HK1087100A - Novel substituted 2,3-benzodiazepine derivatives - Google Patents

Description

Novel substituted 2, 3-benzodiazepine * derivatives

Cross reference to related applications

This application is a continuation-in-part application filed on 4.2.2003 under application serial No. 10/358,053.

Background

Technical Field

The present invention relates to novel heterocyclic substituted 2, 3-benzodiazepine * derivatives, their acid addition salts, and pharmaceutical compositions containing them. The invention also relates to the use of said compounds as AMPA receptor antagonists.

Brief description of the related Art

Over-activation of glutamate receptors has been associated with several acute and chronic central nervous system ("CNS") diseases. A variety of glutamate receptor antagonists have been investigated as therapeutic modalities (see, e.g., Parsons et al, Drug News Perspectrum.11: 523(1998) and Br { hacek over (a) } -Osborne et al, J.Med.chem.43：2609(2000))。

Glutamate receptors of the AMPA (2-amino-3- (3-hydroxy-5-methyl-4-isoxazolyl) -propionic acid) type play an important role in a variety of central nervous system diseases. Inhibition of activation of AMPA-type receptors has been shown to have neuroprotective, antiepileptic, and muscle relaxant effects (see, e.g., cerebrovasc.6：225(1994)；Neurology44 Suppl.8，S14(1994)；J.Pharmacol.Exp.Ther. 260：742(1992))。

Glutamate receptors have been found not only in the CNS, but also in peripheral tissues, suggesting potential opportunities for treatment outside the CNS (see, e.g., skery et al, Trends in pharm. sci.,22: 74(2001). NMDA-type glutamate antagonists have been hypothesized to beneficially affect respiratory inflammation (Said, Trends in pharm.20: 132 (1999); and Said et al, Trends in pharm. Sci,22：344(2001))。

AMPA-type receptors can be inhibited by a variety of competitive and non-competitive antagonists. The therapeutic efficacy of non-competitive antagonists may be superior to competitive ones in that their activity is independent of high concentrations of endogenous glutamate (see, e.g., Vizi et al, CNS Drug Rev,2: 91(1996)). One of the most prominent non-competitive AMPA receptor antagonists is 5- (4-aminophenyl) -8-methyl-9H-1, 3-dioxolo [4, 5-H ]][2，3]Benzodiazepines * (also known as GYKI 52466) which have significant anti-epileptic, muscle relaxant and neuroprotective activity (Tarnawa et al, eur.j. pharmacol,167: 193 (1989); smith, et al, Eur.J. Pharmacol,187: 131 (1990); quardouz et al, Neurosci.Lett.,125: 5 (1991); donevan et al, i.neuron,10：51(1993))。

several non-competitive AMPA antagonists have been described in the literature, including 3, 4-dihydro-5H-or 4, 5-dihydro-3H-2, 3-benzodiazepine *, which contain an acyl group at the 3-position of the ring (see, e.g., hungarian patent nos. 206,719B and 219,777B, U.S. patent No. 5,536,832, european patent publication No. 0699677 a1, and british patent No. 2311779, as well as WO 96/04283, WO 97/28135, WO 99/07707, WO 99/07708, and WO 01/04122). WO 96/06606 (corresponding to U.S. patent No. 5,795,886) describes several 2, 3-benzodiazepine * derivatives having aryl and heteroaryl substituents at C3 (e.g., pyridyl, thienyl, furyl, phenyl, imidazolyl, benzimidazolyl, etc.).

It has been found that the above-mentioned compounds can be used in particular in diseases in which an excessive functioning of the glutamate system can be detected. Such acute disorders of the CNS include, for example, stroke, cerebral ischemia, brain and spinal cord injury, perinatal hypoxia, hypoglycemic nerve injury, and the like. Other chronic diseases in which selected AMPA antagonists may be administered include, for example, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, glaucoma, diabetic retinopathy and Parkinson's disease. Moreover, the enhanced activity of the glutamate system has also been demonstrated in conditions associated with nerve damage (e.g., epilepsy, migraine, bladder incontinence, psychosis-anxiety disorders, schizophrenia, etc., drug abuse, pathological pain, cerebral edema, and tardive dyskinesia), suggesting an attractive therapeutic potential for AMPA antagonists.

Recently, experimental data have shown that selected AMPA antagonists have a beneficial effect on the autoimmune encephalomyelitis induced in rats, a well-established model of multiple sclerosis (Smith et al, Nature Medicine)6: 62(2000)). In addition, AMPA and NMDA receptors in the spinal cord have been implicated in bladder and urinary tract contractions, suggesting that AMPA antagonists may be useful in the treatment of urinary incontinence (Nishizawa et al, adv.in exp.med.& Biol. 4：275(1999))。

2 derivatives GYKI52466 of 2, 3-benzodiazepine * (see above) and (R) -7-acetyl-5- (4-aminophenyl) -8, 9-dihydro-8-methyl-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine * (GYKI 53773, also known as talnpanel) is beneficial. The latter has been shown to be active in clinical trials in epileptic patients (Bialer et al, Epilepsy Res.43：11(2001))。

In addition, GYKI52466 has been reported to inhibit the growth of selected tumor cell types (colon adenocarcinoma, astrocytoma, breast cancer, lung cancer and neuroblastoma) (Rzeski et al, Proc. Nat. Acad. Sci.98: 6372 (2001)).

Summary of The Invention

The present invention relates to novel 2, 3-benzodiazepine * derivatives of formula (I) below, their isomers and their acid addition salts, and to pharmaceutical compositions containing them,

wherein the substituents have the following meanings:

R³represents a substituted or unsubstituted 5-or 6-membered aromatic, saturated or partially saturated heterocyclic ring containing at least 2 heteroatoms, which may be oxygen, sulphur or nitrogen atoms, and when the heterocyclic ring contains 2 heteroatoms, one of which is not nitrogen;

R⁴，R⁵，R⁶and R⁷Independently of one another, represents a hydrogen atom, a halogen atom, C₁-C₃Alkyl, nitro or amino, where the amino groups can be substituted independently of one another by 1 or 2 of the following groups: c₁-C₃Alkyl radical, C₂-C₅Acyl or C₂-C₅Alkoxycarbonyl, or aminocarbonyl, or C₂-C₅An alkylaminocarbonyl group; and is

R⁹Represents C₁-C₃An alkoxy group or a halogen atom, or a salt thereof,

R¹⁰represents a hydrogen or halogen atom or

R⁹And R¹⁰May be taken together to form C₁-C₃An alkylenedioxy group.

Representative compounds include, but are not limited to, (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-propyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- {5- [1- (1E) -propen-1-yl ] -1, 3, 4-thiadiazol-2-yl } -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; and (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * and acid addition salts thereof.

The invention also discloses a composition containing the active ingredientA pharmaceutical composition of a compound of the formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvent, diluent, carrier and filler, wherein R³-R⁷、R⁹And R¹⁰Are as defined herein.

The compounds are useful for treating conditions associated with muscle spasms, epilepsy, acute and chronic forms of neurodegenerative diseases, and for preventing, treating or ameliorating the symptoms of acute and chronic inflammatory diseases.

Referring to a number of publications relating to the extended therapeutic value of AMPA type receptor antagonists, those skilled in the art will appreciate that the compounds of the present invention may be used in a very wide variety of unrelated conditions.

Thus, methods of treating glutamate dysfunction associated with acute or chronic neurodegenerative diseases or in acute or chronic eye diseases associated with glutamate dysfunction are provided. Representative neurodegenerative diseases include, for example, cerebral ischemia (stroke), brain and spinal cord injury, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, essential tremor, Parkinson's disease, multiple sclerosis, and urinary incontinence. Acute or chronic eye diseases associated with glutamate dysfunction include glaucoma or diabetic retinopathy. Also disclosed are methods of treating epilepsy, reducing muscle spasms, reducing pain, or inflammatory diseases comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention. Included among the inflammatory diseases are allergic inflammatory diseases of the airways, which may include allergic rhinitis, intrinsic or extrinsic bronchial asthma, acute or chronic bronchitis, chronic obstructive pulmonary disease, and pulmonary fibrosis.

Detailed Description

The patents, published applications and scientific literature cited herein establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the event of any conflict between any reference cited herein and a particular teaching of this specification, the latter should be taken as a control. Likewise, if any conflict arises between a definition of a word or phrase, as understood in the art, and a definition of the word or phrase specifically taught in the present specification, the latter shall prevail.

The present invention discloses novel substituted 2, 3-benzodiazepine * derivative compounds and methods for their production. Also disclosed are pharmaceutical compositions employing the novel substituted 2, 3-benzodiazepine * derivative compounds and their use in treating a number of disease conditions.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Reference is made herein to various methods and materials known to those skilled in the art. Standard references which illustrate the general principles of pharmacology include Goodman and Gilman' sThe Pharmacological Basis of Therapeutics，10^thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to the skilled person may be used to implement the present invention. However, preferred materials and methods are described. Unless otherwise indicated, materials, reagents and the like referred to in the following specification and examples are commercially available.

As used in this specification, the singular forms "a", "an" and "the" include also the plural forms of the terms they refer to, unless the meaning is clearly excluded. For example, "antagonist" includes mixtures of antagonists.

As used in this specification, the term "comprising" shall be understood to have an open-ended meaning, whether in the transitional phrase or in the claims. That is, the term should be understood as being synonymous with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may also include other steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or components, but may also include other features or components.

The term "about" is used herein to mean about, left-right, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" is used herein to modify a numerical value by a deviation of 20% above and below the stated value.

As used herein, unless otherwise specified, the use of the word "or" having "and/or" includes "means rather than" or "excluding" means.

As used herein, the recitation of a numerical range for a variable is intended to mean that the invention can be practiced using the same variable as any value within the range. Thus, for a variable that is discrete in nature, the variable may be equal to any integer value of a range of values, including the endpoints of the range. Similarly, for a variable that is continuous in nature, the variable may be equal to any real value of a range of values, including the endpoints of the range. As an example, a variable described as having a value between 0 and 2 may be 0, 1 or 2 for a variable that is discrete in nature and 0.0, 0.1, 0.01, 0.001 or any other real value for a variable that is continuous in nature.

The methods of the invention are intended for use with any mammal that may benefit from the methods of the invention. Of such mammals, humans are preferred, although the invention is not intended to be so limited and may be used for veterinary purposes. Thus, according to the present invention, "mammal" or "mammal in need thereof" includes humans as well as non-human mammals, particularly domesticated animals including, but not limited to, cats, dogs, and horses.

It is to be understood that the subject to whom the compounds of the invention are administered need not have a particular state of injury. Indeed, the compounds of the present invention may be administered prophylactically prior to any occurrence of symptoms. The terms "therapeutic", "therapeutically" and variations of these terms are intended to encompass therapeutic, palliative and prophylactic applications. Thus, as used herein, "treating or alleviating a symptom" refers to alleviating, preventing, and/or reversing the symptoms of a subject to which a compound of the present invention has been administered, as compared to the symptoms of a subject not receiving such administration.

Benzodiazepine * of formula (II) below, and its isomers and acid addition salts thereof, are the subject of patent application No. 10/358,053:

(II)

wherein

R¹And R²Independently of one another, represents a hydrogen atom or C₁-C₃An alkyl group, a carboxyl group,

R³represents a substituted or unsubstituted 5-or 6-membered aromatic, saturated or partially saturated heterocyclic ring containing at least 2 heteroatoms, which may be oxygen, sulfur or nitrogen atoms, and when R³When it is a 5-membered ring, one of the heteroatoms is not nitrogen;

R⁴，R⁵，R⁶、R⁷and R⁸Independently of one another, represents a hydrogen atom, a halogen atom, C₁-C₃Alkyl, nitro or amino, where the amino groups can be substituted independently of one another by 1 or 2 of the following groups: c₁-C₃Alkyl radical, C₂-C₅Acyl or C₂-C₅Alkoxycarbonyl, or aminocarbonyl, or C₂-C₅An alkylaminocarbonyl group;

R⁹represents C₁-C₃An alkoxy group or a halogen atom, or a salt thereof,

R¹⁰represents a hydrogen or halogen atom, or

R⁹And R¹⁰May be taken together to form C₁-C₃An alkylenedioxy group.

The present invention relates to 2, 3-benzodiazepine * derivatives of formula (II) as shown in formula (I) below:

wherein R is¹And R⁸Is hydrogen, R²Is CH₃，R⁴、R⁵、R⁶、R⁷、R⁹And R¹⁰Has the meaning as defined above, R³Is a group selected from: substituted or unsubstituted isoxazole, isothiazole, thiazole, thiazoline, 4-thiazolinone, oxazole, oxazoline, 1, 2, 3-thiadiazole, 1, 3, 4-thiadiazolin-2-one, 1, 2, 4-thiadiazolin-3-one, 1, 4, 2-oxathiazoline, 1, 3, 4-oxadiazole, 1, 2, 3-triazole, 1, 3, 4-triazole, 1, 2,3, 4-thiatriazole, tetrazole, 1, 3-thiazin-4-one, and 1, 3, 4-thiadiazin-4-one rings.

Heterocyclic substituents R of the benzodiazepine * ring³Further may be substituted-among others-with one or more of the following substituents: c₁-C₆Alkyl radical, C₂-C₃Alkenyl radical, C₃-C₇Cycloalkyl, trifluoromethyl, C₁-C₃Alkoxy or phenyl, oxo, formyl, carboxy or C₂-C₄Alkoxycarbonyl, C₁-C₃Alkoxymethyl, hydroxymethyl (wherein the hydroxy group may be alkylated or acylated), C₁-C₃Alkylthiomethyl, cyanomethyl or aminomethyl (wherein the amino group may be alkylated or acylated).

The meaning of alkyl includes straight and branched chain alkyl groups. Alkenyl can mean vinyl, 1-propenyl, or 2-propenyl. The meaning of the halogen atom may be a fluorine, chlorine, bromine or iodine atom. The amino group may be unsubstituted or substituted with 1 or 2 alkyl groups, and acylated with an aliphatic or aromatic carboxylic acid or any kind of carbonate.

In the case of compounds of formula (I), the term "isomers" refers to both enantiomers, and where applicable, E and Z isomers, and, furthermore, isomers shall include diastereomers, tautomers, and mixtures thereof, e.g., racemic mixtures.

Salts of the compounds of the formula (I) relate to physiologically acceptable salts with inorganic or organic acids. Suitable inorganic acids may be, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. Suitable organic acids may be, for example, formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid or methanesulfonic acid.

Representative compounds of formula (I) include, but are not limited to, (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-propyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- {5- [1- (1E) -propen-1-yl ] -1, 3, 4-thiadiazol-2-yl } -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; and (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * and acid addition salts thereof.

The compounds of formula (I) and (II) may be prepared in the following manner. Starting from the compound of formula (III) below, the construction corresponding to R³The heterocyclic ring of (a):

wherein R is¹-R¹⁰Are as defined in formulae (I) and (II) above,

the following iso chromenium salts of formula (IVa) wherein R is formed by known methods or compounds of formula (IV) or from compounds of formula (IV)¹，R²，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹And R¹⁰The meaning of (a) is as defined above:

reacting a compound of formula (IV) or (IVa) with a compound having formula (V) or (VI):

H₂N-NH-R³ H₂N-NH-R¹¹

(V) (VI)

wherein R is³Are as defined above, and R¹¹Has the meaning of C₂-C₈An alkoxycarbonyl group or an arylalkoxycarbonyl group,

to obtain the compound of formula (VII) or (VIII).

Converting the hydroxy group of the compound of formula (VII) or (VIII) to a sulfonate and ring closure of the latter intermediate by application of a strong base to give the compound of formula (I), (II) or (IX):

alternatively, the compounds of formula (VII) or (VIII) are converted into compounds of formula (I), (II) or (IX) according to Mitsunobu (Synthesis, I: 1 (1988)). In the compounds of the formula (IX), R is cleaved¹¹And (III) to give a compound of formula (III) which is converted to a compound of formula (I) or (II) according to the process described above. Then, if desired, in the compound of formula (I) or (II) obtained according to any one of the above-mentioned processes, the nitro group is reduced, or the amino group is acylated, alkylated, or, after diazotization, exchanged for a halogen atom or a hydrogen atom, or a halogen atom is exchanged for an amino group, in such a way that it is converted into another compound of formula (I) or (II) and/or the isomer is isolated, if desired, salified.

The compounds of the formulae (III) and (IX) are chiral compounds, and thus the formulae (A), (B), (CIII) and (IX) refer to any single enantiomer or a mixture thereof. The hemiketal-type compounds of formula (IV) and the hydrazone derivatives of formulae (VII) and (VIII) represent different stereoisomers, which are meant to be all individual stereoisomers and mixtures thereof. R¹¹The radical may be C₂-C₈An alkoxycarbonyl group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group.

The starting materials of formula (III) are known from the literature (us patent No. 5,536,832 and british patent No.2,311,779, and WO 97/28135 and WO 01/04122). The synthesis of optically active compounds of formula (III) is also described in hungarian patent No. 219,777 and british patent No.2,311,779.

For example according to Anderson et al (j.am. chem. soc) in the presence of catalytic amounts of acid.117: 12358(1995)) hemiketals of formula (IV) prepared from optically active substituted phenyl-isopropanol can be synthesized by reaction with alkoxycarbonyl-hydrazides (e.g., tert-butoxy-carbamate) containing easily removable alkoxycarbonyl groups. The hydrazone of formula (VIII) obtained after isolation is then converted into the methanesulfonyl ester with methanesulfonyl chloride, for example in the presence of triethylamine, the latter being treated, for example in an alcoholic solution, with a base, for example sodium hydroxide, to yield the benzodiazepine * derivative of formula (IX) in a ring closure reaction. The substituent of the N-3 atom (numbered according to the benzodiazepine * ring) is then cleaved, for example by hydrolysis or other methods such as hydrogenolysis, to produce the desired compound of formula (III). Cleavage of the tert-butoxycarbonyl group can be carried out using trifluoroacetic acid, hydrogen bromide or zinc bromide in dichloromethane.

The heterocyclic moiety (with R) of the compounds of formula (I) or (II) is synthesized starting from the compound of formula (III) according to methods known in the art relating to heterocyclic chemistry³Substituents correspond).

Some compounds of formula (I) or (II) may be synthesized, for example, from 4, 5-dihydro-2, 3-benzodiazepine * derivatives substituted with a thiocarbamoyl group at the 3-position of the benzodiazepine * ring. The latter compound may be obtained from a 4, 5-dihydro-3H-2, 3-benzodiazepine * derivative of formula (III), for example using potassium thiocyanate in acetic acid medium. The 4, 5-dihydro-3-thiocarbamoyl-3H-2, 3-benzodiazepine * thus obtained is reacted with an alpha-haloketone or alpha-haloacetal to give a 2, 3-benzodiazepine * derivative having a substituted or unsubstituted 2-thiazolyl group. In a similar reaction, if a 2-halocarboxylate is used instead of an α -halooxo-compound, a suitable compound containing a 3-thiazolinone ring may be formed.

When the above-mentioned 4, 5-dihydro-2, 3-benzodiazepine * containing a thiocarbamoyl group at the 3-position is reacted with a β -halocarboxylic acid ester (e.g., ethyl 3-bromopropionate), then a novel 2, 3-benzodiazepine * derivative substituted with a 5, 6-dihydro- [1, 3] thiazin-4-one ring can be obtained.

Can synthesize a compound containing 1, 3, 4-thiadiazole group as R³The compound of formula (I) or (II) as a substituent is, for example, by the following means. First, from the formula (III)4, 5-dihydro-3H- [2,3]Benzodiazepine * produces trimethylsilyl derivatives which are then reacted with thiophosgene to produce thiocarboxylic acid chlorides. Finally, the latter is treated with hydrazine to form the thiocarboxylic acid hydrazide derivative. Reacting a 2, 3-benzodiazepine * derivative substituted with a carbothiohydrazide group with an acid anhydride or acid chloride, promoting the partial ring closure of the carbothiohydrazide thus obtained by further acid treatment to form [1, 3, 4]]Thiadiazolyl-2, 3-benzodiazepine *. Another method for synthesizing the latter compound is to react the above-mentioned intermediate thiocarboxylic acid chloride with an acid hydrazide and then treat the resulting carbothiohydrazide derivative having an acyl group on the terminal N-atom with an acid to form a cyclic product.

