ethyl acetate (1/1) to give the title compound as a colorless solid (0.
3 g, melting point 187-188 ° C).

Example 117 2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(5
, 10-Dihydro-4H-tetrazolo [5,1-c] [1,4] benzodiazepin-5-yl) -methanone 2-chloro-4- (3-methyl-pyrazole-1) chloride from Example 18 step e.
-Yl) -benzoyl (0.18 g) in dichloromethane (10 ml),
10,11-Dihydro-5H-tetrazolo [5,1-c] [1,4] benzodiazepine (0.13 g) and diisopropylethylamine (0.145 ml) were added. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water then 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The dichloromethane solution was filtered, concentrated in vacuo to dryness.
The residue was purified by flash column chromatography on silica eluting with hexane / ethyl acetate (1/1) to give the title compound as a colorless solid (0.1
4 g, melting point 110-114 ° C).

Example 118 1- [4- (4H, 10H-Pyrazolo [5,1-c] [1,4] benzodiazepine-5-carbonyl) phenyl] -ethanone 5,10-dihydro-4H-pyrazolo [5 , 1-c] [1,4] Benzodiazepine (0.555 g), 4-acetylbenzoyl chloride (0.657 g) and N
, N-diisopropylethylamine (0.464 g) in dichloromethane (15 m
The mixture in 1) was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium hydrogen carbonate, water and brine, and dried over anhydrous sodium sulfate. The extract was filtered through a thin pad of magnesium borohydride and the filter pad was washed with dichloromethane. The filtrate was concentrated in vacuo to give a yellow solid (1.53g). The solid was triturated with ethyl acetate to give the title compound as a glass (1.53g, mp 201-210 ° C). The mother liquor from the trituration was evaporated and the residue (0.3
0 g) was chromatographed on thin layer silica gel plates (200 micron) using hexane-ethyl acetate (1: 1) as solvent. The solid was triturated with ethyl acetate and combined with the product originally isolated (0.747g). The combined solids were precipitated from a dichloromethane-hexane mixture to give the product as a glass (0.73 g).

Example 119 1- [4- (4H, 10H-Pyrazolo [5,1-c] [1,4] benzodiazepine-5-carbonyl) phenyl] -3- (dimethylamino) -prop-2-ene -1-one 1- [4- (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine-5-carbonyl) phenyl] -ethanone (0.73g), tert-butoxybis- [dimethylamino] ] Methane (0.964 g) in dichloromethane (10
The mixture was stirred at room temperature for 2 days. The mixture was concentrated in vacuo and the residue crystallized from dichloromethane-hexane to give the title compound as yellow crystals (0.6
5 g, melting point 225-230 ° C).

Example 120 [4- (1-Methyl-1H-pyrazol-3-yl) phenyl] (4H, 10
H-pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl) methanone (isomer A) and [4- (2-methyl-1H-pyrazol-3-yl) phenyl] (4H, 10
H-pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl) methanone (isomer B) 1- [4- (4H, 10H-pyrazolo [5,1-c] [1,4] Benzodiazepine-5-carbonyl) phenyl] -3- (dimethylamino) -prop-2-en-1-one (0.83 g), hydrazine (0.198 g) and acetic acid (0.3
A mixture of 36 g) in ethanol (10 ml) was refluxed for 4 hours. Volatiles were removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with water, 1N sodium hydrogen carbonate, water and brine and dried over anhydrous sodium sulfate. The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated in vacuo to give a light yellow solid (0.56).
g). The solid was chromatographed on a thin layer silica gel plate (200 micron) using ethyl acetate as solvent to give a white solid (0.35 g) as a mixture of A and B (1: 4). Crystallization as a mixture of A and B (9: 1) (89 mg, mp 155-156) by multiple fractional crystallizations from ethyl acetate.
C.) and a glassy material (65 mg) as a mixture of A and B (1: 6) was obtained.

Example 121 1- [4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone Step a) Triethylamine (8.80 ml) ) 20 ml of Carrius
) Tube, (4-Bromo-2-chlorophenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (2.3
7 g) was added to a solution of pyridine (1.80 ml). The resulting solution was purged with nitrogen for 25 minutes, then (trimethylsilyl) acetylene (1.67 ml), bis (triphenyl-phosphine) palladium (II) chloride (0.08 g) and copper (I) iodide ( 0.01 g) was added. The tube was filled with nitrogen purged triethylamine, sealed and heated on an oil bath at 90 ° C. for 80 hours. The solution was cooled to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The dichloromethane extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a brown foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) gave the intermediate acetylene as an off-white foam (2.11 g, MS m / z: 418 (M) ⁺ ). The material was used in the next step without further purification.