In a similar reaction, for example, if the above-described N-acyl-thiocarboxylic acid hydrazide derivative is treated with a sulfur binding reagent such as mercury (II) acetate, a benzodiazepine * of formula (I) or (II) containing a [1, 3, 4] oxadiazole ring can be obtained.

4, 5-dihydro-2, 3-benzodiazepine * -3-carbothiohydrazide useful as other novel compounds of formula (I) or (II) substituted with heterocycleThe raw materials of the compound. For example, if N-methyl-carbamoyl-carbothiohydrazide obtained from methyl isocyanate is heated with a concentrated acid (e.g., hydrochloric acid), then the compound is obtained as (5-oxo-4, 5-dihydro- [1, 3, 4)]Thiadiazol-2-yl) groups, and to novel compounds of formula (I) or (II). If the carbothiohydrazide derivative is reacted with bromoacetate, a compound having a 6-membered ring as R can be obtained₃(5-oxo-5, 6-dihydro-4H- [1, 3, 4) of substituent]Thiadiazin-2-yl) - [2,3]Benzodiazepine * derivatives. If the carbothiohydrazide derivative is reacted with an alpha-halo-ketone, for example chloroacetone, it is possible to form, for example, (5-methyl-6H- [1, 3, 4)]Thiadiazin-2-yl) - [2,3]Benzodiazepines *.

Hydroxylamine can be used to obtain the appropriate thiohydroxamic acid from the [2,3] benzodiazepine * -3-thiocarboxylic acid chloride, which can be converted to a heterocyclic compound by reaction with a bifunctional alkylating agent. Furthermore, [1, 4, 2] oxathiazol-3-yl-2, 3-benzodiazepine * may be synthesized from thiohydroxamic acid derivatives, for example, using diiodomethane.

Can prepare the compound containing 3-oxo-2, 3-dihydro- [1, 2, 4]Thiadiazol-5-yl radicals as R³Compounds of formula (I) or (II) for a substituent, for example, by reacting an unsubstituted compound of formula (III) with phenoxycarbonyl isothiocyanate and then converting the resulting phenoxycarbonyl-thiocarbamoyl-benzodiazepine * with a primary amine to an N-alkyl-carbamoyl-thiocarbamoyl-benzodiazepine * which is reacted with, for example, bromine to complete the ring closure between the sulfur and nitrogen atoms.

Synthesis of compounds containing a 4, 5-dihydro-oxazol-2-yl group as R by reacting a compound of formula (III) with chloroethyl isocyanate to form a urea derivative, followed by heating in dimethylformamide in the presence of sodium iodide and potassium carbonate to complete ring closure³A compound of formula (I) or (II) as a substituent.

By reacting 3-bromo-acetyl- [2,3]Benzodiazepines * containing a 2-alkyl-thiazol-4-yl group as R can be synthesized by reaction with a suitable carboxylic thioamide³A compound of formula (I) or (II) as a substituent.

From 3-cyano-2, 3-benzodiazepine * (obtained from 2, 3-benzodiazepine * of formula (III) using cyanogen bromide), it is possible to synthesize compounds containing, inter alia, (1H-tetrazol-5-yl) and (5-alkyl- [1, 2, 4-)]Oxadiazol-3-yl) radical as R³Substituted 2, 3-benzodiazepine *. Tetrazolyl compounds can be synthesized by reacting a nitrile derivative with sodium azide in dimethylformamide in the presence of ammonium chloride, while suitable 1, 2, 4-oxadiazolyl compounds can be obtained if the nitrile compound is first treated with hydroxylamine and the amidoxime thus obtained is reacted with a carboxylic anhydride or acid chloride.

Can be prepared from 3-thiocarbamoyl- [2,3] by first reacting with methyl iodide]Synthesis of benzodiazepine * derivatives containing a1, 2, 4-triazolyl group as R³A compound of formula (I) or (II) for a substituent, followed by condensation of the resulting S-methyl compound with hydrazine, and treatment of the intermediate thus formed with a carboxylic anhydride or acid chloride.

Other exemplary methods of synthesizing compounds of formula (I) or (II) are those wherein a hemiketal of formula (IV) is reacted with a heterocyclic reagent substituted with a hydrazine group in the presence of an acid catalyst. The condensation reaction may be carried out by heating, for example in isopropanol or toluene, in the presence of hydrochloric acid as catalyst, and possibly using a Dean-Stark apparatus. In some cases, it is advantageous to first convert the hemiketal into the isochromenium salt of formula (IVa) with a mineral acid such as perchloric acid, which is reacted with a hydrazine reagent, for example in isopropanol. The hydrazones of formula (VII) thus obtained usually form a mixture of stereoisomers. They can be reacted further, for example with methanesulfonyl chloride in dichloromethane in the presence of triethylamine, and the methanesulfonate obtained after isolation is treated with a concentrated solution of a base in an alcohol or a mixture of the alcohols dichloromethane. By, for example, Mitsunobu reaction (Mitsunobu Synthesis)11(1981)), a ring closure reaction can be achieved.

If desired, the compounds of the formula (I) or (II) obtained by different processes can be reacted with one another) The compounds are converted to other compounds of formula (I) or (II). For example, a heterocyclic ring (R)³Substituent) for the exchange of the reactive halogen atom in the side chain for an amino group, for example by heating with an excess of a suitable amine, or the NH group of an N-containing heterocyclic compound may be alkylated by known methods. The latter conversion can be effected with methyl iodide in the presence of potassium tert-butoxide, for example in the case of triazolyl compounds.

The reduction of the nitro group in the compound of formula (I) or (II) is generally carried out in a polar solvent in the presence of a catalyst such as Raney nickel, platinum or palladium at room temperature or elevated temperature. In addition to gaseous hydrogen, other sources of hydrogen may be used, such as hydrazine hydrate, ammonium formate, potassium formate or cyclohexene. The nitro group can be reduced, for example using tin in the presence of an acid, or by heating in an alcohol using tin (II) chloride. The amino group may be further derivatized by known methods, such as alkylation, acylation or Sandmeyer reaction.

The AMPA antagonistic activity of the compounds of formula (I) or (II) according to the invention is illustrated by the following experiments. The compounds referred to by number refer to the compounds described in the examples numbered below.

Inhibition of AMPA receptors

2 experimental models were used to confirm the inhibition of AMPA receptor activation by the compounds of formula (I) or (II). In the first model, the spreading inhibition caused by glutamate agonists (i.e. AMPA or kainate) was studied, while in the second model, transmembrane ion currents induced by AMPA/kainate receptor activation were directly examined.

Inhibition of AMPA-induced "spreading depression" in isolated chicken retinas

In vitro "spreading depression" model (Sheardown Brain Res.607: 189(1993), the AMPA antagonist action of the compounds of formula (I) or (II) was studied. AMPA antagonists prolong the onset of the "spreading depression" caused by AMPA (5. mu.M)The latency of (2).

TABLE 1

Inhibition of "spreading depression" in chicken retina

Compounds (example numbers)/IC50μM
						GYKI52466 (ref.)	GYKI53773 (REFERENCE)	61	69	86	84
9.5	1.2	1-5	0.9	0.42	0.85

The data in Table 1 show that the compounds of the invention inhibit AMPA-induced "spreading depression", IC₅₀The value is 0.4-5. mu.M.

Inhibition of AMPA-induced transmembrane current

According to for example Bleakman et al (Neuropharmacology)12: 1689(1996)) the activity of the compounds of the invention was studied on acutely isolated cerebellar purkinje cells by measuring 5 μ M AMPA-induced whole cell current. According to the obtained IC₅₀The compounds of the invention are capable of inhibiting AMPA-induced ion current, compared to internationally recognized IC₅₀Reference compound GYKI52466 (5- (4-aminophenyl) -9H-1, 3-dioxolo [4, 5-H) with values of 8.8. mu.M and 1.57. mu.M, respectively][2，3]-benzodiazepine *, Hungarian patent No. 191698) or GYKI53773 ((R) -7-acetyl-5- (4-aminophenyl) -8, 9-dihydro-8-methyl-7H-1, 3-dioxolo [4, 5-H ]][2，3]Benzodiazepine *, U.S. Pat. No. 5,536,832) is 1 to 2 orders of magnitude greater (see table 2).

Table 2.

Inhibition of ionic current caused by 5 μ M AMPA by whole cell patch clamp method System for making

Compounds (example numbers)/IC50μM
						GYKI52466 (ref.)	GYKI53773 (REFERENCE)	61	69	86	84
8.8	1.57	0.49	0.42	0.06	0.09

Anticonvulsant activity

Although a variety of drugs with different activity spectra are used in the treatment of epilepsy, they exhibit serious side effects. Moreover, about 30% of epileptic patients will be resistant to these drugs. As a result, there is a need for new antiepileptic drugs that act through a different mechanism than currently used drugs. For thoseCompounds that exhibit their activity by reducing glutamate-induced central nervous system overactivation are highly desirable (TIPS,15：456(1994))。

an electric shock experiment (j. pharmacol. exp. ther) was used.106: 319(1952)), some of the compounds of the invention were tested for their anti-seizure activity, and the results are shown in Table 3. Penta-tetraaza (j. pharmacol. exp. ther) is used, for example, for inducing clonic seizures and lethality.108: 168(1953), strychnine (j. pharmacol. exp. ther.129: 75(1960), bemetger, nicotine, bicuculline, 4-aminopyridine and mercapto-propionic acid, the spasmolytic activity of the compounds of the invention was investigated. The study compound was administered orally at 3 doses, each using 10 male CD1 mice, typically 60 minutes prior to induction onset. Non-limiting, explanatory results are summarized in table 3.

TABLE 3

Study of anticonvulsant Activity in mice

Method of producing a composite material	Compounds (example numbers)/ED50mg/kg po.
									GYKI52466	GYKI53773	61	69	86	84	89	102
	MES	37.4	8.6	13.1	14.7	6.1	12.5	10.5									13.9
MES 30’									21.9	4.9	11.5	8.7	4.3	10-15	-	-
	Penta tetra nitrogen	119.8	16.8	32.5	46.9	10.0	17.1	11.5									35.7
Strychnine									86.7	17.4	35.4	27.7	10.6	18.2	15.7	26.7
	Beimege	71.9	23.9	34.4	33.3	11.2	16.7	11.2									27.9
Dicentrine									35.0	14.6	31.0	18.1	4.6	17.0	17.1	25.8
	Nicotine	71.8	22.7	59.3	16.8	16.5	77.2	45.9									31.7
4-AP									43.0	8.4	17.6	16.6	10.1	16.6	14.3	20.4
	3-MPA	47.0	17.1	11.0	34.2	4.0	6.8	＞50									＞50

Abbreviations: MES ═ maximal electroshock onset; 4-AP ═ 4-aminopyridine; 3-MPA ═ 3-mercapto-propionic acid

The above data indicate that the compounds of formula (I) or (II) of the present invention exhibit significant anticonvulsant activity in all 8 studies. They exhibit a broader spectrum and a more pronounced anticonvulsant efficacy compared to GYKI52466 and GYKI53773, which are used as reference compounds in the literature. The protective effects exhibited by different convulsant inducers are advantageously predictive of their potential use in the treatment of different classes of epilepsy.

Muscle relaxant activity

Central muscle relaxants are used in clinical situations where the resting tension of skeletal muscles is increased, resulting in muscle rigidity or tremor, either due to brain injury or due to chronic neurodegenerative disease. Muscle spasms are often painful and can interfere with normal movement.

Pour screen experiments described in Randall (j. pharmacol. exp. ther.129: 163(1960)) and in rotarod experiments (Dunham et al, j.am.pharm.assoc.46: 208(1957)), the compounds of the present invention represented by the formula (I) or (II) were examinedMuscle relaxant activity of the compounds. Compounds were administered intraperitoneally at 3 doses using 10 CD 1-mice per dose. The muscle relaxant activity of the compounds of the invention was compared to that of the reference compounds GYKI52466 and GYKI 53773. Representative, non-limiting results are summarized in table 4. From these data, it can be seen that the muscle relaxant activity of the compounds of the invention significantly exceeded that of GYKI53773, which is now in phase II clinical studies.

TABLE 4

Muscle relaxant activity in mice

Compounds (example No.)	Inclined sieve ED50Intraperitoneal (mg/kg)	RotarodED50Intraperitoneal (mg/kg)
			GYKI52466 (ref.)	47.1	25.1
GYKI53773 (REFERENCE)	13.4	2.3
			61	10.7	5.4
69	12.2	1.2
			86	3.9	0.8
84	12.8	1.4
			89	4.3	1.7
102	14.8	2.9

The muscle relaxant activity of the compounds of formula (I) or (II) as tested in the above experiments indicates potential therapeutic use in the treatment of diseases where increased muscle tone can be problematic. Given their skeletal muscle relaxation and anti-tremor activity (discussed below), the compounds may be used to treat essential tremor, multiple sclerosis (spasm + tremor) and parkinson's disease (rigidity + tremor).

Suppression of ischemia

By the "middle cerebral artery occlusion" (MCAO) experiment (Bartus Stroke)11: 2265(1994), and Sydserff et al, Brit.J. Pharmacol.114: 1631(1995)), the compounds of formula (I) or (II) of the present invention were tested for their anti-ischemic activity. After halothane anaesthesia, the blood supply to the left middle cerebral artery of anaesthetised rats was temporarily blocked (60 minutes) by an intra-arterial introduction of emboli, after which the emboli were removed and perfusion was re-established, thus triggering a human "stroke-like" state in the experimental animal model. After 24 hours of histological processing (TTC staining), infarct size was determined by computer-assisted scanning procedure and compared with the results obtained with vehicle-treated control group. Non-limiting, representative results are summarized in table 5.

Table 5.

Inhibition of ischemia in rats

Compounds (example No.)	Dose mg/kg intravenous (6X, every 30 minutes)	Reduction in infarct size compared to control group%
					30 minutes	120 minutes	180 minutes
				Time to first treat after occlusion
GYKI52466 HCl (ref.)	2							39*
			5	34*	47**
GYKI53773 (REFERENCE)	2						47*	49**	26
		61	1		63**	16
	2								46*
		69	2			28
86	1								35*

P < 0.05; p < 0.01; dunnett test calculations (Dunnett j. amer. statist. ass) were performed according to ANOVA.50：1096(1955))

The compounds studied had a strong neuroprotective activity in this experimental model, considered a model of human stroke. Some compounds, such as those described in examples 61 and 86, exhibited significant activity even when administered 3 hours post-occlusion, suggesting a potentially useful clinical application.

Inhibition of autoimmune inflammation

Multiple sclerosis is a chronic autoimmune inflammation of the central nervous system in which the myelin sheath of axons, which ensures safe impulse conduction, is destroyed. Oligodendrocytes forming the myelin sheath primarily express the AMPA/kainate receptor. Thus, glutamate (excitatory neurotransmitter), which is released in large amounts by activated immune cells expressing its activity via the AMPA/kainate receptor, further augments the neurodegenerative process, thereby destroying myelin oligodendrocytes and neuronal axons (Steinman Nature Medicine)6: 15(2000) and Werner et al, J.Neurol.Transmiss.Suppl,60: 375(2000)). As a result of these processes, mild neurological symptoms (e.g., visual, sensory, balance, movement, and urogenital problems) initially develop, gradually aggravating. The treatment of multiple sclerosis remains an unsolved problem despite intensive research in the art (Bjartmar et al, Drugs of Today)38：17(2002))。

Muscular spasticity and intention tremor are of multiple sclerosisThe most severe neurological symptoms (Baker et al, Nature)404: 84(2000)). It is very important to alleviate or cure these symptoms by appropriate therapy.

Immunization with guinea pig Myelin Basic Protein (MBP) and complete freund's adjuvant has been shown to be effective in the autoimmune encephalomyelitis model in rats (Smith et al, Nature Medicine,6: 62(2000)) the activity of 2, 3-benzodiazepine * derivatives having AMPA antagonist activity was further investigated. Compounds were administered intraperitoneally 2 times daily for 8 days starting on day 10 post-immunization and observed during the period of symptom presence. 5-15 animals were used in each group. Their weights were 160-180g (Lewis rat, female) and 180-220g (Lewis rat, male). The activity of the compounds was determined from the symptom score values and compared to the control group (see table 6). Histopathological studies were performed on the brainstem, spinal cord and sciatic nerve using 5-10 animals/group (Gijbels et al, j.94: 2177(1994)). Non-limiting, representative results are shown in table 7.

Table 6.

2, 3-benzodiazepine * with AMPA antagonist Activity on Lewis rat autoimmunity Effect of clinical symptoms of immune encephalomyelitis

Compounds (example No.)	Dosage (mg/kg intraperitoneal)	Neurological symptoms (change compared to control,%)
						Female rat 0-8 days	0-14 days	Male rat for 0-8 days	0-14 days
		GYKI53773 (REFERENCE)	3015	-38*-60*	-27-63**					-43*-8	-29+7
GYKI52466 (ref.)	30					-45	-4	-1	-1
		86	157.53.751.875	-97**-62**-3-40*	-85**-66**-18-39*					-93*-65**-70**+5	-67-70**-77**-8
61	7.53.751.875					-56*-44-18	-53*-48-7	-60*-44*+13	-63**-46*+5
		69	7.53.75	-29+43	-24+58*					-51*+35	-50*-40*

P < 0.05; p < 0.01(Mann-Whitney test)

Table 7.

2, 3-benzodiazepine * derivatives with AMPA antagonist characteristics were administered 24 days after immunization Effect of histological and clinical symptoms of autoimmune encephalomyelitis in Lewis rats

Compounds (example No.)	Dosage (mg/kg intraperitoneal)	Histological symptoms (change,%)		Neurological symptoms (changes,%)
						Rat male	Female	Rat male	Female
		GYKI53773 (REFERENCE)	30	+34	-16					-26	-41
86	157.53.751.875					-66+1+4-25	-53-22-20-15	-67-66-72+54	-85-62-21-42
		61	7.5	-20	-5					-54	-53

Based on our histopathological and pharmacological studies, it was confirmed that the compounds described in examples 86 and 61, for example, are more active than the reference compound GYKI 53773.

There are 3 different mechanisms of action of the tremorogenic agent, such as oxotremorine (Rathbun et al, psychopharmacogology,4: 114(1963)), GYKI 20039(3- (2, 6-dichlorophenyl) -2-ylideneAn amino-thiazolidine; (Andr si et al, Acta physiol.37: 183(1970)) and hamalin, the anti-tremor effect of the 2, 3-benzodiazepine * derivatives of the invention, which have AMPA antagonist characteristics, was studied in a mouse model. Animal number: 5/group. Animal weight: 20-25g (CD1 mouse, male). The activity of the compounds studied was examined by comparing their fractional values with those of the control group. ED was calculated according to the method of Litchfield-Wilcoxon₅₀Values as listed in table 8.

Table 8.

2, 3-benzodiazepine * derivatives with AMPA antagonist characteristics for different chemistries Effect of agent-induced tremor in CD1 mice

Compounds (example No.)	Dosage range (mg/kg p.o.)	ED50(mg/kg po.)
					Oxygradixin 1mg/kg intraperitoneal	GYKI 2003910mg/kg intraperitoneal	Hamalin 40mg/kg intraperitoneal
		GYKI52466 (ref.)	6.25-75.0	20.5(14.9-28.3)				37.1(25.2-54.7)	38.5(25.7-57.9)
GYKI53773 (REFERENCE)	3.125-20.0				5.6(3.6-8.5)	10.6(7.2-15.5)	9.0(-7.4-10.9)
		86	3.125-9.0	4.3(3.5-5.4)				6.8(5.5-8.5)	6.0(4.9-7.4)

According to our studies, the compound described in example 86 is more active than the reference compounds GYKI53773 and GYKI52466, respectively.

It is therapeutically important that 2, 3-benzodiazepine * derivatives, which are characterized as AMPA antagonists, compensate for the deleterious effects of glutamate by blocking the corresponding receptor. Their combined neuroprotective, muscle relaxant, tremor suppressive properties can beneficially affect the progression of pathological neurological diseases and alleviate pathological neurological symptoms, respectively.

Effect of Compounds of the invention on acute and chronic airway inflammatory diseases

Bronchial Hyperresponsiveness (BHR) and Airway Eosinophilia (AEP) are characteristic of bronchial asthma. BHR is characterized by an excessive response to a variety of stimuli, which can induce an increase in resistance to airflow in the airway. AEP is the result of prolonged eosinophil infiltration, mast cell and T cell activation in the airways. In actively (e.g., ovalbumin) immunized rats (e.g., brown norway [ BN ] strain), repeated sensitization followed by antigenic challenge results in pulmonary eosinophilia and bronchial hyperreactivity to different spasmogens (e.g., acetylcholine). This is the most commonly used model for studying the potential antiasthmatic effect of new chemical entities.

BN rats were actively immunized with allergen (ovalbumin). On the first day, subcutaneous administration suspended in Al (OH)₃Ovalbumin (2.5. mu.g ovalbumin +20mg Al (OH)₃In 0.5ml saline) sensitized rats. On days 14 and 21, booster injections (same dose and same route) were performed. At the same time, 0.25ml of Bordetella pertussis (Bordetella pertussis) vaccine was injected intraperitoneally at each time. On day 28, animals were challenged by inhalation of antigen (1% OVA solution vaporized, 1 hour.) experimental compounds were administered orally 2 hours prior to challenge.

48 hours after challenge, they were sacrificed with excess urethane (4-5 ml 15% urethane administered intraperitoneally) to give bronchoalveolar lavage (BALF) and the trachea was excised from the animals. The cell count of eosinophils (cells/ml BALF) was determined manually using a selective dye for eosinophils and counting the cells in a Buerker chamber. BHR was detected using tracheal rings suspended in organ baths. After 30 minutes of equilibrationAnd detecting the response curve of the cumulative concentration of the acetylcholine. At 10^-3M acetylcholine, the maximum response of the control (non-challenged, untreated) tracheal rings was obtained. The height of the reaction was defined as 100%. All other contractions were expressed as a percentage relative to the control response.

Results

Table 9.

GYKI52466 (REF.), GYKI53773 (REF.), and the combinations described in example 86 The substance is used for the airway of BN-rat sensitized by ovalbumin and subjected to antigen attack by inhalation The effects of bronchial hyperreactivity and eosinophilia (mean. + -. standard error, general) P was determined by Student's t-test).

				Compounds (example No.)
					Experiment of	Parameter(s)	Control	Attack of	GYKI52466 (REF.) 3.0mg/kg po
1	ED50*	5.63±0.46	6.74±1.45	5.60±1.53
					p	0.002		0.028
	MAX**	100±0	276±217	135±105
					p	0.001		0.037
	Eosinophil	0.17±0.01	1.24±0.23	0.91±0.13
					p	0.010		NS*
	Experiment of	Parameter(s)	Control	Attack of					GYKI53773 (REF.) 3.0mg/kg po
2					ED50*	5.22±0.59	5.89±0.66	4.64±0.91
	p	0.003		0.001
					MAX**	100±0	163±65	85±43
	p	＜0.001		0.007
					Eosinophil	0.38±0.11	1.24±0.13	1.29±0.11
	p	0.004		NS*
					Experiment of	Parameter(s)	Control	Attack of	863.0mg/kg po
3	ED50*	5.78±0.17	6.99±0.32	4.95±0.59
					p	0.001		0.008
	MAX**	100±0	255±50	81±14
					p	0.001		0.003
	Eosinophil	0.23±0.08	1.43±0.27	1.32±0.32
					p	0.005		NS*

Concentration of acetylcholine (Ach) (-log M) causing 50% contraction compared to control

Relative contraction at maximum Ach concentration compared to control

Basf eosinophil number (x 10)⁶/ml)

^*Not significant (p > 0.05)

Representative results shown in table 9 indicate that representative compounds according to the present invention reduce bronchial hyperreactivity caused by allergens. Eosinophilia is not significantly affected by the applied dose.

The results of the above-mentioned different pharmacological studies indicate that the compounds of formula (I) or (II) according to the invention can beneficially affect a number of diseases and disorders in which glutamate (AMPA/kainate) receptors are involved. As a result, the compounds of the present invention are useful in the treatment of neurological and psychiatric diseases triggered by profoundly enhanced AMPA receptor activity. They therefore have therapeutic utility as anticonvulsants, muscle relaxants and neuroprotective agents. They also show therapeutic value in the treatment of epilepsy, as well as different diseases in which spasticity of skeletal muscle is involved and in the treatment of neurodegenerative diseases such as cerebral ischemia (stroke).

Exemplary neurological diseases that may be beneficially affected or prevented include parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis, olivopontocerebellar atrophy, AIDS dementia, senile dementia. Similar beneficial effects can be achieved in the treatment of neurodegenerative processes caused by cerebrovascular pathologies (stroke, brain and spinal cord injuries) or hypoxia, anoxia or hypoglycemia. The compounds of the present invention may be advantageously used in the treatment of different psychiatric disorders, such as anxiety, schizophrenia, sleep disorders, and withdrawal syndromes which alleviate alcohol and drug abuse. Furthermore, they can be used to inhibit the development of tolerance in the case of sedatives or analgesics.

It is expected that they may be beneficially used in epileptic patients, to cure or alleviate muscle spasms of central origin, and to alleviate pathological pain and treat urinary incontinence.

In one aspect of the invention, methods of blocking the activation of one or more excitatory amino acid receptors in a mammal are provided. The method comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of formula (I) or (II).

In another aspect of the invention, a method of treating epilepsy in a mammal is provided. The method comprises administering to a mammal in need of such treatment an anti-epileptic amount of a compound of formula (I) or (II).

In another aspect of the invention, a method of treating spasticity of the skeletal muscle system in a mammal is provided. The method comprises administering to a mammal in need of such treatment a muscle relaxing amount of a compound of formula (I) or (II).

In another aspect of the invention, a method of treating acute and chronic neurodegenerative diseases in a mammal is provided. The method comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of formula (I) or (II).

In another aspect of the invention, a method of treating an inflammatory disease in a mammal is provided. The method comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of formula (I) or (II).

In other aspects of the invention, the compounds of formula (I) or (II) may be advantageously used for the treatment of multiple sclerosis. Other therapeutic areas in which the compounds of formula (I) or (II) may be used are diseases caused by an excessive function of peripheral glutamate receptors. Such diseases include acute and chronic inflammatory diseases of the airways, particularly allergic inflammation, e.g. pathologies associated with asthma. The results obtained in ovalbumin sensitized rats support this latter potential therapeutic application.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

Using any of the well-known pharmaceutically acceptable carriers, including diluents and excipients (seeRemington′s Pharma ceutical Sciences，18^thEd, Gennaro, Mack Publishing Co., Easton, PA 1990 andRemington：The Science and Practice of Pharmacy，Lippincott，Williams &wilkins, 1995), formulating the compound of formula (I) or (II) in a pharmaceutically acceptable medium. While the type of pharmaceutically acceptable carrier/vehicle employed in the manufacture of the compositions of the invention will vary with the mode of administration of the composition to a mammal, pharmaceutically acceptable carriers are generally physiologically inert and non-toxic. Preparation of pharmaceutical compositionThe agent may contain more than one type of compound of formula (I) or (II) and any other pharmacologically active ingredient that may be used to treat the particular disorder, disease or condition being treated.

The compositions of the present invention may be administered by standard routes (e.g., oral, inhalation, rectal, nasal, topical, including buccal and sublingual, or parenteral, including subcutaneous, intramuscular, intravenous, intradermal, transdermal and intratracheal). In addition, polymers may be added according to standard methods in the art for sustained release of a particular compound.

For oral administration, the compositions of the present invention may be presented as discrete units, such as capsules, caplets, soft capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient, in powder or granular form; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil-in-water liquid emulsion or a water-in-oil emulsion, and a propellant, etc. Alternatively, compositions comprising a compound of formula (I) or (II) may be administered by liquid solutions, suspensions or elixirs, powders, lozenges, micronized particles and osmotic delivery systems.

Formulations suitable for administration by inhalation include those which can be dispensed by inhalation devices known to those skilled in the art. Such formulations may contain carriers such as powders and aerosols. Also included are liquid and powdered compositions suitable for spray and intrabronchial applications, or aerosol compositions for administration by dispensing metered doses ("MDI") through an aerosol unit.

The active ingredient may be formulated in an aqueous pharmaceutically acceptable inhalation medium such as isotonic saline or bacteriostatic water and other types of media well known in the art. The solution is administered by means of a pump or a spray dispenser that is squeeze-to-effect nebulization, or by any other conventional method for causing or effecting inhalation of a desired dose of a liquid composition into the lungs of a patient.

Exemplary powder compositions include pharmaceutically acceptable powdered formulations wherein the active ingredient is intimately mixed with lactose or other inert powders acceptable for intrabronchial administration. The powder composition may be administered by a dispenser, including but not limited to an aerosol dispenser, or enclosed in a frangible capsule, which the patient may insert into a device that punctures the capsule and blows the powder out in a steady flow manner.

The aerosol formulations used in the subject methods typically comprise a propellant, a surfactant and a co-solvent, and may be filled into conventional aerosol containers which are closed by a suitable metering valve.

Formulations suitable for nasal administration, wherein the carrier is a solid, comprise a coarse powder having a particle size in the range of, for example, 20 to 500 microns which is administered by nasal inhalation, i.e. rapid inhalation through the nasal passage from a powder container raised to the vicinity of the nose. Suitable formulations for administration, for example by nasal spray, aerosol or as nasal drops, wherein the carrier is a liquid, include aqueous or oily solutions of the compounds of formula (I) or (II).

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, stabilizers, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

The dosage of the active ingredient depends on the route of administration, the kind and severity of the disease and the weight and age of the patient. The daily dose for an adult patient may be 0.1-500mg, preferably 1-100mg, in a single dose or divided into several doses.

In another aspect of the invention, there is provided a method for treating: (a) acute or chronic neurodegenerative diseases associated with glutamate dysfunction; (b) methods for treating epilepsy; (c) a method for reducing muscle spasm in a mammal; (d) methods for preventing, treating, or alleviating symptoms of acute or chronic inflammatory diseases of the airways; (e) a method for alleviating pathological pain in a mammal. These methods comprise administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II).

The term "therapeutically effective amount" is used to indicate treatment at a dose effective to achieve the therapeutic result sought. Furthermore, the skilled person will appreciate that the therapeutically effective amount of a compound of the invention may be reduced or increased by fine tuning and/or by administering more than one compound of the invention, or by administering a compound of the invention together with another pharmacologically active compound. Thus, the present invention provides a method of adapting administration/treatment to a particular specific emergency in a particular mammal. As described in the examples below, a therapeutically effective amount can be readily determined, for example empirically by starting with relatively low amounts and increasing stepwise, while evaluating beneficial effects,

it will be appreciated by those skilled in the art that the number of administrations of a compound according to the invention will vary from patient to patient, based on the particular medical condition of the patient at any particular time.

The following examples illustrate the compounds according to the invention and the methods for their preparation in detail.

The following examples serve to further illustrate certain preferred embodiments of the invention and are not limiting in nature. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific materials and methods described herein.

Examples

The starting materials for the examples were synthesized as follows:

(±) -8-methyl-5- (4-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro -7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine * (I)

A mixture of 0.90g (9.26mmol) of potassium thiocyanate, 2.00g (6.15 mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * and 40ml of acetic acid was stirred at 100 ℃ for 6 hours. After cooling, the precipitated crystals were filtered off, washed with water and dried to yield 1.80g (76%) of the title compound. Melting point: 242 ℃ and 243 ℃.

Thiocarbamoyl compounds II-X were synthesized according to the above procedure from the corresponding dihydro- [2,3] benzodiazepine *.

(R) -8-methyl-5- (4-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (II)Melting point: 213-215 ℃. Yield: 73%, [ alpha ]]_D：-251°(c＝0.5；CHCl₃).

(S) -8-methyl-5- (4-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (III)Melting point: 213-214 ℃. Yield: 76%, [ alpha ]]_D：+252°(c＝1；CHCl₃).(±) -8-methyl-5- (3-methyl-4-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (IV)

Melting point: 230 ℃ and 236 ℃. Yield: 86 percent.

(±) -8-chloro-4-methyl- (4-nitrophenyl) -3-thiocarbamoyl-4, 5-dihydro -3H-[2，3]Benzodiazepine * (V)

Melting point: 261 ℃ and 265 ℃. Yield: 72 percent.

(±) -7, 8-dichloro-4-methyl-1- (4-nitrophenyl) -3-thiocarbamoyl-4, 5-bis Hydrogen-3H- [2,3]Benzodiazepine * (VI)

Melting point: amorphous. yield: 59 percent.

(±) -8-methyl-5-phenyl-7-thiocarbamoyl-8, 9dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (VII)

Melting point: 225 ℃ and 235 ℃. Yield: 86 percent.

5- (4-Nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (VIII)

Melting point: 235 ℃ and 238 ℃. Yield: 62 percent.

(±) -8-methyl-5- (4-methyl-3-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (IX)Melting point: 201 ℃ and 202 ℃. Yield: 84 percent.

(±) -7-bromo-4-methyl-8-methoxy-1- (4-nitrophenyl) -3-thiocarbamoyl -3, 4-dihydro-3H- [2,3]Benzodiazepine * (X)

Melting point: 250 ℃ and 253 ℃. Yield: 94 percent.

(+ -) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbothio (carbothio) chloride (XI)

3.25g (10.0mmol) (. + -.) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * were dissolved in 90ml of anhydrous toluene by warming, and after addition of 2.17ml (15.5mmol) of triethylamine, reacted with 1.90ml (15.0mmol) of trimethylsilyl chloride at about 28-30 ℃. After stirring at room temperature for 16 hours, the reaction mixture was added dropwise over about 2 hours to a solution of 1.38g (12.0mmol) of thiophosgene in 30ml of anhydrous toluene. The mixture was stirred at room temperature for 5 hours and then diluted with 30ml of toluene. Then decomposed by adding 30ml of water. After separation, the toluene phase was washed 2 times with 30ml of water and then with 10% aqueous sodium chloride solution. After drying, the solvent was evaporated and the residue was treated with diisopropyl ether to yield 3.27g (81%) of crude product.

The crude product was recrystallized from chloroform, petroleum ether.

Yield: 3.05 g. Melting point: it recrystallizes at about 185 c and then melts at 210 c.

By a similar method, compounds XII to XVII of the C-S-chloride type are synthesized from racemic or optically active dihydro- [2,3] benzodiazepine * derivatives:

(R) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbon-sulfur-based chloride (XII)

Melting point: 187-188 ℃. Yield: 80%, [ alpha ]]_D：-610°(c＝0.5；CHCl₃).

(+ -) -8-methyl-5- (3-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbon-sulfur-based chloride (XIII)

Melting point: 198 ℃ and 199 ℃. Yield: 79 percent.

(+ -) -8-methyl-5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbon-sulfur-based chloride (XIV)

Melting point: 210 ℃ and 215 ℃. Yield: 79 percent.

(+ -) -8-methyl-5- (4-methyl-3-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbon-sulfur-based chloride (XV)

Melting point: 201 ℃ and 202 ℃. Yield: 84 percent.

(±) -8-chloro-4-methyl-1- (4-nitrophenyl) -4, 5-dihydro-3H- [2,3]Benzodiazepines Hetero * -3-Carbosulfanyl chloride (XVI)

Melting point: 210 ℃ and 214 ℃ (DMF) yield: 70 percent.

(±) -7-bromo-4-methyl-8-methoxy-1- (4-nitrophenyl) -4, 5-dihydro-3H- [2,3] Benzodiazepine * -3-carbon-sulfur-based chloride (XVII)

Melting point: 199 ℃ and 204 ℃. Yield: 82 percent.

(+ -) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbothiohydrazide (carbothiohydrazide) (XVIII)

1.0g (2.47mmol) of carbosulfanyl chloride XI are added to a stirred solution of 0.37g (7.42mmol) of hydrazine hydrate in 15ml of tetrahydrofuran at 5-10 ℃ over a period of about 0.5 h, the mixture is then, after stirring for 1h, poured into water and the precipitated product is filtered off to give 0.89g (90%) of crude product. After drying, it is used in the further reaction step. The melting point of the product after recrystallization from ethanol was 196 ℃.

Carbothiohydrazide derivatives XIX-XXII were synthesized by similar methods:

(R) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbothiohydrazide (XIX)

Melting point: 140 ℃ and 142 ℃. Yield: 99%, [ alpha ]]_D：-201°(c＝0.5；CHCl₃).

(±) -8-chloro-4-methyl-1- (4-nitrophenyl) -4, 5-dihydro-3H- [2,3]Benzodiazepines Hetero * -3-carbothiohydrazide (XX)

Melting point: 210 ℃ and 211 ℃. Yield: 61 percent.

(±) -7-bromo-4-methyl-8-methoxy-1- (4-nitrophenyl) -4.5-dihydro-3H- [2.3] Benzodiazepine * -3-carbothiohydrazide (XXI)

Melting point: 196 ℃ and 201 ℃. Yield: 98 percent.

(+ -) -8-methyl-5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbothiohydrazide (XXII)

Melting point: 188 ℃ and 190 ℃. Yield: 98 percent.

(+ -) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbonitrile (XXIII)

A mixture of 3.25g (10mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *, 20ml dimethylformamide, 2.76g (20mmol) potassium chloride and 1.80g (17mmol) cyanogen bromide was stirred at room temperature for 20 hours. After pouring into water, the precipitated crystals are filtered off and washed with water to yield 3.34g (95%) of the title compound, m.p.: 172 ℃ and 176 ℃.

(+ -) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbamidoxime (XXIV)

A mixture of 2.80g (8.0mmol) of compound XXIII, 30ml of 2-methoxyethanol, 0.84g (10mmol) of sodium acetate and 0.60g (8.8mmol) of hydroxylamine hydrochloride is stirred for 0.5 h and then concentrated in vacuo. The residue is treated with water, the precipitated crystals are filtered off and washed with water to yield 3.05g (100%) of the title compound, m.p.: 138 ℃ and 145 ℃.

(+ -) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carboxylic acid (2-chloroethyl) -amide (XXV)

A mixture of 1.0g (3.07mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *, 25ml of anhydrous dichloromethane and 0.62g (5.88mmol) 2-chloroethyl isocyanate was stirred at room temperature for 24 hours and then concentrated. The residue was purified by reflux in ethanol to yield 1.25g (94%) of the title compound, m.p.: 222 ℃ and 223 ℃.

(+ -) -phenyl (8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-)Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -3-carbosulfanyl) -carbamates (XXVI)

0.37g (3.80mmol) of potassium thiocyanate was dissolved in 8ml of acetone, and 0.48ml (3.80mmol) of phenyl chloroformate was then added dropwise to the mixture at room temperature. The reaction mixture was stirred at room temperature for 0.5 hour, then at 40 ℃ for 0.25 hour. The mixture was then cooled with ice-water and a solution of 1.04g (3.20mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * in 15ml acetone was added dropwise over 0.5H. After stirring for 0.5 h, most of the solvent was evaporated, the residue was treated with water, the crystals were filtered and washed with water to yield 1.73g (90%) of the title compound. Melting point: 160 ℃.

(+ -) -1-methyl-3- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbosulfanyl } -urea (XXVII)

1.57g (3.11mmol) of compound XXVI was dissolved in 8ml of dimethylformamide, and to the ice-cooled stirred solution, 0.35ml (4.04mmol) of 40% aqueous methylamine solution was added dropwise. After stirring for 2 hours, the mixture was poured into water and the precipitated crystals were filtered off and washed with water to give 1.56g of crude product which was recrystallized from ethanol. Yield: 1.01g (73%). Melting point: 192 ℃ and 193 ℃.

Compounds XXVIII and XXIX were synthesized analogously.

(+ -) -1-cyclopropyl-3- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]BenzodiazepinesHetero * -7-carbosulfanyl } -urea (XXVIII)

Melting point: 281 + 283 ℃ (ethyl acetate) yield: 80 percent of

(+ -) -1-ethyl-3- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbosulfanyl } -urea (XXIX)

Melting point: 176-: 73 percent.