[0264]   Step b) A solution of 1% sulfuric acid in tetrahydrofuran with mercury (II) sulphate
Saturated Intermediate acetylene (1.0 ml in tetrahydrofuran (5 ml)
0 g) for 50 hours in the above mercury (II) sulfate-tetrahydrofuran solution (30 m
Stirred with l). Additional amounts of mercury (II) sulfate (0.01 g) and water
(0.3 ml) was added. After stirring for 120 hours, the reaction mixture was poured into water and stirred.
Extracted with chloromethane. A dichloromethane solution was added to saturated aqueous sodium bicarbonate and
It was washed successively with water and water. The dichloromethane solution was dried over anhydrous magnesium sulfate,
Filtered and evaporated to dryness to give a brown solid. Dissolve with hexane-ethyl acetate (1: 1)
Purification by flash chromatography on silica gel leaving a white
A solid was obtained (0.30 g, mp 98-100 ° C). MS, m / z: 364 (M) ⁺

Example 122 1- [4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone Tributyl (ethoxyvinyl) tin (1 0.17 g) to (4-bromo-2-chlorophenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone (1.24 g) in toluene (10 ml). Medium solution. The resulting solution was purged with nitrogen for 10 minutes, then bis (triphenylphosphine) palladium (II) chloride (0.11 g) was added. The reaction mixture was heated to reflux for 24 hours. The solution was cooled to room temperature and 5% aqueous hydrochloric acid (10 ml) was added. After stirring for 1 hour, the mixture was filtered through a pad of diatomaceous earth. Diethyl ether (5 ml) was added to the filtrate and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a brown glass. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) gave a white solid (0.30g). M
S, m / z: 364 (M) ⁺

Example 123 [2-chloro-4- (3-methyl-4-ethynyl-phenyl) (5H, 11H
-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone By treatment of the intermediate acetylene of Example 121 step a with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature. After removal of the solvent, the title compound was obtained in 84% yield as an orange-yellow solid. Melting point 84-86 ° C
, MS, m / z: 346 (M) ⁺

Methods of Preparing Pharmaceutical Formulations The present invention also includes methods of making the formulations disclosed herein. The process of the present invention is: a) blending the PEG and surfactant components to form a first carrier mixture, preferably using mixing or stirring; b) increasing the temperature of the first carrier mixture from about 75 ° C to about 95 ° C. C, preferably about 80 C to about 9
C) adding active ingredients to make a first pharmaceutical composition mixture; d) until the first pharmaceutical composition mixture is clear, preferably from about 115 ° C to about 170 ° C.
C, preferably about 130 ° C to about 150 ° C, more preferably about 135 ° C to
Stirring the first pharmaceutical composition mixture at about 145 ° C, preferably with heating; e) bringing the first pharmaceutical composition to about 75 ° C to about 95 ° C, preferably about 80 ° C.
Cooling to 0 ° C to about 90 °; g) adding the total amount of sucrose fatty acid ester and / or povidone, preferably while stirring until the final pharmaceutical composition mixture is clear, to form the final pharmaceutical composition mixture.

When using any antioxidants or preservatives such as BHA, BHT: a) PEG component (eg PEG400), preferably with mixing or stirring.
And a mixture of PEG1000) and a surfactant component (eg, polysorbate 80) to form a first carrier mixture; b) a temperature of the first carrier mixture of about 75 ° C to about 95 ° C, preferably about 80 ° C. ~ About 9
C) raise to 0 ° C .; c) add any antioxidant or preservative component to the first carrier mixture to make a second carrier mixture, then stir it until the second carrier mixture becomes a clear solution ,
Or mixing; d) adding the active ingredients to form a first pharmaceutical composition mixture; e) preferably with heating, until the first pharmaceutical composition mixture is transparent, preferably at about 130 ° C to about 150 ° C. Stirring the first pharmaceutical composition mixture, more preferably at about 135 ° C to about 145 ° C; f) bringing the first pharmaceutical composition to about 75 ° C to about 95 ° C, preferably about 80 ° C to about 90 ° C.
G) Addition of the total amount of sucrose fatty acid ester and / or povidone, preferably with stirring until the final pharmaceutical composition mixture is clear, may be used to make the final pharmaceutical composition mixture. .

One of ordinary skill in the art will appreciate that the viscosity and morphology of the final formulation can be operated within the temperature range of ingredients and manufacturing processes within the scope of the present invention. For example, fluid or semi-solid compositions can be prepared with the more fluid PEG, surfactant and PVP species within the scope of the present invention. A more gel-like viscous or semi-solid composition will give a higher molecular weight PE
It can be produced using a combination of G component and PVP component with higher K value. Furthermore, if milling or other processing of the final composition is desired, the components can be cooled below their melting point. To create a more pelletized initial composition, the fluid composition of the present invention is sprayed onto a chilled Teflon® coated surface to form small solid spheres which are individually coated. It may be coated on or collected for further processing. Specific non-limiting examples of formulations within the scope of the present invention are provided below.

Example 1 50 mg / capsule: Oral formulation with 10% drug loading In the formulation of Example 1, instead of polysorbate 80, Tween (Tween) was used.
) A series of other sorbates, such as 20, 40 and 60, may also be used alone or in combination with each other and / or polysorbate 80.