(+ -) -1- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -7-carbosulfanyl } -4-methyl-semicarbazide (XXX)

To a stirred solution of 0.40g (1.0mmol) of compound XVIII in 15ml chloroform, 0.07ml (1.2mmol) of methyl isocyanate is added. After 1 hour, the reaction mixture was washed with sodium bicarbonate solution and water, concentrated, and the resulting solid was purified by refluxing in ethanol. The target product was 0.36g, yield: 88 percent. Melting point: at 200 ℃.

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (XXXI)

Based on literature (Ling et al, J.chem.Soc.Perkin Trans.1: 1423(1995)) and british patent specification No.2,311,779.

Melting point: 159 ℃ 160 ℃ (ethanol)]_D：+172°(c＝1；CHCl₃).

(R) -7- (tert-Butoxycarbonyl) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (XXXII)

According to the literature (Anderson et al, j.am.chem.soc.117: 12358(1995))The method, except that hydrazinocarboxylic acid tert-butyl ester is used to replace acethydrazide, prepares the compound.

Melting point: 168- & ltalpha & gt 169 ℃ isopropanol]_D：-444°(c＝0.6；CHCl₃).

Example 1

(+ -) -8-methyl-5- (4-nitrophenyl) -7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.00g (2.60mmol) of starting material I, 2.54g (12.89mmol) of bromoacetaldehyde diethyl acetal and 10ml of dimethylformamide is stirred at 80 ℃ for 40 minutes. The reaction mixture was then diluted with water and the resulting crude product was recrystallized from ethanol to yield 0.85g (80%) of the title compound. Melting point: 145-150 ℃.

Example 2

(R) -8-methyl-5- (4-nitrophenyl) -7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material II according to the procedure described in example 1. Melting point: 108 ℃ and 110 ℃, yield: 89%, [ alpha ]]_D：+514°(c＝0.5；CHCl₃)

Example 3

(S) -8-methyl-5- (4-nitrophenyl) -7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material III according to the procedure described for example 1. Melting point: 114 ℃ and 116 ℃, yield: 83%, [ alpha ]]_D：-522°(c＝0.6；CHCl₃)

Example 4

(±) -8-methyl-7- (4-methyl-thiazol-2-yl) -5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.76g (1.98mmol) of starting material I, 1.10g (11.88mmol) of chloroacetone and 15ml of dimethylformamide is stirred at 80-90 ℃ for 40 minutes. The reaction mixture was then diluted with water, the precipitated crystals were filtered off, dried and purified by refluxing in ethanol to yield 0.69g (82%) of the title compound; melting point: 188-189 ℃.

Example 5

(±) -8-methyl-7- (5-methyl-thiazol-2-yl) -5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.50g (3.90mmol) of starting material I, 3.57g (19.50mmol) of 2-bromopropionaldehyde dimethyl acetal and 15ml of dimethylformamide was stirred at 90 ℃ for 1.5 hours. The reaction mixture was then diluted with water and the resulting crude product was purified by column chromatography using silica gel (MN Kieselgel 60; Macherey-Nagel, Duren, Germany) as adsorbent and a mixture of toluene-ethyl acetate (16: 1) as eluent to yield 1.08g (66%) of the title compound; melting point: 193-.

Example 6

(±) -7- (4, 5-dimethyl-thiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9- dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.60g (1.56mmol) of starting material I, 1.02g (9.57mmol) of 3-chloro-2-butanone and 8ml of dimethylformamide is stirred at 90 ℃ for 3 hours. After cooling, the precipitated crystals were filtered off, dried and purified by recrystallization from dimethylformamide and water to yield 0.49g (76%) of the title compound; melting point: > 260 ℃ (dec.).

Example 7

(±) -8-methyl-5- (4-nitrophenyl) -7- (4-phenyl-thiazol-2-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.45g (1.17mmol) of starting material I, 0.35g (1.76mmol) of phenacyl bromide and 7ml of dimethylformamide is stirred at 80 ℃ for 30 minutes. After cooling, the precipitated crystals are filtered off, washed with ethanol and dried to yield 0.50g (88%) of the title compound; melting point: > 260 ℃ (dec.).

Example 8

(±) -7- (4-ethoxycarbonyl-thiazol-2-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.45g (1.17mmol) of starting material I, 0.46g (2.36mmol) of ethyl bromopyruvate and 7ml of dimethylformamide is stirred at 80 ℃ for 30 minutes. After cooling, the precipitated crystals are filtered off, washed with ethanol and dried to yield 0.41g (85%) of the title compound; melting point: 242 ℃ and 243 ℃.

Example 9

(±) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-bis chloro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.00g (2.6mmol) of starting material I, 2.13g (10.40mmol) of 2-bromoethylamine hydrobromide and 10ml of dimethylformamide is stirred at 90-100 ℃ for 4 hours. After dilution with water, the precipitated crystals were filtered off, dissolved in dichloromethane and washed several times with 10% sodium bicarbonate solution. After drying, the product was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of hexane-ethyl acetate (1: 1) as eluent to yield 0.80g (75%) of the title compound; melting point: 185 ℃ and 187 ℃.

Example 10

(R) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material II according to the procedure described for example 9.

Melting point: 118-124 ℃. Yield: 73%, [ alpha ]]_D：+575°(c＝0.4；CHCl₃).

Example 11

(S) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material III according to the procedure described for example 9.

Melting point: 120 ℃ and 125 ℃. Yield: 71% [ alpha ]]_D：-594°(c＝0.4；CHCl₃).

Example 12

(±) -7- (4, 5-dihydro-4-oxo-thiazol-2-yl) -8-methyl-5- (4-nitrobenzol Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.00g (2.6mmol) of starting material I, 1.19g (7.78mmol) of methyl bromoacetate and 10ml of dimethylformamide is stirred at 80-90 ℃ for 1 hour. After dilution with water, the resulting crude product was purified by reflux in methanol to yield 1.00g (91%) of the title compound; melting point: 218 ℃ and 220 ℃.

Example 13

(±) -7- (4, 5-dihydro-5-methyl-4-oxo-thiazol-2-yl) -8-methyl-5- (4-nitro-n-tit Phenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

A mixture of 1.00g (2.60mmol) of starting material I, 0.94g (5.19mmol) of ethyl 2-bromopropionate and 10ml of dimethylformamide is stirred at 80-90 ℃ for 2 hours. After dilution with water, the crude product obtained is purified by reflux in 15ml of ethanol, yielding 1.08g (95%) of the title compound; melting point: 213-214 ℃.

Example 14

(±) -7- (5, 6-dihydro-4-oxo-4H-1, 3-thiazin-2-yl) -8-methyl-5- (4-Nitro) Phenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

A mixture of 2.00g (5.20mmol) of starting material I, 1.89g (10.44mmol) of ethyl 3-bromopropionate and 20ml of dimethylformamide is stirred at 80-90 ℃ for 3 hours. The reaction mixture was diluted with 25% sodium chloride solution and extracted with dichloromethane. After drying and concentration, the crude product was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of ethyl acetate-methanol (2: 1) as eluent to yield 1.34g (59%) of the title compound;

melting point: 220 ℃ and 221 ℃.

Example 15

5- (4-Nitrophenyl) -7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained according to the procedure described for example 1 from starting material VIII and bromoacetaldehyde diethyl acetal. Melting point: 203-215 ℃. Yield: 77 percent.

Example 16

(±) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (2-thiazolyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material IV according to the procedure described for example 1. Melting point: 171 ℃ and 175 ℃. Yield: 46 percent.

Example 17

(±) -8-methyl-5-phenyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained according to the procedure described for example 1 from starting material VII. Melting point: 180 ℃ and 184 ℃. Yield: 51 percent.

Example 18

(±) -7-bromo-4-methyl-8-methoxy-1- (4-nitrophenyl) -3- (2-thiazole) Yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material X according to the procedure described in example 1. Melting point: 184 ℃ and 190 ℃. Yield: 54 percent.

Example 19

(±) -8-chloro-4-methyl-1- (4-nitrophenyl) -3- (2-thiazolyl) -4, 5-dihydro -3H-[2，3]Benzodiazepine *

The title compound was obtained from starting material V according to the method described in example 1. Melting point: 213-216 ℃. Yield: 67%.

Example 20

(±) -8-chloro-4-methyl3- (4-methyl-thiazol-2-yl) -1- (4-nitrophenyl) -4, 5- dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material V according to the procedure described for example 4. Melting point: 209 ℃ and 216 ℃. Yield: 94 percent.

Example 21

(±) -3- (4, 5-dihydro-thiazol-2-yl) -8-chloro-4-methyl-1- (4-nitrobenzene Yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material V according to the procedure described for example 9. Melting point: 225 ℃ and 227 ℃. Yield: and 69 percent.

Example 22

(±) -3- (4, 5-dihydro-3-oxo-thiazol-2-yl) -8-chloro-4-methyl-1- (4-nitro-group Phenyl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material V according to the procedure described for example 12. Melting point: 226-228 ℃. Yield: 96 percent.

Example 23

(±) -7, 8-dichloro-4-methyl-3- (4-methyl-thiazol-2-yl) -1- (4-nitrobenzeneYl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained according to the procedure described for example 4 from starting material VI. Melting point: 240 ℃ and 242 ℃. Yield: 77 percent.

Example 24

(+ -) -7- (4, 5-dihydro-)Oxazole (oxazole) (I)Azol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dihydro-heterocyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.43g (3.32mmol) of the starting material XXV, 1.38g (9.98mmol) of anhydrous potassium carbonate, 0.24g (1.60mmol) of sodium iodide and 24ml of dimethylformamide was stirred at 100 ℃ for 4 hours. The mixture was then diluted with water and the precipitated crude product was recrystallized from ethanol to yield 1.00g (76%) of the title compound; melting point: 194 ℃ and 196 ℃.

Example 25

(±) -8-methyl-5- (4-nitrophenyl) -7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.57g (1.43mmol) of the starting material XVIII, 6ml of triethyl orthoformate and a catalytic amount of hydrochloric acid is stirred at 80 ℃ for 1 hour. After cooling, the precipitated crystals are filtered off, washed with ethanol and dried to yield 0.45g (77%) of the title compound; melting point: 212 ℃ and 213 ℃.

Example 26

(R) -8-methyl-5- (4-nitrophenyl) -7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material XIX according to the procedure described for example 25. Melting point: 144-: 88%, [ alpha ]]_D：+428°(c＝0.2；CHCl₃)

Example 27

(±) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

To an ice-cooled stirred mixture of 1.0g (2.50mmol) of the starting material XVIII, 35ml of dichloromethane, 0.40ml (2.75mmol) of triethylamine was added 0.22ml (2.80mmol) of acetyl chloride. The thus-obtained solution was left at room temperature for 16 hours, then 0.6g of p-toluenesulfonic acid was added, and the mixture was stirred at 40 ℃ for 2 hours. The reaction mixture was then washed with sodium bicarbonate solution and water to neutrality, dried, and concentrated. The crude product was treated with methanol and then recrystallized from ethanol to yield 0.99g (91%) of the title compound. Melting point: 213-215 ℃.

Example 28

(R) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Method A.

The title compound was obtained from starting material XIX by acylation with acetic anhydride according to the procedure described for example 27. The crude product obtained was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of n-hexane-ethyl acetate (1: 1) as eluent. After concentration of the fractions containing the title compound, the residue was treated with isopropyl ether to yield 0.95g of solid foam (polymorph). 89 percent.

Method B.

To a solution of 4.04g (10.0mmol) of the starting material XII, 3ml of dimethylformamide, 1.40ml (10.0mmol) of triethylamine and 0.06g (0.5mmol) of 4-dimethylaminopyridine, 1.48g (20.0mmol) of acethydrazide was added. The reaction mixture was stirred at 50 ℃ for 5 hours, then diluted with water, the precipitated crystals were filtered off and washed with water. According to which¹H-NMR Spectroscopy, thus obtained 4.5g of (R) -N' - { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine * -7-carbosulfanyl } -acethydrazide is a mixture of rotamers. (the sample analyzed was purified by column chromatography using a mixture of n-hexane-ethyl acetate (1: 1) as eluent and crystallized from 0.5mol of ethyl acetate, melting point: 118 ℃ C.).

To a suspension of the above intermediate in 50ml of ethanol, 0.75ml of concentrated hydrochloric acid was added, and the thus-obtained solution was refluxed for 2 hours. After concentration and treatment with water, 4.2g of crude product are obtained. Purification by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of n-hexane-ethyl acetate as eluent and drying in vacuo at 60 ℃ gave the title compound having melting points 101-102 ℃. [ alpha ] to]_D：+453°(c＝0.5；CHCl₃).

The compounds of examples 29-34 were obtained according to the procedure described for example 27, using the appropriate acid chloride.

Example 29

(±) -7- (5-cyclopropyl-1, 3, 4-thiadiazole-2-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 142 ℃ and 145 ℃; yield: 49 percent.

Example 30

(±) -7- (5-ethyl-1, 3, 4-thiadiazole-2-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 163 ℃ and 164 ℃; yield: 84 percent.

Example 31

(R) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 105 ℃; yield: 63% [ alpha ]]_D：+418°(c＝0.5；CHCl₃).

Example 32

(+ -) -8-methyl-5- (4-nitrophenyl) -7- (5-trifluoromethyl-1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 184 ℃ and 185 ℃; yield: 67%.

Example 33

(+ -) -8-methyl-5- (4-nitrophenyl) -7- (5-phenyl-1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 210 ℃ and 212 ℃; yield: 56 percent.

Example 34

(±) -7- (5-chloromethyl-1, 3, 4-thiadiazole-2-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 210 ℃ and 211 ℃; yield: and 64 percent.

Example 35

(±) -7- (5-cyclopropylaminomethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (4- Nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodi (benzo-b) Aza *

A mixture of 5ml of dimethylformamide, 0.44g (0.96mmol) (. + -.) -7- (5-chloromethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * (example 34) and 0.37ml (5.31mmol) of cyclopropylamine was stirred at 70-80 ℃ for 1H. The reaction mixture was then poured into 20% sodium chloride solution and the precipitated crude product was extracted into ethyl acetate. The solution was washed with water, dried and evaporated to yield 0.39g (85%) of the title compound as a solid foam.

Example 36

(+ -) -8-chloro-4-methyl-1- (4-nitrophenyl) -3- (1, 3, 4-thiadiazole-2- Yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material XX according to the procedure described in example 25. Melting point: 188 ℃; yield: 86 percent of the total weight

Example 37

(±) -8-chloro-4-methyl-3- (5-methyl-1, 3, 4-thiadiazole-2-yl) -1- (4-nitrobenzene Yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material XX according to the procedure described in example 27. Melting point: 162-164 ℃; yield: 52 percent.

Example 38

(±) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (5-methyl-1, 3, 4-thiadiazole -2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

The title compound was obtained from starting material XXII according to the procedure described for method a of example 28.

Melting point: 228 ℃ and 240 ℃; yield: 74 percent.

Example 39

(±) -8-methyl-5- (4-methyl-3-nitrophenyl) -7- (5-methyl-1, 3, 4-thiadiazole -5-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

The title compound was obtained from starting material XV following the procedure described for method B of example 28.

Melting point: 220 ℃ (ethanol); yield: 57 percent.

Example 40

(±) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -5- (3-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from starting material XIII following the procedure described for method B of example 28.

Melting point: 118 ℃ and 119 ℃; yield: 67%.

EXAMPLE 41

(±) -7-bromo-4-methyl-3- (5-methyl-1, 3, 4-thiadiazole-2-yl) -8-methoxy -1- (4-nitrophenyl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *

The title compound was obtained from starting material XXI following the procedure described for method a of example 28.

Melting point: 229-233 deg.C; yield: 76 percent.

Example 42

(±) -8-methyl-7- (5-methyl-6H-1, 3, 4-thiadiazin-2-yl) -5- (4-Nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.00g (2.50mmol) of the starting material XVIII, 20ml of dimethylformamide and 0.57g (6.16mmol) of chloroacetone is stirred at room temperature for 2 hours. After dilution with water, the precipitated crystals are filtered off and purified under reflux in ethyl acetate to yield 0.73g (67%) of the title compound; melting point: 203 ℃ and 204 ℃.

Example 43

(±) -7- (5, 6-dihydro-5-oxo-4H-1, 3, 4-thiadiazin-2-yl) -8-methyl -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3] Benzodiazepine *

A mixture of 1.00g (2.50mmol) of starting material XVIII, 20ml of dimethylformamide and 0.94g (6.14mmol) of methyl bromoacetate is stirred at 70 ℃ for 1.5 hours. After dilution with water, the precipitated crystals are filtered off and purified under reflux in ethyl acetate to yield 0.41g (37%) of the title compound; melting point: 294 ℃ 295 ℃ (dec.).

Example 44

(±) -8-methyl-5- (4-nitrophenyl) -7- (5-oxo-4, 5-dihydro-1, 3, 4-thia-bis Oxazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodi (benzo-b) Aza *

A mixture of 2.14g (4.69mmol) of starting material XXX and 122ml of concentrated hydrochloric acid was stirred at 80 ℃. A solid precipitated from the starting solution. The reaction mixture was concentrated to about half its volume, diluted with 40ml of water and made basic with sodium bicarbonate solution. The precipitated product was filtered off and washed with water to yield 1.40g (70%) of the title compound. Melting point: 288 ℃.

Example 45

(R) -8-methyl-5- (4-nitrophenyl) -7- (5-methyl-1, 3, 4-oxadiazole-2- Yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *

2.2g (5.15mmol) of (R) -N' - (8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H) are stirred][2，3]Benzodiazepine * -7-carbosulfanyl) -acethydrazide (intermediate of method B of example 28), 44ml of ethanol and 1.72g (5.39mmol)The mixture of mercury (II) acetate was refluxed for 2 hours. The residue obtained from the concentration was dissolved in dichloromethane and filtered through a neutral alumina column. After washing the column, the filtrate was concentrated and the residue was purified by column chromatography using a mixture of silica gel (MN Kieselgel60) as adsorbent and n-hexane-ethyl acetate (1: 2.5) as eluent to yield 1.07g (51%) of the title compound. Melting point after recrystallization from ethanol: 202 ℃ and 204 ℃. [ alpha ] to]：-249°(c＝0.22；CHCl₃).

Example 46

(±) -8-methyl-7- (2-methyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazole-5- Yl) -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

To an ice-cooled stirred solution of 0.44g (1.0mmol) of starting material XXVI I in 8ml of chloroform was added a solution of 0.19g (1.2mmol) of bromine in 3ml of chloroform. After 0.5 h, the reaction mixture was diluted with 15ml chloroform and washed with sodium bicarbonate solution and water. The resulting residue was concentrated with stirring with methanol and filtered to yield 0.36g (82%) of the title compound. Melting point after recrystallization from ethyl acetate: 296 deg.C.

The compounds of examples 47 and 48 are analogously obtained from the starting materials XXVIII and XXIX, respectively.

Example 47

(±) -7- (2-cyclopropyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazole-5-yl) -8-methyl The radical-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 246 ℃ and 247 ℃ (ethyl acetate), yield: and 64 percent.

Example 48

(±) -7- (2-ethyl-3-oxo-2, 3-dihydro-1, 2, 4-thia-twoAzol-5-yl) -8-methyl -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3] Benzodiazepine *

Melting point: 250 ℃ and 256 ℃, yield: 60 percent.

Example 49

(±) -7- (4-carboxythiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 9ml of ethanol, 0.85g (1.89mmol) (. + -.) -7- (4-ethoxycarbonyl-thiazol-2-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * (example 8) and 7ml of 1N sodium hydroxide solution was stirred at 90 ℃. After cooling, acidification with acetic acid, dilution with water and filtration of the precipitated crystals, washing with water and drying give 0.78g (98%) of the title compound; melting point: is > 260 ℃.

Example 50

(±) -8-methyl-5- (4-nitrophenyl) -7- (5-tetrazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 0.60g (1.70mmol) of starting material XXIII, 3ml of dimethylformamide, 0.12g (1.87mmol) of sodium azide and 0.10g (1.87mmol) of ammonium chloride was stirred at 140 ℃ for 30 minutes. The cooled reaction mixture is diluted with water and the precipitated crystals are filtered off. The product thus obtained was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of chloroform-methanol (99: 1) as eluent to yield 0.68g (54%) of the title compound; melting point: 263 and 264 ℃.

Example 51

(±) -8-methyl-5- (4-nitrophenyl) -7- (1, 2, 4-oxa-bisAzol-3-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 1.50g (3.91mmol) of starting material XXIV and 15ml of triethyl orthoformate in the presence of 0.05ml of 36% hydrochloric acid was stirred at 110 ℃ for 30 minutes and then concentrated in vacuo. The residue is stirred with water, the precipitated crystals are filtered off, washed with water and recrystallized from 2-methoxyethanol to yield 1.15g (75%) of the title compound; melting point: 190 ℃ and 196 ℃.

Example 52

(±) -8-methyl-7- (5-methyl-1, 2, 4-oxadiazole-3-yl) -5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 3.0g (7.82 mmol) of starting material XXIV and 15ml of acetic anhydride is stirred at 110 ℃ for 1 hour, after cooling, diluted with water and extracted with dichloromethane. The organic layer was concentrated and the residue was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of n-hexane-ethyl acetate (2: 1) as eluent to yield 1.58g (50%) of the title compound; melting point: 191 ℃ and 200 ℃.

Example 53

(±) -8-methyl-7- (2-methylthiazol-4-yl) -5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(±) -7-bromoacetyl-8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

A mixture of 4.80g (14.7mmol) of starting material I, 24ml of dimethylformamide, 2.16g (15.5mmol) of bromoacetic acid and 4.56g (22mmol) of dicyclohexylcarbodiimide was stirred for 20 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was taken up in ethyl acetate, washed with water, concentrated and recrystallized from ethanol to yield 4.83g (73%) of the title compound; melting point: 183 ℃ and 186 ℃.

Step B

The product obtained in step A was dissolved in 45ml of dimethylformamide, 4.96g (65mmol) of thioacetamide was added, and after stirring the mixture at 80 ℃ for 1 hour, it was then cooled and poured into water. The precipitated crude product was filtered off, washed with water and purified by column chromatography using a mixture of silica gel (MNKieselgel 60) as adsorbent, hexane-ethyl acetate (9: 1) as eluent to yield 1.67g (37%) of the title compound; melting point: 178 ℃ and 190 ℃.

Example 54

(±) -8-methyl-5- (4-nitrophenyl) -7- (2-pyrimidinyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

1- {6- [ (4-Nitrophenyl) - (pyrimidin-2-yl-hydrazono) -methyl ] -benzo-1, 3-dioxol-5-yl } -propan-2-ol

A stirred mixture of 3.29g (9.99mmol) (. + -.) -7-methyl-5- (4-nitrophenyl) -7, 8-dihydro-5H- [1, 3] dioxolo [4, 5-g ] isochroman-5-ol, 40ml ethyl acetate and 1.0ml (1.15mmol) perchloric acid is refluxed for 1 hour. After cooling, the precipitated (. + -.) -7-methyl-5- (4-nitrophenyl) -7, 8-dihydro- [1, 3] dioxolo [4, 5-g ] isochromen-6-ylium perchlorate is filtered off, stirred at reflux temperature with 1.6g (14.55mmol) 2-hydrazinopyrimidine in 50ml isopropanol for 2 hours and then concentrated. The residue was dissolved in dichloromethane and washed several times with water. After drying and evaporation, the crude product was purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent and a mixture of toluene-ethyl acetate (0.1: 4) as eluent to yield 2.71g (64%) of the title compound; melting point: 125 ℃ and 127 ℃.

Step B

1- {6- [ (4-Nitrophenyl) - (pyrimidin-2-yl-hydrazono) -methyl ] -benzo-1, 3-dioxol-5-yl } -propane-2-ol methanesulfonate

2.35g (5.58mmol) of the compound prepared in step A are dissolved in 50ml of anhydrous dichloromethane. The solution was cooled to 0 ℃ and after addition of 2.1ml (15.07mmol) triethylamine, 0.87ml (11.22mmol) methanesulfonyl chloride was added over 20 minutes and the mixture was stirred at room temperature for 3 hours. After washing with water, drying and concentration, 2.69g (54%) of the title compound are formed as intermediate; melting point: 122-124 ℃.

Step C

A mixture of 3.13g (6.27mmol) of the compound prepared in step B, 60ml of a 1: 1 dichloromethane-methanol mixture and 0.52ml (6.90mmol) of 50% sodium hydroxide solution is stirred at room temperature for 1.5 hours. After filtration, the reaction mixture was concentrated and the residue was treated with water and recrystallized from 3-fold dimethylformamide containing 10% water to yield 1.96g (77%) of the title compound; melting point: 261 ℃ and 263 ℃.

Example 55

(±) -7- (3-chloropyridazin-6-yl) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

1- {6- [ (6-Chloropyridazin-3-yl) -hydrazono- (4-nitrophenyl) -methyl ] - (benzo-1, 3-dioxol-5-yl) } -propan-2-ol

A stirred mixture of 2.00g (6.07mmol) (. + -.) -7-methyl-5- (4-nitrophenyl) -7, 8-dihydro-5H- [1, 3] dioxolo [4, 5-g ] isochroman-5-ol, 32ml isopropanol, 0.3ml hydrochloric acid and 1.04g (7.28mmol) 4-hydrazino-6-chloropyridazine was refluxed for 3 hours. After dilution with water, the precipitated crystals were filtered off, dried, recrystallized first from ethyl acetate and then from dimethylformamide containing 10% water to yield 1.53g (55%) of the title compound; melting point: 135 ℃ and 137 ℃.

Step B

A mixture of 0.3g (0.66mmol) of the compound prepared in step A, 10ml of dimethylformamide and 0.34g (1.30mmol) of triphenylphosphine was stirred at room temperature for 5 minutes, then 0.20ml (1.27mmol) of diethyl azodicarboxylate was added and stirring was continued for 24 hours. After dilution with sodium chloride solution, the precipitated product is filtered off, dried and purified by column chromatography using silica gel (MNKieselgel 60) as adsorbent and a mixture of chloroform-methanol (99: 1) as eluent. The residue obtained by concentration was crystallized by refluxing in ethanol to yield 0.12g (42%) of the title compound; melting point: 254 ℃ and 255 ℃.

Example 56

(+ -) -8-methyl-5- (4-nitrophenyl) -7- (1H (2H) -1, 2, 4-triazole-3-) Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(±) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-S-methyl-Thiomethylimine acid salt

Starting material I from dimethylformamide with methyl iodide in the presence of potassium carbonate at room temperature gave the title compound. Melting point: 191 ℃ and 192 ℃, and the yield is as follows: 94 percent.

Step B

A mixture of 3.0g (7.53mmol) of the compound obtained in step A, 110ml of 2-methoxyethanol and 4.50g (74.93mmol) of formylhydrazine is stirred at 110 ℃ for 16 hours in the presence of catalytic amounts of p-toluenesulfonic acid. The residue obtained from the concentration was treated with 10% sodium carbonate solution, the crude product obtained was filtered, dried and purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent, a mixture of hexane-ethyl acetate (1: 2) as eluent to yield 1.86g (63%) of the title compound; melting point: 154 ℃ and 156 ℃.

Example 57

(±) -8-methyl-7- (5-methyl-2 (1) H-1, 2, 4-triazole-3-yl) -5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A mixture of 15ml of 2-methoxyethanol, 0.41g (1.03mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-S-methyl-thiomethanamide acid salt (step A of example 56) and 0.35g (4.68 mmol) of acethydrazide is stirred at 110 ℃ for 16 hours in the presence of catalytic amounts of p-toluenesulfonic acid. The residue obtained from the concentration was treated with 10% sodium carbonate solution, the crude product obtained was filtered, dried and purified by column chromatography using silica gel (MN Kieselgel60) as adsorbent, a mixture of hexane-ethyl acetate (1: 2) as eluent to yield 0.32g (78%) of the title compound; melting point: 144 ℃ in 147 ℃ (solid foam).

Example 58

(±) -7- (1, 5-dimethyl-1H-1, 2, 4-triazole-3-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (isomer I) and (. + -.) -7- (2, 5-dimethyl-2H-1, 2, 4-triazol-3-yl) -8-methyl -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3] Benzodiazepine * (isomer II)

0.57g (5.08mmol) of potassium tert-butoxide, 2.05g (5.04mmol) (+ -) -8-methyl-7- (5-methyl-2 (1) H-1, 2, 4-triazol-3-yl) -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]BenzodiazepinesA mixture of hetero * (example 57), 40ml tetrahydrofuran and 0.32ml (5.14mmol) iodomethane was stirred at room temperature for 16 h. The reaction mixture was then diluted with water, extracted with ethyl acetate, the organic layer dried, and concentrated. The 2 products formed in the reaction were separated by column chromatography using silica gel (MN Kieselgel60) as adsorbent and ethyl acetate as eluent. First of all obtain a compound having R_F: 0.55 of isomer II, which is refluxed in ethanol, yielding 0.30g (14%), melting point: 185 ℃ and 187 ℃. Then collecting the product with R_F: 0.26 of isomer I, which, after refluxing in ethanol, weighs 0.67g (32%), m.p.: 193-.

Example 59

(±) -8-methyl-7- (1-methyl-1H-1, 2, 4-triazole-3-yl) -5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * (isomer I) and (. + -.) -8-methyl-7- (2-methyl-2H-1, 2, 4-triazol-3-yl) -5- (4- Nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodi (benzo-b) Aza * (isomer II)

0.41g (3.65mmol) of potassium tert-butoxide, 1.4g (3.57mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -7- (1H (2H) -1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]A mixture of benzodiazepine * (example 56), 35ml tetrahydrofuran and 0.23ml (3.69mmol) iodomethane was stirred at room temperature for 16 h. After dilution with water, the reaction mixture was extracted with ethyl acetate, the organic layer was dried, and concentrated. The 2 products formed in the reaction were separated by column chromatography using silica gel (MN Kieselgel60) as adsorbent and ethyl acetate as eluent. Having R_F: 0.22 isomer I weight 0.37g, yield: 26%, melting point: 115 ℃ and 117 ℃. Having R_F: isomer II of 0.63 is 0.35g, yield: 24%, melting point: 92-94 ℃.

Examples 60 to 119

General procedure for the reduction of the nitro group of the compounds obtained in the above examples.

Method A

2.0mmol of nitro compound is dissolved in a mixture of methanol-dichloromethane, 6-10mmol of 85-98% hydrazine hydrate and 0.1-2g of Rani catalyst are added, and the mixture is stirred at 20-40 ℃ for 1-5 hours. After filtration of the catalyst, the filtrate is concentrated, the residue is treated with water and the product is filtered off.

Method B

5.5g of Rani catalyst were prehydrogenated in 250ml of a 2: 1 methanol-dichloromethane mixture, 20.0mmol of nitro compound were then added to 250ml of the above solvent mixture, and the mixture thus obtained was hydrogenated at atmospheric pressure. After filtration of the catalyst, the filtrate is concentrated, the residue is treated with water, the product is filtered off, washed and dried.

Method C

A stirred mixture of 1.82mmol of nitro compound, 30ml of ethanol and 2.46g (10.91mmol) of tin (II) chloride dihydrate was refluxed for 3 hours. The reaction mixture was concentrated, and then an aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. After separation, the aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with sodium chloride solution, dried, and concentrated. The residue is purified by column chromatography or recrystallization, if desired.

Method D

3.4mmol of the nitro compound was dissolved in 35ml of a methanol-dichloromethane (1: 1) mixture, 0.4g of a 10% palladium on activated carbon catalyst and 0.47g of potassium carbonate were added, and the thus-obtained mixture was hydrogenated in the presence of 1ml of water. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated, and the residue was treated with water and filtered.

Method E

4.0mmol of the nitro compound was dissolved in 48ml of methanol containing 5% of water, 0.20g of catalyst, palladium on activated carbon 10%, was added, and then 3.5 equivalents of concentrated aqueous potassium formate solution was added dropwise at room temperature, and the mixture was stirred at the above temperature. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated, and the residue was treated with water and filtered.

Table 10.

2, 3-benzodiazepines * containing aminophenyl groups

(unless otherwise stated, recording at 250MHz¹H NMR Spectrum)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				60	(±) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	187-190	78
Method A	1H NMR(CDCl3)δ1.32(3H，d，6.5Hz)，2.78(1H，dd，14.0Hz，9.7Hz)，2.97(1H，dd，14.0Hz，4.9Hz)，3.80(2H，br)，5.26(1H，m)，5.98(2H，m)，6.65(1H，s)，6.67(1H，d，4.0Hz)，6.73(2H，dm)，6.80(1H，s)，7.37(1H，d，4.0Hz)，7.55(2H，dm)MS：EI(70eV)：[M]+.：378，m/z：363，279，278，253，252
				61	(R) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	125-130	84-578°(c＝1，CHCl3)
Method A	1H NMR(CDCl3)δ1.29(3H，d，6.5Hz)，2.77(1H，dd，14.0Hz，9.7Hz)，3.00(1H，dd，14.0Hz，4.9Hz)，3.92(2H，br)，5.23(1H，m)，5.98(2H，m)，6.62(1H，d，4.0Hz)，6.65(1H，s)，6.72(2H，dm)，6.80(1H，s)，

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					7.32(1H，d，4.0Hz)，7.55(2H，dm)
62	(S) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	124-128	94+546°(c＝0.34，CHCl3)
				Method A	1H NMR(DMSO-d6)δ1.15(3H，d，6.5Hz)，2.60(1H，dd，13.6Hz，10.5Hz)，2.94(1H，dd，13.6Hz，4.8Hz)，4.99(1H，m)，5.72(2H，br)，6.03(2H，m)，6.60(2H，dm)，6.62(1H，s)，6.81(1H，d，4.0Hz)，7.04(1H，s)，7.27(1H，d，4.0Hz)，7.55(2H，dm)MS：EI(70eV)：[M]+.：378，m/z：377，363，279，278，253，252CI：[M+H]+：379，[M]+.：378，m/z：363
63	(±) -5- (4-aminophenyl) -8-methyl-7- (4-methyl-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	190-191(EtOH)	65
				Method A	1H NMR(CDCl3)δ1.30(3H，d，6.5Hz)，2.29(3H，s)，2.77(1H，dd，14.0Hz，10.0Hz)，2.92(1H，dd，14.0Hz，5.1Hz)，3.94(2H，br)，5.27(1H，m)，5.97(2H，m)，6.20(1H，s)，6.53(2H，dm)，6.70(1H，s)，6.88(1H，s)，7.53(2H，dm)
64	(±) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	165-167	47
				Method A	1H NMR(DMSO-d6)δ1.17(3H，d，6.5Hz)，2.25(3H，s)，2.60(1H，dd，13.9Hz，10.3Hz)，2.94(1H，dd，13.9Hz，5.1Hz)，4.95(1H，m)，5.70(2H，br)，6.05(2H，dm)，6.57(1H，s)，6.62(2H，dm)，6.93(1H，s)，7.04(1H，s)，7.36(2H，dm)
65	(±) -5- (4-aminophenyl) -8-methyl-7- (4, 5-dimethyl-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	240-242(EtOH)	83
				Method A	1H NMR(DMSO-d6)δ1.16(3H，d，6.5Hz)，2.06(3H，s)，2.13(3H，s)，2.62(1H，dd，14.0Hz，10.0Hz)，2.92(1H，dd，14.0Hz，5.0Hz)，4.97(1H，m)，5.70(2H，br)，6.04(2H，dm)，6.60(1H，s)，6.62(2H，dm)，7.02(1H，s)，7.34(2H，dm)
66	(±) -5- (4-aminophenyl) -7- (4-phenyl-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	221-223(EtOH)	89
				Method A	1H NMR(CDCl3)δ1.29(3H，d，6.5Hz)，2.80(1H，dd，14.0Hz，9.4Hz)，3.00(1H，dd，14.0Hz，4.8Hz)，3.93(2H，br)，5.40(1H，m)，5.98(2H，m)，6.62(1H，s)，6.70(2H，dm)，6.78(1H，s)，7.29(1H，t)，7.39(1H，t)，7.50(1H，s)，7.57(2H，dm)，7.86(2H，d)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				67	(±) -5- (4-aminophenyl) -7- (4-ethoxycarbonyl-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	251-252(EtOH)	83
Method A	1H NMR(CDCl3)δ1.29(3H，d，6.5Hz)，1.38(3H，t)，2.76(1H，dd，14.0Hz，10.0Hz)，2.92(1H，dd，14.0Hz，5.0Hz)，3.98(2H，br)，4.33(2H，q)，5.40(1H，m)，6.00(2H，m)，6.68(1H，s)，6.69(2H，dm)，6.82(1H，s)，6.86(1H，s)，7.51(2H，dm)
				68	(±) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	145-150(EtOH)	84
Method A	1H NMR(CDCl3)δ1.21(3H，d，6.5Hz)，2.70(1H，dd，14.0Hz，10.0Hz)，2.96(1H，dd，14.0Hz，5.0Hz)，3.20(1H，m)，3.70(1H，m)，3.90(2H，br)，4.17(2H，m)，5.09(1H，m)，5.98(2H，dm)，6.60(1H，s)，6.66(2H，dm)，6.73(1H，s)，7.47(2H，dm)MS：EI(70eV)：[M]+.：380，m/z：365，339，279，264，253，252
				69	(R) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	148-150(EtOH)	82-239°(c＝0.5，CHCl3)
Method A	1H NMR(DMSO-d6)δ1.16(3H，d，6.5Hz)，2.60(1H，dd，14.0Hz，10.0Hz)，2.90(1H，dd，14.0Hz，4.0Hz)，3.25(2H，m)，4.00(2H，m)，4.82(1H，m)，5.73(2H，br)，6.07(2H，dm)，6.64(s)，6.64(2H，dm)，7.02(1H，s)，7.30(2H，dm)MS：EI(70eV)：[M]+.：380，m/z：365，339，279，278，264，253，252CI：[M+H]+：381，[M]+.：380，m/z：279
				70	(S) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolHeterocyclopenteno- [4, 5-h][2，3]Benzodiazepine *	150-152	92+175°(c＝0.51，CHCl3)
Method A	MS：EI(70eV)：[M]+：380，m/z：365，339，279，278，264，253，252CI：[M+H]+：381，[M]+：380，m/z：279
				71	(±) -5- (4-aminophenyl) -7- (4, 5-dihydro-4-oxo-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	218-220(EtOH)	85
Method A	1H NMR(DMSO-d6)δ1.29(3H，d，6.5Hz)，2.61(1H，dd，13.0Hz，12.0Hz)，2.96(1H，dd，13.0Hz，5.0Hz)，3.72(2H，m)，5.08(1H，m)，6.01(2H，br)，6.06(2H，dm)，6.60(2H，dm)，6.62(1H，s)，7.10(1H，s)，7.40(2H，dm)
				72	(+ -) -5- (4-aminophenyl) -7- (4, 5-dihydro-5-)	200-204	63

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					Methyl-4-oxo-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	(EtOH)
Method A	1H NMR(DMSO-d6) δ 1.32(d) and 1.45(d, overlapping, diastereomers), 2.60(1H, dd, 13.0Hz, 12.0Hz), 2.94(1H, dd, 13.0Hz, 5.0Hz), 3.96 and 4.05(1H, q), 5.08(1H, m), 6.0(2H, br), 6.07(2H, dm), 6.60(2H, dm), 6.62(1H, s), 7.08(1H, s), 7.40(2H, dm) MS: EI (70 eV): [ M ] A]+.：408，m/z：393，279，265，253，252
				73	(±) -5- (4-aminophenyl) -7- (5, 6-dihydro-4-oxo-4H-1, 3-thiazin-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	226-228(EtOH)	90
Method A	1H NMR(DMSO-d6)δ1.25(3H，d，6.5Hz)，2.35(2H，m)，2.57(1H，dd，13.0Hz，12.0Hz)，2.88(1H，dd，13.0Hz，4.0Hz)，3.05(2H，m)，5.21(1H，m)，5.97(2H，br)，6.09(2H，dm)，6.60(1H，s)，6.62(2H，dm)，7.04(1H，s)，7.42(2H，dm)MS：EI(70eV)：[M]+.：408，m/z：295，279，253，252
				74	5- (4-aminophenyl) -7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	200-204	52
Method A	1H NMR(DMSO-d6)δ2.88(2H，t)，4.21(2H，t)，5.70(2H，s)，6.08(2H，s)，6.60(1H，s)，6.62(2H，dm)，6.89(1H，d，4.0Hz)，7.08(1H，s)，7.28(1H，d，4.0Hz)，7.37(2H，dm)
				75	(±) -5- (4-amino-3-methylphenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	225-227	78
Method B	MS：EI(70eV)：[M]+.：392，m/z：377，293，266CI：[M+H]+：393，[M]+.：392，m/z：266
				76	(±) -1- (4-aminophenyl) -4-methyl-8-methoxy-3- (2-thiazolyl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *	105-107	57
Method D	MS：EI(70eV)：[M]+.：364，m/z：349，265，223CI：[M+H]+：365，[M]+.：364
				77	(±) -1- (4-aminophenyl) -8-chloro-4-methyl-3- (2-thiazolyl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *	104-107	72
Method A	1H NMR(CDCl3)δ1.31(3H，d，6.5Hz)，2.96(1H，dd，13.0Hz，10.0Hz)，3.10(1H，dd，13.0Hz，5.0Hz)，5.35(1H，m)，6.68(1H，d，4.0Hz)，6.72(2H，dm)，7.21(1H，d，4.0Hz)，7.25(1H，d，1.0Hz)，7.27(1H，d，7.0Hz)，7.34(1H，dd)，7.53(2H，dm)
				78	(±) -1- (4-aminophenyl) -8-chloro-4-methyl	173-175	90