[0271]

[Table 4]

1. Polysorbate 80, PEG400 and PEG1000 were weighed into a suitable mixing vessel, stirred using a fixed top mixer and warmed to 85 ± 5 ° C. 2. BHT and BHA were added to the mixing vessel very slowly to prevent lump formation. Stirring was continued at 85 ± 5 ° C. until a clear solution was formed. 3. The active ingredient was added to the container at 85 ± 5 ° C. very slowly to prevent lump formation. The temperature was slowly raised to 125 ± 5 ° C. and stirred until the active ingredient was completely dissolved. 4. In step 4 the solution was cooled to 60 ± 5 ° C. 5. To prevent lump formation, povidone, USP, K-17 (Plasdone (Plasdon
done) C-15, ISP) was slowly added to Step 5. The solution was raised to 85 ± 5 ° C. Stir until the solution is clear. 6. A Hoflinger and Karg (H & K) 800L encapsulator was used to package 480 mg of the final solution (step 10) in size 1 capsules at 38 ± 5 ° C. During encapsulation, the body of the capsule was cooled with cold nitrogen and passed through dry ice. 7. The capsules were band sealed with a gelatin solution.

Example 2 50 mg / Capsule: Oral Formulation with 10% Drug Loading The surfactant (Poloxamer 188) used in the formulation can be replaced by a series of other polymers such as Pluronic L44, Pluronic L101. .

[0274]

[Table 5]

The formulation is prepared similar to that of Example 1 (50 mg / capsule), except that 12% poloxamer is used in place of polysorbate 80 in the formulation. The weight put in the capsule is 480 mg.

Example 3 50 mg / Capsule Example 3 provides a formulation with a combination of two or more surfactants.

[0277]

[Table 6]

The formulation of Example 3 was similar to that of Example 1 (50 mg / capsule) except that two surfactants, polysorbate 40 and poloxamer 188 were added in step 1 along with PEG400 and PEG1000. Manufactured. The weight put in the capsule is 480 mg.

Example 4 25 mg / capsule: Oral formulation with 5% drug loading

[Table 7]

The formulation of Example 4 had a heating temperature of 1 to solubilize the active ingredient in Step 3.
It is manufactured similarly to the 50 mg / capsule formulation above, except 115 ± 5 ° C. instead of 20 ± 5 ° C. The weight put in the capsule is 455 mg.

Example 5 100 mg / capsule: Oral formulation with 15% drug loading

[Table 8]

The formulation has a heating temperature of 120 ± 5 for solubilizing the active ingredient in Step 3.
Manufactured as in the 50 mg / capsule formulation above, except 145 ± 5 ° C instead of ° C. The weight to be encapsulated is 650 mg in a size 0 hard gelatin capsule.

Example 6 150 mg active ingredient in size 00 capsules

[Table 9]

The formulation of Example 6 had a heating temperature of 1 to solubilize the active ingredient in Step 3.
Manufactured similarly to the 50 mg / capsule formulation, except 150 ± 5 ° C. instead of 45 ± 5 ° C. The weight to be encapsulated is 910 mg in a size 00 hard gelatin capsule.

The following specific examples 7-11, shown in Table 1 below, show various concentrations of PEG.
Formulation as above to make a formulation of 400, PEG 1000, two PVP components with individual K values of 15 and 19 and a 10% active ingredient with a combination of BHA and BHT as co-ingredients. You can

[0286]

[Table 10]

Similarly, Examples 12 to 32 below are prepared using PEG400, PEG1000, K
PHA having a value of 17, BHA and B as active ingredients, antioxidants or preservatives
It may be formulated according to the methods herein using HT and the additional ingredients listed as "other."

[0288]

[Table 11]

[0289]

[Table 12]

[0290]

[Table 13]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/32 A61K 47/32 47/34 47/34 A61P 7/00 A61P 7/00 7/12 7 / 12 13/02 13/02 13/12 13/12 43/00 111 43/00 111 C07D 487/04 152 C07D 487/04 152 153 153 // C07M 9:00 C07M 9:00 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Richard William Saunders United States 10964 New York, Woods, Paris Drive 4 (72) Inventor Made Bakir Fauj United States 07960 Dukes Court 1F Term, Morristown, NJ 4C050 AA01 AA07 BB04 CC11 EE02 FF01 GG01 HH04 4C076 AA55 BB01 CC17 DD08 DD09 DD37 DD68 DD70 EE16 EE23 FF39 GAFF09 4C086 A02 MA04 MA05 MA37 MA52 NA11 ZA51 ZA84 ZC41

Claims (22)