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					-3- (4-methyl-thiazol-2-yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *
Method A	1H NMR(CDCl3)δ1.26(3H，d，6.5Hz)，2.27(3H，d，1.0Hz)，2.81(1H，dd，14.0Hz，9.7Hz)，3.02(1H，dd，14.0Hz，5.0Hz)，3.95(2H，br)，5.28(1H，m)，6.20(1H，q，1.0Hz)，6.70(2H，dm)，7.17(1H，d，2.2Hz)，7.22(1H，d，8.2Hz)，7.33(1H，dd，8.2Hz，2.2Hz)，7.51(2H，dm)
				79	(±) -1- (4-aminophenyl) -3- (4, 5-dihydro-thiazol-2-yl) -8-chloro-4-methyl-4, 5-dihydro-3H- [2,3]Benzodiazepine *	213-216(MeOH)	79
Method A	1H NMR(DMSO-d6)δ1.08(3H，d，6.5Hz)，2.68(1H，dd，14.0Hz，10.0Hz)，3.06(1H，dd，14.0Hz，5.0Hz)，3.20(2H，m)，4.02(2H，m)，5.68(2H，s)，4.92(1H，m)，6.60(2H，dm)，7.09(1H，d，1.0Hz)，7.28(2H，dm)，7.41(1H，d，7.0Hz)，7.48(1H，dd)
				80	(±) - (4- (4-aminophenyl) -3- (4, 5-dihydro-4-oxo-thiazol-2-yl) -8-chloro-4-methyl-4, 5-dihydro-3H- [2,3]benzodiazepine *	226-228(iPrOH)	75
Method A	1H NMR(DMSO-d6)δ1.32(3H，d，6.5Hz)，2.68(1H，dd，13.8Hz，12.0Hz)，3.08(1H，dd，13.8Hz，4.8Hz)，3.77(2H，m)，5.10(1H，m)，6.12(2H，br)，6.66(2H，dm)，7.17(1H，d，2.0Hz)，7.41(2H，dm)，7.52(1H，d，8.0Hz)，7.54(1H，dd，8.0Hz，2.0Hz)
				81	(±) -1- (4-aminophenyl) -7, 8-dichloro-3- (4-methyl-thiazol-2-yl) -4-methyl-4, 5-dihydro-3H- [2,3]Benzodiazepine *	182-184(EtOH)	48
Method A	1H NMR(CDCl3)δ1.28(3H，d，6.5Hz)，2.30(3H，s)，2.80(1H，dd，14.0Hz，9.6Hz)，3.02(1H，dd，14.0Hz，4.9Hz)，3.96(2H，br)，5.31(1H，m)，6.22(1H，q，1.0Hz)，6.69(2H，dm)，7.28(1H，s)，7.39(1H，s)，7.50(2H，dm)
				82	(±) -5- (4-aminophenyl) -7- (4, 5-dihydro-oxazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	166-167(EtOH)	87
Method A	1H NMR(DMSO-d6)δ1.20(3H，d，6.5Hz)，2.31(1H，dd，13.8Hz，12.0Hz)，2.78(1H，dd，13.8Hz，5.8Hz)，3.61(2H，m)，4.18(2H，m)，4.51(1H，m)，5.66(2H，br)，6.03(2H，dm)，6.51(1H，s)，6.53(2H，dm)，6.98(1H，s)，7.30(2H，dm)MS：EI(70eV)：[M]+.：364，m/z：349，323，279，278，252CI：[M+H]+：365，[M]+.：364
				83	(±) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	192-194(50％EtOH-H2O)	77

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				Method A	1H NMR(DMSO-d6)δ1.20(3H，d，6.5Hz)，2.62(1H，dd，13.9Hz，10.8Hz)，2.99(1H，dd，13.9Hz，5.2Hz)，5.01(1H，m)，5.78(2H，br)，6.03(2H，dm)，6.58(1H，s)，6.60(2H，dm)，7.07(1H，s)，7.32(2H，dm，)
84	(R) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	219-220 (Ethyl formate)	67-490°(c＝0.9，CHCl3)
				Method C	1H NMR(CDCl3)δ1.33(3H，d，6.5Hz)，2.80(1H，dd，14.0Hz，9.9Hz)，2.97(1H，dd，14.0Hz，5.0Hz)，4.02(2H，br)，5.30(1H，m)，5.98(2H，dm)，6.65(1H，s)，6.68(2H，dm)，6.80(1H，s)，7.51(2H，dm，)，8.50(1H，s)
85	(±) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	143-148	89
				Method A	1H NMR(CDCl3)δ1.32(3H，d，6.5Hz)，2.56(3H，s)，2.76(1H，dd，14.0Hz，10.0Hz)，2.93(1H，dd，14.0Hz，5.0Hz)，4.00(2H，br)，5.19(1H，m)，5.98(2H，dm)，6.64(1H，s)，6.70(2H，dm)，6.79(1H，s)，7.48(2H，dm，)MS：EI(70eV)：[M]+.：393，m/z：378，279，278，253，252CI：[M+H]+：394，[M]+.：393，m/z：252
86	(R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	168-170(50％EtOH-H2O)	78-482°(c＝0.5，CHCl3)
				Method B.C	1H NMR(DMSO-d6)δ1.23(3H，d，6.5Hz)，2.50(3H，s)，2.60(1H，dd，13.8Hz，9.6Hz)，2.97(1H，dd，13.8Hz，4.9Hz)，4.93(1H，m)，5.78(2H，br)，6.03(2H，dm)，6.58(1H，s)，6.60(2H，dm)，7.09(1H，s)，7.31(2H，dm)
87	(±) -5- (4-aminophenyl) -7- (5-cyclopropyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	145-148 (precipitation with water)	75
				Method A	1H NMR(DMSO-d6)δ0.88(2H，m)，1.05(2H，m)，1.22(3H，d，6.5Hz)，2.22(1H，m)，2.61(1H，dd，14.0Hz，10.0Hz)，2.99(1H，dd，14.0Hz，5.0Hz)，4.97(1H，m)，5.78(2H，br)，6.05(2H，dm)，6.60(1H，s)，6.63(2H，dm)，7.06(1H，s)，7.36(2H，dm)
88	(±) -5- (4-aminophenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4，5-h][2，3]Benzodiazepine *	135-138	67
				Method of producing a composite material	1H NMR(CDCl3)δ1.35(3H，t)，1.36(3H，d，6.5Hz)，2.79(1H，dd，14.0

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				A	Hz，10.0Hz)，2.98(2H，q)，2.99(1H，dd，14.0Hz，5.0Hz)，3.98(2H，br)，5.25(1H，m)，6.02(2H，dm)，6.63(1H，s)，6.73(2H，dm)，6.82(1H，s)，7.51(2H，dm，)
89	(R) -5- (4-aminophenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	142-	47-602°(c＝0.5，EtOH)
				Method E	MS：EI(70eV)：[M]+.：407，m/z：392，279，278，253，252CI：[M+H]+：408，[M]+.：407
90	(±) -5- (4-aminophenyl) -8-methyl-7- (5-trifluoromethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	216-218	33
				Method A	1H NMR(CDCl3)δ1.39(3H，d，6.5Hz)，2.80(1H，dd，14.0Hz，10.0Hz)，2.93(1H，dd，14.0Hz，5.0Hz)，4.06(2H，br)，5.28(1H，dm)，6.00(2H，dm)，6.61(1H，s)，6.69(2H，dm)，6.81(1H，s)，7.48(2H，dm，)MS：EI(70eV)：[M]+.：447，m/z：432，279，253，252CI：[M+H]+：448，[M]+.：447，m/z：252
91	(±) -5- (4-aminophenyl) -7- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	228-230(50％EtOH-H2O)	84
				Method A	1H NMR(DMSO-d6)δ1.28(3H，d，6.5Hz)，2.67(1H，dd，14.0Hz，10.0Hz)，3.01(1H，dd，14.0Hz，5.0Hz)，5.02(1H，m)，5.81(2H，br)，6.07(2H，dm)，6.59(1H，s)，6.61(2H，dm)，7.08(1H，s)，7.40(2H，dm)，7.45(3H，m)，7.81(2H，d)MS：EI(70eV)：[M]+.：455，m/z：440，295，279，253，252CI：[M+H]+：456，[M]+.：455，m/z：295
92	(±) -5- (4-aminophenyl) -7- (5-cyclopropylamino-methyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	135-138	35
				Method A	1H NMR(CDCl3)δ0.45(4H，m)，1.33(3H，d，6.5Hz)，2.28(1H，m)，2.75(1H，dd，14.0Hz，9.9Hz)，2.85(1H，dd，14.0Hz，4.9Hz)，4.0(2H，br)，4.10(2H，s)，5.26(1H，m)，6.00(2H，m)，6.60(1H，s)，6.68(2H，dm)，6.80(1H，s)，7.49(2H，dm)
93	(±) -1- (4-aminophenyl) -8-chloro-4-methyl-3- (1, 3, 4-thiadiazol-2-yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *	125-128	79
				Method A	1H NMR(DMSO-d6)δ1.18(3H，d，6.5Hz)，2.69(1H，dd，14.0Hz，10.8Hz)，3.14(1H，dd，14.0Hz，5.1Hz)，5.05(1H，m)，5.83(2H，s)，6.62(2H，dm)，7.10(1H，s)，7.33(2H，dm)，7.51(2H，m)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				94	(±) -1- (4-aminophenyl) -8-chloro-4-methyl-3- (5-methyl-1, 3, 4-thiadiazol-2-yl) -4, 5-dihydro-3H- [2,3]Benzodiazepine *	131-133	88
Method A	1H NMR(DMSO-d6)δ1.18(3H，d，6.5Hz)，2.70(1H，dd，14.0Hz，10.3Hz)，3.11(1H，dd，14.0Hz，5.3Hz)，2.50(3H，s)，4.96(1H，m)，5.80(2H，s)，6.62(2H，dm)，7.10(1H，s)，7.32(2H，dm)，7.51(2H，m)
				95	(±) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	140-144	72
Method B	MS：EI(70eV)：[M]+.：407，m/z：392，293，266CI：[M+H]+：408，[M]+.：407，m/z：266
				96	(±) -5- (3-amino-4-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	125	70
Method B	1H NMR(500MHz)(DMSO-d6)δ1.17(3H，d，6.5Hz)，2.10(3H，s)，2.51(3H，s)，2.72(1H，dd，14.1Hz，9.1Hz)，3.05(1H，dd，14.1Hz，4.5Hz)，5.01(2H，s)，5.03(1H，m)，6.07(2H，dm)，6.55(1H，s)，6.70(1H，dd)，6.83(1H，d，1.2Hz)，7.00(1H，d，7.8Hz)，7.06(1H，s)
				97	(±) -5- (3-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	197-198(iPrOH)	77
Method B.C	1H NMR(500MHz)(DMSO-d6)δ1.17(3H，d，6.5Hz)，2.51(3H，s)，2.77(1H，dd，14.2Hz，8.6Hz)，3.08(1H，dd，14.2Hz，4.3Hz)，5.06(1H，m)，5.24(2H，s)，6.07(2H，dm)，6.54(1H，s)，6.67(1H，d)，6.71(1H，d)，6.74(1H，d)，7.06(1H，s)
				98	(±) -1- (4-aminophenyl) -4-methyl-3- (5-methyl-1, 3, 4-thiadiazole-2-yl) -8-methoxy-4, 5-dihydro-3H- [2,3]Benzodiazepine *	180-184	84
Method D	MS：EI(70eV)：[M]+.：379，m/z：364，265，238，223CI：[M+H]+：380，[M]+.：379，m/z：223
				99	(±) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-6H-1, 3, 4-thiadiazin-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	154-157	85
Method A	1H NMR(DMSO-d6)δ1.20(3H，d，6.5Hz)，2.10(3H，s)，2.55(1H，dd，14.0Hz，11Hz)，2.92(1H，dm)，2.92(1H，dd，14.5Hz)，3.28(1H，d，14.5Hz)，5.10(1H，m)，5.70(2H，s)，6.02(2H，dm)，6.55(2H，dm)，7.01(1H，s)，7.38(2H，dm)，7.60(1H，s)
				100	(+ -) -5- (4-aminophenyl) -7- (5, 6-dihydro-5-)	172-176	83

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					oxo-4H-1, 3, 4-thiadiazin-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *
Method A	1H NMR(DMSO-d6)δ1.16(3H，d，6.5Hz)，2.49(1H，dd，14.0Hz，10.0Hz)，2.87(1H，dd，14.0Hz，5.2Hz)，3.31(2H，s)，4.78(1H，m)，5.68(2H，s)，6.05(2H，dm)，6.65(1H，s)，6.66(2H，dm)，7.00(1H，s)，7.32(2H，dm)，10.5(1H，s)
				101	(±) -5- (4-aminophenyl) -8-methyl-7- (5-oxo-4, 5-dihydro-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	263-264	47
Method C	1H NMR(DMSO-d6)δ1.17(3H，d，6.5Hz)，2.58(1H，dd，14.0Hz，10.4Hz)，2.97(1H，dd，14.0Hz，5.4Hz)，4.71(1H，m)，5.65(2H，s)，6.04(2H，dm)，6.61(2H，dm)，6.62(1H，s)，7.01(1H，s)，7.23(2H，dm)，11.81(1H，br s)MS：EI(70eV)：[M]+.：395，m/z：394，306，252CI：[M+H]+：396，[M]+.：395，m/z：280
				102	(R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	145-149	86-663°(c＝0.5，EtOH)
Method A	MS：EI(70eV)：[M]+.：377，m/z：252CI：[M+H]+：378，[M]+.：377，m/z：252
				103	(±) -5- (4-aminophenyl) -8-methyl-7- (2-methyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazol-5-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	213(EtOH)	67
Method A	1H NMR(DMSO-d6)δ1.23(3H，d，6.5Hz)，2.70(1H，dd，13.8Hz，10.2Hz)，3.03(1H，dd，13.8Hz，4.2Hz)，3.06(3H，s)，4.91(1H，m)，5.90(2H，s)，6.08(2H，dm)，6.61(1H，s)，6.61(2H，dm)，7.06(1H，s)，7.30(2H，dm)
				104	(±) -5- (4-aminophenyl) -7- (2-cyclopropyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	265-267	82
Method A	1H NMR(DMSO-d6)δ0.85(4H，m)，1.22(3H，d，6.5Hz)，2.75(1H，dd，14.0Hz，10.0Hz)，2.75(1H，m)，3.02(1H，dd，14.0Hz，4.7Hz)，4.92(1H，m)，5.90(2H，s)，6.07(2H，dm)，6.60(1H，s)，6.63(2H，dm)，7.04(1H，s)，7.30(2H，dm)
				105	(±) -5- (4-aminophenyl) -7- (2-ethyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazol-2-yl) -8-	212-214	59

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					Methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzo (b) isDiaza *
Method A	1H NMR(CDCl3)δ1.25(3H，t)，1.27(3H，d，6.5Hz)，2.80(1H，dd，14.0Hz，9.0Hz)，3.01(1H，dd，14.0Hz，4.0Hz)，3.72(2H，q)，4.07(2H，br)，5.13(1H，m)，6.03(2H，dm)，6.65(1H，s)，6.67(2H，dm)，6.80(1H，s)，7.37(2H，dm)MS：EI(70eV)：[M]+.：423，m/z：408，279，252，160CI：[M+H]+：424，[M]+.：423
				106	(±) -5- (4-aminophenyl) -7- (4-carboxy-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	＞260(dec.)	97
Method A	MS：EI(70eV)：[M]+.：422，m/z：407，279，253
				107	(±) -5- (4-aminophenyl) -8-methyl-7- (5-tetrazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	＞360	68
Method A	MS：EI(70eV)：[M]+.：363，m/z：295，294，252CI：[M+H]+：364，[M]+.：363，m/z：295
				108	(±) -5- (4-aminophenyl) -8-methyl-7- (1, 2, 4-oxadiazole-3-yl) -7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine * hydrochloride	124-126	48
Method A	MS：EI(70eV)：[M]+.：363，m/z：348，253，252CI：[M+H]+：364，[M]+.：363，m/z：252
				109	(±) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 2, 4-oxadiazole-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	130-135	74
Method A	MS: EI (70eV) (hydrochloride): [ M ] A]+.：377，m/z：362，278，252CI：[M+H]+：378，[M]+.：377，m/z：252
				110	(±) -5- (4-aminophenyl) -8-methyl-7- (2-methyl-thiazol-4-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	132-135	22
Method C	MS：EI(70eV)：[M]+.：392，m/z：377，279，253，252CI：[M+H]+：393，[M]+.：392
				111	(±) -5- (4-aminophenyl) -8-methyl-7- (2-pyrimidinyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	233-235(EtOH)	96
Method A	1H NMR(DMSO-d6)δ1.23(3H，d，6.5Hz)，2.50(1H，dd，14.0)Hz，10.0Hz)，2.89(14.0Hz，4.8Hz)，5.18(1H，m)，5.71(2H，s)，6.03(2H，

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					dm)，6.58(2H，dm)，6.60(1H，s)，6.60(1H，t，4.8Hz)，7.43(1H，s)，7.30(2H，dm)，8.33(2H，d，4.8Hz)
112	(±) -5- (4-aminophenyl) -7- (3-chloropyridazin-6-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxoleno- [4, 5-H][2，3]Benzodiazepine *	164-166(EtOH)	94
				Method A	MS：EI(70eV)：[M]+.：407/409，m/z：392/394，355，279，278，253，252CI：[M+H]+：408/410，[M]+.：407/409，m/z：279
113	(±) -5- (4-aminophenyl) -8-methyl-7- (1H (2H) -1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	178-181	64
				Method A	MS：EI(70eV)：[M]+.：362，m/z：347，279，252
114	(±) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1H (2H) -1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	166-169	72
				Method A	MS：EI(70eV)：[M]+.：376，m/z：361，279，252
115	(±) -5- (4-aminophenyl) -8-methyl-7- (2-methyl-2H-1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	182-183	83
				Method A	MS：EI(70eV)：[M]+.：376，m/z：361，279，252
116	(±) -5- (4-aminophenyl) -8-methyl-7- (1-methyl-1H-1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	165-168	83
				Method A	MS：EI(70eV)：[M]+.：376，m/z：361，253，252
117	(±) -5- (4-aminophenyl) -8-methyl-7- (2, 5-dimethyl-2H-1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	185-187	78
				Method A	MS：EI(70eV)：[M]+.：390，m/z：375，279，265，252
118	(±) -5- (4-aminophenyl) -8-methyl-7- (1, 5-dimethyl-1H-1, 2, 4-triazol-3-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	197-200	85

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				Method C	MS：EI(70eV)：[M]+.：390，m/z：375，253，252
119	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	158-160	83-515°(c＝0.38，CHCl3)
				Method B	1H NMR(DMSO-d6)δ1.18(3H，d，5.4Hz)，2.07(s，3H)，2.47(s，3H)，2.57(dd，1H，13.7Hz，10.3Hz)，2.95(dd，1H，13.7Hz，4.9Hz)，4.92(m，1H)，5.2-5.8(br，2H)，6.01(s，br，1H)，6.06(s，br，1H)，6.55(s，1H)，6.64(d，1H，8.2Hz)，7.04(s，1H)，7.17(d，1H，8.2Hz)，7.25(s，br，1H)MS：EI(70eV)：[M]+.：407，m/z：392，293，278，266CI：[M+H]+：408，[M]+.：407

Example 120-

General procedure for the Synthesis of 2, 3-benzodiazepines * containing an acetylamino-phenyl group

The 2, 3-benzodiazepine * containing an aminophenyl group was dissolved in dichloromethane and stirred at room temperature with excess acetic anhydride. After completion of the reaction, the mixture was washed with a sodium hydrogencarbonate solution and water, then dried, and concentrated.

Table 11.

2, 3-benzodiazepine * derivatives substituted with an acetylaminophenyl group

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				120	(±) -5- (4-acetylaminophenyl) -8-methyl-7- (5-methyl-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	176-179	65
121	(±) -5- (4-acetylaminophenyl) -8-methyl-7- (4-methyl-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	236-238(50％EtOH-H2O)	65
				122	(±) -5- (4-acetylaminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	211-213(EtOH)	96
123	(R) -5- (4-acetylaminophenyl) -8-methyl	126 (heavy)	95

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	Row) 172-	-140°(c＝0.44，CHCl3)
124	(S) -5- (4-Acetylaminophenyl) -8-methyl-7- (2-thia-neAzolyl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	124-128	95+134°(c＝0.48，CHCl3)
				125	(R) -5- (4-Acetylaminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	143-145	95+108°(c＝0.45，CHCl3)
126	(S) -5- (4-acetylaminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	148-154	91-111°(c＝048，CHCl3)
				127	(±) -5- (4-acetylaminophenyl) -7- (4, 5-dihydro-oxazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	124-128	44
128	(±) -5- (4-acetylaminophenyl) -8-methyl-7- (2-pyrimidinyl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	162-163(EtOH)	96
				129	(±) -5- (4-acetylaminophenyl) -7- (3-chloro-pyridazin-6-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	164-170	78
130	(R) -5- (4-Acetylaminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	276-277(MeOH)	73-114°(c＝0.5，CHCl3)
				131	(±)-5- (4-acetylamino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	258-262	63

Example 132

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (4, 5-dihydro-thiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7-thiocarbamoyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

This compound was prepared from starting compound XXXI according to the method described for starting compound I. Melting point: 123 ℃ and 125 ℃. Yield: 70 percent.

Step B

The product of step a was converted to the title compound according to the method described for example 9. Melting point: 130 ℃ and 135 ℃. Yield: 81 percent.

Example 133

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (thiazol-2-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was obtained from the intermediate described in step a of example 132, following the procedure described for example 1. Melting point: 138 ℃ and 142 ℃. Yield: and 55 percent.

Example 134

(R) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl-4-nitro Phenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl chloride

This compound was prepared from starting compound XXXI according to the procedure described for starting compound XI. Melting point: 193 ℃ and 196 ℃. Yield: 85% [ alpha ]]_D：-500.0°(c＝0.5；CHCl₃).

Step B

2.50g (6.0mmol) of the compound obtained in step A are reacted with 1.28g (21.3mmol) propionylhydrazine in 10ml dimethylformamide at 70 ℃ for 2 hours. The cooled reaction mixture was poured into water and the resulting precipitate was collected by filtration. The wet mass was further reacted with 0.5ml of concentrated hydrochloric acid at the boiling point in 24ml of ethanol for 1 hour. The solvent was evaporated, the residue was dissolved in dichloromethane and extracted with sodium bicarbonate solution and water. Evaporation of the solvent gave the crude title product, which was purified by column chromatography using a mixture of n-hexane-ethyl acetate (1: 1) as eluent, giving 1.15g (yield: 49%) of the product. Melting point: 129 ℃ and 130 ℃.

Example 135

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (5-propyl-1, 3, 4-thiadiazole -2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

In accordance with the method as set forth in embodiment 134,but using butyrhydrazide, the title compound was obtained. Melting point: 143 ℃ and 145 ℃. Yield: 73% [ alpha ]]_D：+343.3°(c＝0.5；CHCl₃).

Example 136

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbothiohydrazide

The step a intermediate of example 134 was converted to the carbothiohydrazide according to the procedure described for starting material XVIII. Melting point: 109 ℃ and 115 ℃. Yield: 91% [ alpha ]]_D：-276.5°(c＝0.5；CHCl₃).

Step B

In analogy to the procedure described for example 25, the compound of step a was reacted with triethyl orthoformate and a catalytic amount of hydrochloric acid to give the title product. Melting point: 182 ℃ and 189 ℃. Yield: 92% [ alpha ]]_D：+356.0°(c＝0.5；CHCl₃).

Example 137

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (5-methoxymethyl-1, 3, 4- Thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzene and its derivatives Diaza *

The compound of step A from example 136 (2.07g, 5.0mmol) was reacted in 10ml of dimethylformamide with 1.86g (5.5mmol) of pentachlorophenol methoxyacetate at 50 ℃ for 2 hours. The reaction mixture was diluted with water and the resulting precipitate was isolated by filtration. The wet intermediate was taken up in ethanol (24ml) and 0.50ml concentrate was addedHydrochloric acid, which was boiled for 1 hour. The solvent was evaporated to give a residue, which was dissolved in dichloromethane and the solution was washed with 5% sodium carbonate solution and water. Evaporation of the solvent gave the crude title product, which was purified by column chromatography; a mixture of n-hexane-ethyl acetate (2: 1) was used as eluent to give 2.21g of pure product. Melting point: 153-155 ℃. Yield: 91% [ alpha ]]_D：+317.5°(c＝0.5；CHCl₃).

The compound of example 138-148 was prepared in analogy to the procedure described in example 137 using the appropriate activated carboxylic acid derivative as reagent (e.g.acid chloride, anhydride, pentachlorophenol ester, N-hydroxysuccinimide ester of the corresponding carboxylic acid).

Example 138

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (5-isopropyl-1, 3, 4-thia-dia- Oxazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodi (benzo-b) Aza *

Melting point: 130 ℃ and 133 ℃. Yield: 90 percent.

Example 139

(R) -7- (5-cyclopropyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl-4-nitro-n-methyl-tert-butyl-benzyl-ethyl-benzyl-4-methyl-benzyl- Phenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepines Hetero *

Melting point: 126 ℃ and 130 ℃. Yield: 93 percent.

Example 140

(R) -7- (5-hydroxymethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl-4-) Nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodi (benzo-b) Aza *

Melting point: 142 ℃ and 145 ℃. Yield: 67%.

Example 141

(R) -7- (5-acetoxymethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl) Radical-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3] Benzodiazepine *

Melting point: 110-115 ℃. Yield: 97 percent.

Example 142

(R) -7- (5-cyanomethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl-4-) Nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo[4，5-h][2，3] Benzodi (benzo-b) Aza *

Melting point: 118 ℃ and 122 ℃. Yield: 98 percent.

Example 143

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- (5-methylthiomethyl-1, 3, 4- Thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzene and its derivatives Diaza *

Melting point: 132 ℃ and 134 ℃. Yield: 96 percent.

Example 144

(R) -7- (5-ethoxycarbonyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl) -4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzene and its derivatives Diaza *

Melting point: 115 ℃ and 118 ℃. Yield: 80% [ alpha ]]_D：+140.3°(c＝0.5；CHCl₃).

Example 145

(R) -7- (5-benzyloxycarbonyl-aminomethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl -5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 240 ℃ and 243 ℃. Yield: 95 percent.

Example 146

(R) -8-methyl-5- (3-methyl-4-nitrophenyl) -7- {5- [1- (1E) -propene-1- Base of]-1, 3, 4-thiadiazol-2-yl } -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Melting point: 232 ℃ and 237 ℃. Yield: 28% [ alpha ]]_D：-359.2°(c＝0.4；CHCl₃).

Example 147

(R) -7- (5-hexyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-5- (3-methyl-4-nitro Phenyl) -8, 9-dihydro-7H-1, 3-dioxoleno[4，5-h][2，3] Benzodiazepine *

Melting point: 217 ℃ and 224 ℃. Yield: 66 percent.

Example 148

(R) -7- (5, 6-dihydro-5-oxo-4H-1, 3, 4-thiadiazin-2-yl) -8-methyl -5- (3-methyl-4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The title compound was prepared from the compound obtained in step a of example 136 using the procedure described for example 43, but using pentachlorophenol chloroacetate as alkylating agent. Melting point: 207-211 ℃. Yield: 70% [ alpha ]]_D：+378.5°(c＝0.5；CHCl₃).

Example 149

(R) -8-methyl-5- (4-nitrophenyl) -7- (1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The process of example 45 was followed from (R) -N' - { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine * -7-carbosulfanyl } -carbohydrazide gives the title compound. Melting point: 145-147 ℃. Yield: 35%, [ alpha ]]_D：-604.0°(c＝0.5；CHCl₃).

Example 150

(±) -8-methyl-5- (4-nitrophenyl) -7- (1, 2,3, 4-thiatriazol-5-yl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

A solution of 1.00g (2.5mmol) of the starting material XVIII, 0.37ml (4.6mmol) of trifluoroacetic acid in 10ml of formamide is stirred for 5 minutes at 25 ℃. A solution of 0.16g (2.5mmol) of sodium nitrite in 0.30ml of water is then added dropwise. After 0.5 h, the reaction mixture is diluted with water, the precipitate formed is filtered off, washed with water and dried to yield 0.92g (90%) of the title compound. Melting point: 109 ℃ and 110 ℃.

Example 151

(±) -8-methyl-5- (4-nitrophenyl) -7- (2-methyl-1, 3-oxazol-5-yl) -8, 9- dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(±) -N' - {2- [ 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-yl ] -2-oxoethyl } -acetamide

A solution of 1.5g (4.6mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *, 0.5g (4.6mmol) N-acetylglycine and 1.0g (5.0mmol)1, 3-dicyclohexylcarbodiimide was stirred in 15ml dichloromethane at 25 ℃ for 3 hours. The precipitated 1, 3-dicyclohexylurea is filtered off and the filtrate is evaporated to dryness. The crude product was purified by column chromatography using a mixture of ethyl acetate-hexane (1: 1) as eluent to yield 1.1g (58%) of the title compound.

Step B

0.74g (2.8mmol) of triphenylphosphine were dissolved in 10ml of dichloromethane and a solution of 0.2ml (2.8mmol) of bromine in 1ml of dichloromethane was added. After 30 minutes, a solution of 1.0g (2.4mmol) of the compound prepared in step A and 1.0ml (7.1mmol) of triethylamine in 5ml of dichloromethane is added and the mixture is boiled under nitrogen for 3 hours. The resulting solution was washed with water, dried, and concentrated to dryness. The crude product was purified by column chromatography using a mixture of ethyl acetate-hexane (1: 1) as eluent to yield 0.6g (62%) of the title compound. Melting point: 203-.

Example 152

(±) -7- (2, 4-dimethyl-1, 3-oxazole-5-yl) -8-methyl-5- (4-nitrobenzene Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Following the procedure described in example 151, but using (. + -.) -N- (2- [ 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-yl ] -1-methyl-2-oxoethyl } -acetamide as intermediate, the title compound was obtained in 76-78 ℃ melting point and 68% yield.

Example 153

(R) -5- (3-chloro-4-nitrophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -7- (tert-Butoxycarbonyl) -5- (3-chloro-4-nitrophenyl) -8-methyl-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

According to the literature (Anderson et al, am.117: 12358(1995)) prepared using 3-chloro-4-nitrobenzaldehyde and tert-butyl carbazate as key reagents. Melting point: 160 ℃ and 162 ℃.

Step B

(R) -5- (3-chloro-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

The compound (8.2 g; 18.2mmol) obtained in step A was dissolved in ethyl acetate (82ml) containing 12% hydrochloric acid. The solution was maintained at room temperature for 3 hours. The solvent was then evaporated, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and water. Evaporation gave 5.3g (81%) of the title product. Melting point: 165 ℃ and 170 ℃. [ alpha ] to]_D：+65.0°(c＝0.5；CHCl₃).

Step C

(R) -5- (3-chloro-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl chloride

This compound was prepared from the intermediate obtained in step B according to the procedure described for starting material XI. Melting point: 132 ℃ and 134 ℃. Yield: 88% [ alpha ]]_D：-533.0°(c＝0.5；CHCl₃).

Step D

The title compound was obtained from the compound prepared in step C according to the procedure described for method B of example 28. Melting point: 151 ℃ and 152 ℃. Yield of：89％.[α]_D：+284.1°(c＝0.5；CHCl₃).

Example 154

(R) -5- (3-chloro-4-nitrophenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thia-zole Oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzo (b) is Diaza *

Step A

(R) -5- (3-chloro-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbothiohydrazide

The compound obtained in step C of example 153 was converted into the title compound according to the method described for starting material XVIII. Melting point: 126 ℃ and 127 ℃; yield: 85 percent.

Step B

The title compound was prepared according to the method described for example 137 using the compound obtained in step a. Melting point: 208-210 ℃; yield: 65% [ alpha ]]_D：+470.6°(c＝0.5；CHCl₃).

Example 155

(±) -8-methyl-7- (3-methyl-isoxazol-5-yl) -5- (4-nitrophenyl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(±) -1- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-yl } -butane-1, 3-dione

A solution of 4.0g (12.3mmol) (. + -.) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *, 0.52ml (13.5mmol) diketene in 80ml toluene was stirred at 80 ℃ for 3 hours. The reaction mixture was washed with water, dried, and concentrated. The residue was triturated with diisopropyl ether to give 4.0g (80%) of the title compound. Melting point: 169-171 ℃.

Step B

(±) -4- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-yl } -4-thioxo-butan-2-one

A solution of 3.0g (7.2mmol) of the compound of step A, 2.4g (5mmol) of Lawesson's reagent in 500ml of toluene is stirred at reflux temperature for 4 hours. The reaction mixture was then filtered and the solvent was evaporated. The crude product was purified by column chromatography using a mixture of ethyl acetate-hexane (1: 3) as eluent to yield 2.1g (70%) of the title compound. Melting point: 178 ℃ and 185 ℃.

Step C

A solution of 1.9g (4.5mmol) of the compound obtained in step B and 0.6g (9.0mmol) of hydroxylamine hydrochloride in 20ml of ethanol was stirred and heated under reflux for 3 hours. The reaction mixture was diluted with water and the precipitate formed was filtered off. The crude product was purified by column chromatography using a mixture of ethyl acetate-hexane (1: 3) as eluent to yield 0.60g (32%) of the title compound. Melting point: 179 ℃ and 182 ℃.

Example 156

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thia-ne Oxadiazol-2-yl) -7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -7- (tert-Butoxycarbonyl) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

According to the literature (Anderson et al, J.am.chem Soc.117：12358(1995) The compound was prepared according to the synthesis method described above, but using 3, 5-dimethyl-4-nitrobenzaldehyde and tert-butyl carbazate as key reagents. Melting point: 222 ℃ and 223 ℃. [ alpha ] to]_D：-443.0°(c＝0.5；CHCl₃).

Step B

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

The compound obtained in step a was hydrolyzed according to the method described in step B, example 153. Melting point: 193 ℃; yield: 88% [ alpha ]]_D：+181°(c＝0.5；CHCl₃).

Step C

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl chloride

The compound obtained in step B was converted into the title carbon thio derivative according to the method described for starting compound XI. Melting point: 216 ℃; yield: 82% [ alpha ]]_D：-389°(c＝0.5；CHCl₃).

Step D

The title compound of this example was prepared according to method B described in example 28 from the compound obtained in step C. Melting point: 235 ℃; yield: 86% [ alpha ]]_D：+221°(c＝0.5；CHCl₃).

Example 157

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxa Oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzo (b) is Diaza *

Step D of example 156 was treated with mercury (II) acetate according to the procedure described in example 45The thiosemicarbazide-type intermediate of (1) for 16 hours. Melting point: 132-133 ℃; yield: 90% [ alpha ]]_D：-436°(c＝0.5；CHCl₃).

Example 158

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-bis Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -5- (3, 5-dimethyl-4-nitrophenyl) -8-methyl-7-thiocarbamoyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

This intermediate was prepared from the compound obtained in step B of example 156 by the method described for starting material I, but during the reaction significant hydrolysis of the title product to the corresponding urea derivative was also noted. The title compound was isolated by column chromatography using a mixture of hexane-ethyl acetate (3: 1) as eluent. Melting point: 228 ℃ and 230 ℃; yield: 18 percent.

Step B

The intermediate compound obtained in step a was reacted with bromoacetaldehyde diethyl acetal as described in example 1. Melting point: 167 deg.C; yield: 46 percent.

Example 159

(R) -8-methyl-7- (2-methyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazole-5- Yl) -5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -phenyl- (8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -3-carbosulfanyl) -carbamate

Prepared as described for starting compound XXVI, but from (R) -8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *. The crude product was used without further purification.

Step B

(R) -1-methyl-3- { 8-methyl-5- (4-nitrophenyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl } -urea

The intermediate of step a is reacted with methylamine according to the method described for racemic starting compound XXVII. Melting point: 164 ℃; yield: 63% [ alpha ]]_D：-526°(c＝0.5；CHCl₃).

Step C

The title product was obtained by reacting the compound of step B with bromine according to the procedure described for example 46. Melting point: 177-180 ℃; yield: 98% [ alpha ]]_D：+438°(c＝0.5；CHCl₃).

Example 160

(±) -7- (5, 5-dimethyl-4-oxo-4, 5-dihydro-thiazol-2-yl) -8-methyl -5- (4-nitrophenyl) -1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

To a suspension of 1.20g (2.86mmol) of starting material I in 10ml of dimethylformamide was added 1.67g (8.58mmol) of ethyl-. alpha. -bromoisobutyrate. The mixture was stirred at 80 ℃ for 1 hour and at 100 ℃ and 110 ℃ for 23 hours. The solution was diluted with water and the separated oil was extracted into dichloromethane. After washing and drying, the solvent was evaporated and the residue was purified by column chromatography using a mixture of hexane-ethyl acetate (1: 1) as eluent. The fractions containing the main product were evaporated to yield 0.80g of the title compound as a gum.

Example 161

(R) -8-methyl-5- (4-nitrophenyl) -7- (1, 2, 3-thiadiazol-5-yl) -8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

To an ether solution containing a high excess of diazomethane, a solution of 2.42g (3.0mmo1) of starting material XII in 40ml of tetrahydrofuran is added dropwise at-15 ℃. The solution was kept at room temperature for 5 days until TLC confirmed complete conversion. Evaporation gave a residue which was purified by column chromatography using a mixture of hexane-ethyl acetate (3: 1) as eluent. 2.13g of the title product are obtained. Melting point: 175 ℃ and 176 ℃. [ alpha ] to]_D：-96°(c＝0.5；CHCl₃).

Example 162

(R) -5- (2-bromo-3-methyl-4-nitrophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thia-ne Oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzo (b) is Diaza *

Step A

(R) -5- (2-bromo-3-methyl-4-nitrophenyl) -7- (tert-butoxycarbonyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

According to the literature (Anderson et al, j.am.chem.soc.117: 12358(1995)) using 2-bromo-3-methylbenzaldehyde and tert-butyl carbazate.

MS：EI(70eV)：[M]⁺.：517/519，mz：417/419，376/378，57

CI：[M+H]⁺：518/520

Step B

(R) -5- (2-bromo-3-methyl-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

The compound obtained in step a was hydrolyzed according to the method disclosed in example 153, step B.

MS：EI(70eV)：[M]⁺.：417/419，m/z：402/404，374/376，338，160

CI：[M+H]⁺：418/420，[M]⁺.：417/419

Step C

(R) -5- (2-bromo-3-methyl-4-nitrophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl chloride

The compound obtained in step B was converted into the title compound according to the method described for starting material XI.

MS：EI(70eV)：[M]⁺.：495/497，m/z：460/462，401/403，355/357

CI：[M+H]⁺：496/498/500，m/z：460/462

Step D

The title compound obtained in step C was further reacted with acethydrazide according to the procedure described in method B of example 28 to give the title compound as a foam.