[Claims] 1. a) from about 1% to about 20% by weight of structural formula: Wherein A, B, E, G are independently CH or nitrogen; D is independently C-W or nitrogen; R ¹ is alkanoyl having 2 to 7 carbon atoms, CN, COOH, CONH ₂ , embedded image A group selected from: or R ² , R ³ and R ⁵ are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms,
Branched alkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or perfluoroalkyl having 1 to 6 carbon atoms; R ⁴ is hydrogen, linear alkyl having 1 to 6 carbon atoms A branched alkyl having 3 to 7 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, an alkoxyalkyl having 2 to 7 carbon atoms, or an alkanoyl having 2 to 7 carbon atoms, a carbon atom having 3 to 7 carbon atoms. Is an acyl substituent selected from the group consisting of alkenoyl, cycloalkanoyl having 3 to 7 carbon atoms, aroyl or arylalkanoyl; X and Y are independently hydrogen, linear alkyl having 1 to 6 carbon atoms, Carbon atom 3
~ 7 branched chain alkyls, cycloalkyls with 3 to 7 carbon atoms, perfluoroalkyls with 1 to 6 carbon atoms, alkoxyalkyls with 2 to 7 carbon atoms, halogens (including chlorine, bromine, fluorine and iodine). ), Alkoxy having 1 to 6 carbons, hydroxy, CF ₃ , or perfluoroalkyl having 2 to 6 carbons; W is hydrogen, halogen (preferably chloro, bromo or iodo), alkyl, carbon 2 to 7 Alkoxyalkyl, hydroxyalkyl having 1 to 6 carbons,
Or CH ₂ NR ⁶ R ⁷ ; R ⁶ and R ⁷ are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 7 carbon atoms; or Together with the nitrogen atom of CH ₂ NR ⁶ R ⁷ , R ⁶ and R ⁷ include but are not limited to the group: Form a 5- or 6-membered ring which may contain one or more additional heteroatoms such as; R ⁸ is straight-chain alkyl of 1 to 6 carbon atoms; R ⁹ is independently Hydrogen, trimethylsilyl or linear alkyl having 1 to 6 carbon atoms] or a pharmaceutically acceptable salt thereof; b) about 1% to about 18% by weight of a surfactant component; c) about 50% to about 80% by weight of one or more polyethylene glycol components; d) about 1% to about 20% by weight i) one or more sucrose fatty acid esters; or ii) about 15-90. A polyvinylpyrrolidone having a K value; or iii) a pharmaceutical composition comprising the components of the combination of one or more sucrose fatty acid esters and polyvinylpyrrolidone. 2. The active ingredient has the structural formula: Wherein A and B are independently CH or nitrogen; D is C-W or nitrogen; R ¹ is alkanoyl having 2 to 7 carbon atoms or R ² , R ³ and R ⁵ are independently hydrogen, linear alkyl having 1 to 6 carbon atoms, branched alkyl having 3 to 7 carbon atoms, 3 carbon atoms. it is to seven cycloalkyl or carbon 1-6 ^{perfluoroalkyl,; R 4, X, Y} , W, R 6, R 7 and ^{R 8} are represented by are as defined in claim 1] Or a pharmaceutically acceptable salt thereof. 3. The active ingredient is: (4-fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone , [4- (4-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)- Methanone, (4-pyrazol-1-yl-2-trifluoromethyl-phenyl)-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone, [4- (3-cyclopropyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl ) -Methanone, [4- (4-methyl-imidazol-1-yl) -2-trifluoromethyl-
Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10-
Yl)-(4- [1,2,4] triazol-1-yl-2-trifluoromethylphenyl) -methanone, (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo [2,1] −
c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (5-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (4-methyl-pyrazol-1-yl) -phenyl- (5
H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (4-methyl-imidazol-1-yl) -phenyl]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (1,2,4-triazol-1-yl) -phenyl ]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, (2-chloro-4-pyrrol-1-yl-phenyl)-(5H, 11H-pyrrolo [ 2,1-c] [1,4] benzodiazepin-10-yl) -methanone, (2-chloro-4-pyrazol-1-yl-phenyl)-(5H, 11H-pyrrolo [2,1-c] [ 1,4] benzodiazepin-10-yl) -methanone, [2-chloro-4- (1H-imidazol-1-yl) -phenyl]-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone, [2-chloro-4- (3-methylpyrazol-1-yl) -phenyl]-(3
-Methyl-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-
10-yl) -methanone, (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2- (3-methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl ]-(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [2- (4-methyl-pyrazol-1-yl) -4-trifluoromethyl- Pyrimidin-5-yl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, 1- [4- (5H, 11H-pyrrolo [2,1- c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone; 3-dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1
, 4] Benzodiazepine-10-carbonyl) -phenyl] -2-propene-1
-One; [4- (1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- ( 1-methyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (1-ethyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (1-propyl-1H-pyrazol-3-yl) -phenyl]-(5H
, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl)-
Methanone; [4- (1-butyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (1-methoxymethyl-1H-pyrazol-3-yl) -phenyl]-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1 , 4] Benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -ethanone; 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine- 10-Carbonyl) -phenyl] -pyrazol-1-yl} -propan-1-one; [4- (1-Cyclopropanecarbonyl-1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [ 2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10- Carbonyl) -pheny ]]-Pyrazol-1-yl} -butan-1-one; (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-{4- [1- (thiophen-2-carbonyl) -1H-pyrazole-3
-Yl] phenyl} -methanone; {4- [1- (5-Fluoro-2-methyl-benzoyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c ] [1,4]
Benzodiazepin-10-yl) -methanone; {4- [1- (2-Methyl-benzoyl) -1H-pyrazol-3-yl]-
Phenyl}-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; {4- [1- (2-chloro-4-fluoro-benzoyl) -1H- Pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [1,4]
Benzodiazepin-10-yl} -methanone; {4- [1- (2,4-Dichloro-benzoyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 2- (2,4-dichloro-phenyl) -1- {3- [4- (5H, 11H-pyrrolo [2,1-c] [1, 4] benzodiazepine-10-carbonyl) -phenyl] pyrazol-1-yl} -ethanone; {4- [1- (biphenyl-2-carbonyl) -1H-pyrazol-3-yl] -phenyl}-(5H, 11H -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; {4- [1- (4'-trifluoromethyl-biphenyl-2-carbonyl)-
1H-pyrazol-3-yl] -phenyl}-(5H, 11H-pyrrolo [2,1
-C] [1,4] benzodiazepin-10-yl) -methanone; 3-dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1.
, 4] Benzodiazepine-10-carbonyl) -phenyl] -2-butene-1-
ON; [4- (5-methyl-1H-pyrazol-3-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-carbonyl) -benzamide; N- (dimethylaminomethylene) -4- (5H, 11H-pyrrolo [2,1-c
] [1,4] Benzodiazepine-10-carbonyl) -benzamide; N- (1-dimethylaminoethylene) -4- (5H, 11H-pyrrolo [2,1]
-C] [1,4] benzodiazepine-10-carbonyl) -benzamide; (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-[4- (2H- [1,2,4] Triazol-3-yl) -phenyl]
-Methanone; [4- (2-methyl-2H- [1,2,4] triazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-
10-yl) -methanone; [4- (5-methyl-2H- [1,2,4] triazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1, 4] benzodiazepine-
10-yl) -methanone; [4- (2,5-dimethyl-2H- [1,2,4] triazol-3-yl)
-Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (3-methyl [1,2,4] oxadiazole-5) -Yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone; 1-methyl-4- (4-methylphenyl) -1H-pyrazole; 4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid; [4- (1-methyl- 1H-pyrazol-4-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 6- (1-methyl-1H-pyrazol-4-yl) -pyridine-3-carboxylic acid; [6- (1-Methyl-1H-pyrazol-4-yl) -pyridin-3-yl]
-(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl) -methanone; [4- (pyrazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [2
, 1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (3-methyl-pyrazol-1-yl)-(5H, 11H-pyrrolo [2
, 1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (4-methyl-pyrazol-1-yl)-(5H, 11H-pyrrolo [2
, 1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (3,5-dimethyl-pyrazol-1-yl) -phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl)-[4- (3-Trifluoromethyl-pyrazol-1-yl) -phenyl] -methanone; [4- (imidazol-1-yl) -phenyl]-(5H, 11H-pyrrolo [
2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (4-methyl-imidazol-1-yl) -phenyl]-(5H, 11
H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 4-bromo-2-chloro-benzoic acid methyl ester; 2-chloro-4- (3-dimethylamino-propyne -1-yl) Benzoic acid methyl ester; 2-chloro-4- (3-dimethylamino-propen-1-one-1-yl)-
Benzoic acid methyl ester; 2-Chloro-4- (1H-pyrazol-3-yl) -benzoic acid methyl ester; 2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid; [2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -phenyl]-(5H , 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone; 2-chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester; 2-chloro-4- (2-methyl-1H-pyrazol-3-yl) -Benzoic acid; [2-chloro-4- (2-methyl-1H-pyrazol-3-yl) -phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10.
-Yl) -methanone; 2-chloro-4-cyanobenzoic acid methyl ester; 2-chloro-4-cyanobenzoic acid; 3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1, 4] benzodiazepine-10-carbonyl) -benzonitrile; 3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzoic acid; 3-chloro- 4- (5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide; N- (1-dimethylaminoethylene) -3-chloro-4- (5H, 11H- Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide; [2-chloro-4- (5-methyl-2H- [1,2,4] triazole-3-
YL) phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -methanone; N- (dimethylaminomethylene) -3-chloro-4- (5H, 11H -Pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide; [2-chloro-4- (2H-1,2,4-triazol-3-yl) phenyl]-(5H , 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10
-Yl) -methanone; [2-chloro-4- (2-methyl-2H- [1,2,4] triazole-3-
Yl) phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -methanone; 4-[(2,5-dimethyl-2H- [1,2,4 ] Triazol-3-yl)
-2-Chloro-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4]
Benzodiazepine-10-carbonyl) -methanone; [2-chloro-4- (1H-tetrazol-5-yl) phenyl]-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [2-chloro-4- (3-methyl-pyrazol-1-yl) phenyl]-(3
-Dimethylaminomethyl-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; (3-bromo-5H, 11H-pyrrolo [2,1-c] [1 , 4] Benzodiazepin-10-yl)-[2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] -methanone; (4-Bromo-2-chlorophenyl)-(5H, 11H-pyrrolo [2,1-c
] [1,4] Benzodiazepin-10-yl) -methanone; [2-Bromo-4- (3-methyl-pyrazol-1-yl) -phenyl]-(
5H, 11H) -Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; (2,4-difluoro-phenyl)-(5H, 11H-pyrrolo [2,1-c].
[1,4] benzodiazepin-10-yl) -methanone; [2-fluoro-4- (3-methyl-pyrazol-1-yl) -phenyl]-
(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; methyl 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoate; 4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethylbenzoic acid; [4- (3-Methylpyrazol-1-yl) -2-trifluoromethylphenyl]-(5H, 11H-pyrrolo [5,1-c] [1,4] benzodiazepine-1
0-yl) -methanone; 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester and 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) ) Benzoic acid methyl ester; 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid; (2,6-dichloropyridin-3-yl)-(5H, 11H-pyrrolo [2 , 1
-C] [1,4] benzodiazepin-10-yl) -methanone; (2-chloro-6-pyrazol-1-yl-pyridin-3-yl)-(5H,
11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [2-chloro-6- (3-methylpyrazol-1-yl) -pyridin-3-yl]-( 5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-1
0-yl) -methanone; [2-chloro-6- (4-methylpyrazol-1-yl) -pyridin-3-yl]-(5H, 11H-pyrrolo [2,1-c] [1,4]. Benzodiazepine-1
0-yl) -methanone; [2-chloro-4- (3-methyl-1,2,4-triazol-1-yl)-
Phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; [4- (3-methyl-1,2,4-triazol-1-yl) 2-Trifluoromethyl-phenyl]-(5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 4-hydrazino-2-methoxybenzoic acid methyl ester hydrochloride (1: 1)
Hydrate (2: 1); 2-methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid methyl ester; 2-methoxy-4- (3-methyl-pyrazol-1-yl)- Benzoic acid; [2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl]-
(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; (3-Dimethylaminomethyl-5H, 11H-pyrrolo [2,1-c] [1,4
] Benzodiazepin-10-yl)-[2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] -methanone; [2-Hydroxy-4- (3-methyl-pyrazol-1-yl] -(5H, 1
1H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 2-chloro-4-iodo-benzoic acid methyl ester; 4-bromo-1-methyl-1H-pyrazole; 1 -Methyl-4-tributylstannyl-1H-pyrazole; 2-chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid
Methyl ester; 2-chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid; [2-chloro-4- (1-methyl-1H-pyrazol-4-yl) phenyl]
-(5H, 11H-Pyrrolo [2,1-c] [1,4] benzodiazepine-10-
Yl) -methanone; [2-chloro-4- (3-methyl-pyrazol-1-yl) phenyl]-(4
H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl)
-Methanone; [2-chloro-4- (3-methyl-pyrazol-1-yl) phenyl]-(5
, 10-Dihydro-4H-tetrazolo [5,1-c] [1,4] benzodiazepin-5-yl) -methanone; 1- [4- (4H, 10H-pyrazolo [5,1-c] [1, 4] benzodiazepine-5-carbonyl) phenyl] -ethanone; 1- [4- (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine-5-carbonyl) phenyl] -3- (dimethylamino) ) -Prop-2-en-1-one; [4- (1-methyl-1H-pyrazol-3-yl) phenyl]-(4H, 1
0H-pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl) -methanone; [4- (2-methyl-1H-pyrazol-3-yl) phenyl]-(4H, 1
0H-pyrazolo [5,1-c] [1,4] benzodiazepin-5-yl) -methanone; 1- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10 -Carbonyl) -3-chlorophenyl] -ethanone; 1- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone; [2 -Chloro-4- (3-methyl-4-ethynyl-phenyl)-(5H, 11
H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone; 4. The active ingredient is [2-chloro-4- (3-methyl-pyrazole-
The pharmaceutical according to claim 1, which is 1-yl) -phenyl- (5H, 11H) -pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone or a pharmaceutically acceptable salt thereof. Composition. 5. A) about 5% to about 16% by weight of the active ingredient or a pharmaceutically acceptable salt thereof; b) about 5% to about 15% by weight of a surfactant ingredient; c) about 55% by weight. % To about 70% by weight of one or more polyethylene glycol components; d) about 1% to about 20% by weight i) one or more sucrose fatty acid esters; or ii) polyvinyl having a K value of about 15 to 90. Pyrrolidone; or iii) A pharmaceutical composition according to claim 1 comprising the components of a combination of one or more sucrose fatty acid esters as described above and polyvinylpyrrolidone. 6. The surfactant component is polysorbate 20, polysorbate 60.
, Polysorbate 40, polysorbate 80, span 80 sorbitan oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid, ursodeoxycholic acid, pluronic or poloxamer, or a combination thereof. The pharmaceutical composition according to 1. 7. The one or more polyethylene glycol components are from about 190 to about 34.
The pharmaceutical composition according to claim 1, comprising one or more polyethylene glycols having an average molecular weight of 50. 8. The one or more polyethylene glycol components are about 400-154.
The pharmaceutical composition according to claim 5, comprising one or more polyethylene glycols having an average molecular weight of 0. 9. The pharmaceutical composition of claim 5, wherein the one or more polyethylene glycol components comprises a mixture of PEG400 and PEG100 in a ratio of about 2.5: 1 to about 1: 2.5. 10. The pharmaceutical composition according to claim 1, wherein the polyvinylpyrrolidone component has a K value of about 17. 11. A) from about 1% to about 20% by weight of the active ingredient of claim 1 or a pharmaceutically acceptable salt thereof; b) from about 1% to about 18% by weight of a surfactant ingredient; c) about 50% to about 80% by weight of one or more polyethylene glycol components; d) about 1% to about 20% by weight of one or more sucrose fatty acid esters or polyvinyl having a K value of about 15-90. Pyrrolidone; e) A pharmaceutical composition comprising about 0.1% to about 4% by weight of one or more antioxidants or preservatives. 12. A) The surfactant component is polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, span 80 sorbitan oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid. , Ursodeoxycholic acid, pluronic or poloxamer, or a combination thereof; b) one or more polyethylene glycol components comprises one or more polyethylene glycols having an average molecular weight of about 400 to 1540; c) one or more antioxidants. The agent or preservative is selected from ascorbyl palmitate, benzyl alcohol, butylhydroxyanisole, or butylhydroxytoluene, or a combination thereof. 11. The pharmaceutical composition according. 13. A) about 5% to about 16% by weight of the active ingredient of claim 1 or a pharmaceutically acceptable salt thereof; b) about 5% to about 15% by weight of a surfactant ingredient; c) about 55% to about 70% by weight of one or more polyethylene glycol components; d) about 1% to about 20% by weight of one or more sucrose fatty acid esters or polyvinyl having a K value of about 15-90. Pyrrolidone; e) about 0.3% to about 2.5% by weight BHA and / or about 0.005%.
The pharmaceutical composition according to claim 11, comprising from BHT to about 0.15% by weight. 14. A) about 5% to about 16% by weight of the active ingredient or a pharmaceutically acceptable salt thereof; b) about 5% to about 15% by weight of polysorbate 20, polysorbate 60,
Polysorbate 40, polysorbate 80, span 80 sorbitan oleate,
Polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid,
A surfactant component comprising ursodeoxycholic acid, a pluronic or poloxamer, or a combination thereof; c) about 55% to about 70% by weight of one or more polyethylene glycol components having an average molecular weight of about 400-1540; d) Polyvinylpyrrolidone (PVP) having a K value of about 15 to 90 of about 1% to about 20% by weight; e) about 0.3% to about 2.5% by weight of BHA and / or about 0.005%.
The pharmaceutical composition according to claim 11, comprising from BHT to about 0.15% by weight. 15. The pharmaceutical composition according to claim 1, which is contained in a hard or soft gelatin capsule. 16. About 1% to about 20% by weight of the active ingredient or a pharmaceutically acceptable salt thereof; about 1% to about 18% by weight of a surfactant ingredient; about 50% to about 8%.
0% by weight of one or more polyethylene glycol components; and from about 1% to about 20%.
A method of formulating a pharmaceutical composition comprising, by weight, one or more sucrose fatty acid ester or polyvinylpyrrolidone having a K value of about 15-90; or a combination of one or more sucrose fatty acid ester and polyvinylpyrrolidone. A) combining a surfactant component and one or more polyethylene glycol components to form a first carrier mixture; b) increasing the temperature of the first carrier mixture to about 75 ° C to about 95 ° C; c) activity. Making a first pharmaceutical composition mixture by adding the ingredients or pharmaceutically acceptable salts thereof; d) stirring until the first pharmaceutical composition mixture is clear; e) the first pharmaceutical composition from about 75 ° C to about 95 ° C. May be cooled to ℃; g) adding one or more sucrose fatty acid esters and / or the total amount of povidone to make a final pharmaceutical composition mixture; How to butterflies. 17. A) combining a surfactant component and one or more polyethylene glycol components to form a first carrier mixture; b) increasing the temperature of the first carrier mixture to about 80 ° C to about 90 ° C. C) adding the active ingredient or a pharmaceutically acceptable salt thereof to form a first pharmaceutical composition mixture; d) increasing the temperature of the first pharmaceutical composition to about 135 ° C to about 145 ° C, and Stir until the mixture is clear; e) Cool the first pharmaceutical composition to about 80 ° C to about 90 ° C; g) Add the total amount of sucrose fatty acid ester (s) and / or povidone. 14. The method of claim 13, wherein the method comprises the step of making a final pharmaceutical composition mixture. 18. About 1% to about 20% by weight of the active ingredient of claim 1 or a pharmaceutically acceptable salt thereof; about 5% to about 18% by weight of a surfactant component; about 5%.
0% to about 80% by weight of one or more polyethylene glycol components; about 1% by weight
To about 20% by weight of one or more sucrose fatty acid esters or components of polyvinylpyrrolidone having a K value of about 15 to 90; and about 0.1% to about 3% by weight.
A method of formulating a pharmaceutical composition comprising one or more adjuvants according to: a) combining one or more polyethylene glycol components and a surfactant component to form a first carrier mixture; b) Increasing the temperature of one carrier mixture to about 75 ° C to about 95 ° C; c) adding one or more antioxidants or preservatives to the first carrier mixture to make a second carrier mixture; d) the active ingredient or its Making a first pharmaceutical composition mixture by adding a pharmaceutically acceptable salt; e) stirring until the first pharmaceutical composition mixture is clear; f) cooling the first pharmaceutical composition to about 75 ° C to about 95 ° C. G) from about 1% to about 20% of one or more sucrose fatty acid esters or about 15%;
A method characterized by adding polyvinylpyrrolidone having a K value of ˜90 to make a final pharmaceutical composition mixture. 19. The surfactant component comprising polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, span 80 sorbitan oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid. , Ursodeoxycholic acid, pluronic or poloxamer, or a combination thereof; b) one or more polyethylene glycol components comprises one or more polyethylene glycols having an average molecular weight of about 400 to 1540; c) one or more antioxidants. The agent or preservative is selected from ascorbyl palmitate, benzyl alcohol, butylhydroxyanisole, or butylhydroxytoluene, or a combination thereof. The method of claim 18, wherein. 20. About 1% to about 20% by weight of the active ingredient of claim 1 or a pharmaceutically acceptable salt thereof; about 5% to about 18% by weight surfactant ingredient; about 5%.
0% to about 80% by weight of one or more polyethylene glycol components; about 1% by weight
To about 20% by weight of polyvinylpyrrolidone having a K value of about 15 to 90; and about 0.3% to about 2.5% by weight butylhydroxyanisole and about 0.
A method of formulating a pharmaceutical composition comprising an antioxidant or preservative component of 005 wt% to about 0.15 wt% butyl hydroxytoluene, wherein a) one or more, preferably using mixing or stirring. Mixing the polyethylene glycol component and the surfactant component to form a first carrier mixture; b) increasing the temperature of the first carrier mixture to about 75 ° C to about 95 ° C; c) antioxidant to the first carrier mixture. An agent or preservative component is added to form a second carrier mixture; d) an active ingredient or a pharmaceutically acceptable salt thereof is added to form a first pharmaceutical composition mixture; e) the temperature of the first pharmaceutical composition mixture is adjusted. Raised to about 130 ° C to about 150 ° C; f) stirring or mixing the first pharmaceutical composition mixture until the first pharmaceutical composition mixture is clear; g) bringing the first pharmaceutical composition to about 75 ° C to about 95 ° C. H) about 1% to about Wherein the step of creating a final pharmaceutical composition mixture by adding the components of 0% povidone. 21. a) The surfactant component is polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, span 80 sorbitan oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholate, sodium deoxytaurocholate, chenodeoxycholic acid. 19. The method of claim 18, wherein the component of the one or more polyethylene glycols comprises one or more polyethylene glycols having an average molecular weight of about 400-1540, wherein: b) comprises ursodeoxycholic acid, pluronic or poloxamer, or a combination thereof; 22. About 5% to about 16% by weight of the active ingredient of claim 1 or a pharmaceutically acceptable salt thereof; about 5% to about 15% by weight surfactant ingredient; about 5%.
5% to about 70% by weight of one or more polyethylene glycol components; about 5% by weight
To about 15% by weight of polyvinylpyrrolidone having a K value of about 15 to 90; and about 0.3% to about 2.5% by weight butylhydroxyanisole and about 0.
A method of formulating a pharmaceutical composition comprising an antioxidant or preservative component of 005 wt% to about 0.15 wt% butyl hydroxytoluene, wherein a) one or more, preferably using mixing or stirring. Mixing the polyethylene glycol component and the surfactant component to form a first carrier mixture; b) increasing the temperature of the first carrier mixture to about 80 ° C to about 90 ° C; c) antioxidant to the first carrier mixture. An agent or preservative component is added to form a second carrier mixture; d) an active ingredient or a pharmaceutically acceptable salt thereof is added to form a first pharmaceutical composition mixture; e) the temperature of the first pharmaceutical composition mixture is adjusted. Raised to about 135 ° C to about 145 ° C; f) stirring or mixing the first pharmaceutical composition mixture until the first pharmaceutical composition mixture is clear; g) bringing the first pharmaceutical composition to about 80 ° C to about 90 ° C. H) about 5% to about Wherein the step of creating a final pharmaceutical composition mixture of 5% by adding components of povidone.