MS：EI(70eV)：[M]⁺.：515/517，m/z：500/502，401/403，59

CI：[M+H]⁺：516/518

Table 12.

2, 3-benzodiazepines * containing aminophenyl groups

(unless otherwise stated, recording at 500MHz¹H NMR Spectrum)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				163	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (4, 5-dihydro-thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	125-128	53-282.0°(c＝0.5，CHCl3)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				Method of producing a composite material*B	1H NMR(DMSO-d6)d 1.10(3H，d，6.0Hz)，2.06(3H，s)，2.53(1H，dd，14.0Hz，10.0Hz)，2.86(1H，dd，14.0Hz，4.5Hz)，3.0-3.2(2H，m)，3.93(1H，m)，4.05(1H，m)，4.85(1H，m)，5.35(2H，s)，6.04(1H，s)，6.07(1H，s)，6.55(1H，s)，6.61(1H，d，8.5Hz)，6.98(1H，s)，7.13(1H，d，br，8.5Hz)，7.22(1H，s，br)
164	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	124-127	86-619.5°(c＝0.5，CHCl3)
				Method B	1H NMR(DMSO-d6)d 1.16(3H，d，6.0Hz)，2.09(3H，s)，2.59(1H，dd，14.0Hz，10.5Hz)，2.95(1H，dd，14.0Hz，5.5Hz)，5.01(1H，m)，5.47(2H，s，br)，6.03(1H，d，1.1Hz)，6.08(1H，d，1.1Hz)，6.58(1H，s)，6.64(1H，d，8.0Hz)，6.83(1H，d，3.5Hz)，7.05(1H，s)，7.21(1H，dd，8.0Hz，2.0Hz)，7.28(1H，d，3.5Hz)，7.31(1H，d，2.0Hz)
165	(R) -5- (4-amino-3-methylphenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	129-133(EtOH)	90-534.9°(c＝0.5，CHCl3)
				Method B	1H NMR(DMSO-d6)d 1.20(3H，d，6.1Hz)，1.23(3H，t，7.6Hz)，2.07(3H，s)，2.58(1H，dd，14.0Hz，10.6Hz)，2.85(2H，q，7.6Hz)，2.95(1H，dd，14.0Hz，5.4Hz)，4.93(1H，m)，5.50(2H，s，br)，6.03(1H，d，1.0Hz)，6.08(1H，d，1.0Hz)，6.57(1H，s)，6.63(1H，d，8.4Hz)，7.06(1H，s)，7.20(1H，dd，8.4Hz，2.1Hz)，7.25(1H，d，2.1Hz)MS：EI(70eV)：[M]+.：421，m/z：406，293，266CI：[M+H]+：422，[M]+.：421
166	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-propyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	150-154(EtOH)	56-516.0°(c＝0.5，CHCl3)
				Method B	1H NMR(DMSO-D6)d 0.91(t，7.5Hz)，1.20(3H，d，6.1Hz)，1.66(2H，m)，2.08(3H，s)，2.58(1H，dd，13.8Hz，10.6Hz)，2.80(2H，t，7.2Hz)，2.96(1H，dd，13.8Hz，5.1Hz)，4.94(1H，m)，5.50(2H，s)，6.03(1H，s)，6.08(1H，s)，6.57(1H，s)，6.64(1H，d，8.3Hz)，7.05(1H，s)，7.19(1H，dd，8.3Hz，2.1Hz)，7.25(1H，d，2.1Hz)
167	(R) -5- (4-amino-3-methylphenyl) -8-methyl	143-148	63

See the general procedure given in examples 60-118 above for the reduction of the nitro group of each 2, 3-benzodiazepine *

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	(EtOAc)	-527.3°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.21(3H，d，6.1Hz)，2.08(3H，s)，2.61(1H，dd，13.6Hz，10.6Hz)，3.00(1H，dd，13.6Hz，5.0Hz)，5.00(1H，m)，5.52(2H，s，br)，6.03(1H，d，0.7Hz)，6.08(1H，d，0.7Hz)，6.58(1H，s)，6.64(1H，d，8.3Hz)，7.07(1H，s)，7.20(1H，dd，8.3Hz，2.1Hz)，7.28(1H，d，2.1Hz)，8.78(1H，s)MS：EI(70eV)：[M]+.：393，m/z：378，266CI：[M+H]+：394，[M]+.：393
				168	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	171-172(EtOH)	86-540.0°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.21(3H，d，6.1Hz)，2.08(3H，s)，2.60(1H，dd，14.0Hz，11.0Hz)，2.97(1H，dd，14.0Hz，5.4Hz)，4.57(1H，d，12.7Hz)，4.60(1H，d，12.7Hz)，4.98(1H，m)，5.3-5.8(2H)，6.03(1H，s)，6.08(1H，s)，6.58(1H，s)，6.65(1H，d，8.6Hz)，7.06(1H，s)，7.21(1H，dd，8.6Hz，2.2Hz)，7.26(1H，d，2.2Hz)
				169	(R) -5- (4-amino-3-methylphenyl) -7- (5-isopropyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	134-140	83-518.8°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.20(3H，d，6.2Hz)，1.26(3H，d，6.9Hz)，1.28(3H，d，6.9Hz)，2.07(3H，s)，2.58(1H，dd，13.8Hz，10.8Hz)，2.95(1H，dd，13.8Hz，5.5Hz)，3.18(1H，m)，4.94(1H，m)，5.51(2H，s，br)，6.03(1H，s)，6.08(1H，s)，6.57(1H，s)，6.64(1H，d，8.4Hz)，7.06(1H，s)，7.21(1H，dd，8.4Hz，2.1Hz)，7.24(1H，d，2.1Hz)
				170	(R) -5- (4-amino-3-methylphenyl) -7- (5-cyclopropyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	124-128	47-504.1°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-D6)d 0.86(2H，m)，1.03(2H，m)，1.16(3H，d，6.2Hz)，2.07(3H，s)，2.23(1H，m)，2.57(1H，dd，14.0Hz，10.8Hz)，2.95(1H，dd，14.0Hz，5.5Hz)，4.92(1H，m)，5.50(2H，s)，6.03(1H，s)，6.08(1H，s)，6.55(1H，s)，6.64(1H，d，8.3Hz)，7.05(1H，s)，7.19(1H，dd，8.3Hz，2.1Hz)，7.23(1H，d，2.1Hz)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				171	(R) -5- (4-amino-3-methylphenyl) -7- (5-hydroxymethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	184-186	75-540.0°(c＝0.5，CHCl3)
Method A	1H NMR(DMSO-d6)d 1.20(3H，d，6.1Hz)，2.08(3H，s)，2.60(1H，dd，13.9Hz，10.6Hz)，2.97(1H，dd，13.9Hz，5.3Hz)，4.61(2H，d，5.8Hz)，4.95(1H，m)，5.52(2H，s)，5.81(1H，t，5.8Hz)，6.03(1H，s)，6.08(1H，s)，6.58(1H，s)，6.65(1H，d，8.5Hz)，7.06(1H，s)，7.19(1H，dd，8.5Hz，2.0Hz)，7.26(1H，d，2.0Hz)
				172	(R) -7- (5-acetoxymethyl-1, 3, 4-thiadiazol-2-yl) -5- (4-amino-3-methylphenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	204-206(EtOH)	45-560.0°(c＝0.5，CHCl3)
Method E	1H NMR(DMSO-d6)d 1.21(3H，d，6.2Hz)，2.07(3H，s)，2.08(3H，s)，2.60(1H，dd，14.0Hz，11.0Hz)，2.97(1H，dd，14.0Hz，5.4Hz)，4.99(1H，m)，5.20(1H，d，13.1Hz)，5.24(1H，d，13.1Hz)，5.55(2H，s)，6.03(1H，s)，6.09(1H，s)，6.59(1H，s)，6.65(1H，d，8.4Hz)，7.06(1H，s)，7.21(1H，dd，8.4Hz，2.1Hz)，7.26(1H，d，2.1Hz)
				173	(R) -5- (4-amino-3-methylphenyl) -7- (5-cyanomethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	135-140	25-517.9°(c＝0.5，CHCl3)
Method A	1H NMR(DMSO-d6)d 1.21(3H，d，6.2Hz)，2.08(3H，s)，2.61(1H，dd，13.9Hz，11.0Hz)，2.99(1H，dd，13.9Hz，5.5Hz)，4.40(2H，s)，4.96(1H，m)，5.55(2H，s)，6.03(1H，d，0.7Hz)，6.09(1H，d，0.7Hz)，6.59(1H，s)，6.65(1H，d，8.3Hz)，7.06(1H，s)，7.21(1H，dd，8.3Hz，1.8Hz)，7.26(1H，d，1.8Hz)
				174	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methylthiomethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	177-180(EtOH)	57-496.0°(c＝0.5，CHCl3)
Method A	1H NMR(DMSO-d6)d 1.21(3H，d，6.1Hz)，2.03(3H，s)，2.08(3H，s)，2.60(1H，dd，13.8Hz，10.6Hz)，2.97(1H，dd，13.8Hz，5.3Hz)，3.91(1H，d，14.7Hz)，3.95(1H，d，14.7Hz)，4.96(1H，m)，5.52(2H，s)，6.03(1H，d，0.9Hz)，6.09(1H，d，0.9Hz)，6.59(1H，s)，6.65(1H，d，8.4Hz)，7.06(1H，s)，7.21(1H，dd，8.4Hz，2.0Hz)，7.25(1H，d，2.0Hz)
				175	(R) -5- (4-amino-3-methylphenyl) -7- (5-ethane	135-140	86

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					Oxycarbonyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *		-606.3°(c＝0.5，CHCl3)
Method E	1H NMR(DMSO-d6)d 1.15(3H，d，6.2Hz)，1.30(3H，t，7.1Hz)，2.09(3H，s)，2.64(1H，dd，13.8Hz，11.3Hz)，2.99(1H，dd，13.8Hz，5.4Hz)，4.30(2H，m)，5.11(1H，m)，5.65(2H，s)，6.04(1H，s)，6.09(1H，s)，6.61(1H，s)，6.65(1H，d，8.3Hz)，7.08(1H，s)，7.25(1H，dd，8.3Hz，2.0Hz)，7.26(1H，d，2.0Hz)
				176	(R) -5- (4-amino-3-methylphenyl) -7- (5-aminomethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	139-140(EtOH)	31-482.2°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.21(3H，d，6.0Hz)，2.08(3H，s)，2.59(1H，dd，13.9Hz，13.9Hz)，2.95(1H，dd，13.9Hz，5.1Hz)，3.87(2H，s)，4.95(1H，m)，5.50(2H，s)，6.03(1H，s)，6.07(1H，s)，6.57(1H，s)，6.65(1H，d，8.1Hz)，7.05(1H，s)，7.21(1H，d，br，8.1Hz)，7.26(1H，s，br)
				177	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- {5- [1- (1E) -propen-1-yl]-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	139-143	65-498.9°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.21(3H，d，6.2Hz)，1.86(1H，dd，6.8Hz，1.8Hz)，2.08(3H，s)，2.59(1H，dd，14.0Hz，10.8Hz)，2.98(1H，dd，14.0Hz，5.4Hz)，4.98(1H，m)，5.53(2H，s，br)，6.03(1H，s)，6.08(1H，s)，6.32(1H，dq，15.7Hz，6.8Hz)，6.55(1H，dq，15.7Hz，1.8Hz)，6.57(1H，s)，6.44(1H，d，8.4Hz)，7.06(1H，s)，7.22(1H，dd，8.4Hz，2.1Hz)，7.26(1H，d，2.1Hz)
				178	(R) -5- (4-amino-3-methylphenyl) -7- (5-hexyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	180-181	75-485.2°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 0.84(3H，t，7.0Hz)，1.20(3H，d，6.1Hz)，1.2-1.3(6H，m)，1.62(2H，m)，2.07(3H，s)，2.58(1H，dd，13.9Hz，10.5Hz)，2.82(2H，t，7.5Hz)，2.95(1H，dd，13.9Hz，5.4Hz)，4.94(1H，m)，5.49(2H，s)，6.03(1H，s)，6.08(1H，s)，6.57(1H，s)，6.64(1H，d，8.4Hz)，7.05(1H，s)，7.19(1H，dd，8.4Hz，2.2Hz)，7.25(1H，d，2.2Hz)
				179	(R) -5- (4-amino-3-methylphenyl) -8-methyl	175-180	61

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					- (5, 6-dihydro-5-oxo-4H-1, 3, 4-thiadiazin-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *		-686.0°(c＝0.5，CHCl3)
Method B	1H NMR(DMSO-d6)d 1.15(3H，d，6.4Hz)，2.05(3H，s)，2.48(1H，dd，13.8Hz，10.4Hz)，2.85(1H，dd，13.8Hz，5.3Hz)，3.32(2H，s)，4.75(1H，m)，5.42(2H，s)，6.04(1H，s)，6.07(1H，s)，6.55(1H，s)，6.61(1H，d，8.4Hz)，6.99(1H，s)，7.15(1H，dd，8.4Hz，1.8Hz)，7.26(1H，d，1.8Hz)，10.47(1H，s)
				180	(R) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	187-190	78-604.0°(c＝0.5，CHCl3)
Method A	1H NMR(CDCl3)d 1.45(3H，d，6.0Hz)，2.73(1H，dd，14.0Hz，10.5Hz)，2.86(1H，dd，14.0Hz，5.5Hz)，3.99(2H，s，br)，4.94(1H，m)，5.98(1H，d，1.0Hz)，6.02(1H，d，1.0Hz)，6.64(1H，s)，6.68(2H，d，8.0Hz)，6.82(1H，s)，7.56(2H，d，8.0Hz)，7.99(1H，s)
				181	(R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	140-145	85-554.8°(c＝0.5，CHCl3)
Method B	MS：EI(70eV)：[M]+.：391，m/z：266CI：[M+H]+：392
				182	(R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzo (b) isDiaza *	98-100	92-266.0°(c＝0.5，CHCl3)
Method C	1H NMR(DMSO-d6)d 1.18(3H，d，6.0Hz)，2.50(3H，s)，2.65(1H，dd，14.0Hz，9.9Hz)，2.98(1H，dd，14.0Hz，4.9Hz)，4.95(1H，m)，5.95(2H，s)，6.05(1H，s)，6.09(1H，s)，6.63(1H，s)，6.83(1H，d，8.6Hz)，7.07(1H，s)，7.24(1H，dd，8.6Hz，2.0Hz)，7.44(1H，d，2.0Hz)MS：EI(70eV)：[M]+.：427/429，m/z：412/414，313/315，286/288，160CI：[M+H]+：428/30，[M]+.：427/429
				183	(R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H][2，3]Benzodiazepine *	105-109	91-350.0°(c＝0.5，CHCl3)

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				Method C	1H NMR(DMSO-d6)d 1.20(3H，d，6.1Hz)，2.67(1H，dd，14.1Hz，10.3Hz)，3.00(1H，dd，14.1Hz，5.4Hz)，3.32(3H，s)，4.58(1H，d，13.0Hz)，4.62(1H，d，13.0Hz)，5.01(1H，m)，5.98(2H，s，br)，6.05(1H，s)，6.09(1H，s)，6.64(1H，s)，6.84(1H，d，8.4Hz)，7.07(1H，s)，7.29(1H，dd，8.4Hz，1.8Hz)，7.44(1H，d，1.8Hz)MS：EI(70eV)：[M]+.：457/459，m/z：442/444，313/315，286/288，160CI：[M+H]+：458/60，[M]+.：457/459
184	(R) -5- (4-amino-2-bromo-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	Foam	98
				Method A	1H NMR(CDCl3)d 1.25(3H，d，6.2Hz)，2.25(3H，s)，2.53(3H，s)，2.93(1H，dd，14.6Hz，7.3Hz)，3.25(1H，dd，14.6Hz，3.1Hz)，3.4-4.3(2H)，5.43(1H，m)，5.92(1H，d，1.4Hz)，5.93(1H，d，1.4Hz)，6.36(1H，s)，6.69(1H，d，8.1Hz)，6.72(1H，s)，7.12(1H，d，8.1Hz)MS：EI(70eV)：[M]+.：485/487，m/z：470/472，406，265，219CI：[M+H]+：486/488
185	(±) -5- (4-aminophenyl) -8-methyl-7- (3-methyl-isoxazol-5-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	100-103	87
				Method C	1H NMR(DMSO-d6)d 1.16(3H，d，6.5Hz)，2.07(3H，s)，2.45(1H，dd，14.0Hz，11.5Hz)，2.88(1H，dd，14.0Hz，6.0Hz)，4.58(1H，m)，5.26(1H，s)，5.70(2H，s)，6.02(1H，s)，6.07(1H，s)，6.56(1H，s)，6.58(2H，d，8.5Hz)，7.03(1H，s)，7.36(2H，d，8.5Hz)MS：EI(70eV)：[M]+.：376，m/z：306，265，252，82，54CI：[M+H]+：377，[M]+.：376
186	(R) -5- (4-aminophenyl) -8-methyl-7- (1, 2, 3-thiadiazol-5-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	220-221	33-705.0°(c＝0.5，CHCl3)
				Method A	1H NMR(DMSO-d6)d 1.18(3H，d，6.1Hz)，2.60(1H，dd，13.8Hz，11.4Hz)，2.95(1H，dd，13.8Hz，5.1Hz)，4.75(1H，m)，5.81(2H，s，br)，6.03(1H，s)，6.08(1H，s)，6.59(1H，s)，6.61(2H，d，8.4Hz)，7.08(1H，s)，7.35(2H，d，8.4Hz)，8.10(1H，s)MS：EI(70eV)：[M]+.：379，m/z：351，336，279，252

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
					CI：[M+H]+：380，m/z：352
187	(±) -5- (4-aminophenyl) -8-methyl-7- (2-methyl-1, 3-oxazol-5-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	148-150	88
				Method A	1H NMR(DMSO-d6)d 1.07(3H，d，5.3Hz)，2.23(3H，br)，2.40(1H，dd，13.7Hz，7.7Hz)，2.83(1H，dd，13.7Hz，5.6Hz)，4.31(1H，m)，5.58(s，br)，6.03(1H，s)，6.05(1H，s)，6.54(2H，d，8.2Hz)，6.57(1H，s)，7.00(1H，s)，7.28(2H，d，8.2Hz)MS：EI(70eV)：[M]+.：376，m/z：335，306，265，252CI：[M+H]+：377
188	(±) -5- (4-aminophenyl) -8-methyl-7- (2, 4-dimethyl-1, 3-oxazol-5-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	180-182	92
				Method A	1H NMR(DMSO-d6)d 0.94(3H，d，6.1Hz)，1.76(3H，s)，2.29(3H，s)，2.43(1H，dd，13.8Hz，3.3Hz)，2.79(1H，dd，13.8Hz，6.6Hz)，4.13(1H，m)，5.53(s，br)，6.07(1H，s)，6.08(1H，s)，6.52(2H，d，8.4Hz)，6.58(1H，s)，6.99(1H，s)，7.18(2H，d，8.4Hz)MS：EI(70eV)：[M]+.：390，m/z：349，334，306，279，265，252CI：[M+H]+：391，[M]+.：390
189	(R) -5- (4-amino-3, 5-dimethylphenyl) -8-methyl-7- (thiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	202-203	75-686.0°(c＝0.3，CHCl3)
				Method A	MS：EI(70eV)：[M]+.：406，m/z：391，307，280
190	(R) -5- (4-amino-3, 5-dimethylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	280-281	74-538.0°(c＝0.5，CHCl3)
				Method A	1H NMR(DMSO-d6)d 1.18(3H，d，6.1Hz)，2.11(6H，s)，2.49(3H，s)，2.57(1H，dd，13.9Hz，10.8Hz)，2.95(1H，dd，13.9Hz，5.1Hz)，4.93(1H，m)，5.19(2H，s，br)，6.03(1H，d，0.5Hz)，6.08(1H，d，0.5Hz)，6.56(1H，s)，7.05(1H，s)，7.12(2H，s)MS：EI(70ey)：[M]+.：421，m/z：406，307，306，280CI：[M+H]+：422

Example numbering	Name (R)	Melting Point (. degree. C.) recrystallization solvent	Yield (%) [ alpha]D
				191	(R) -5- (4-amino-3, 5-dimethylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H)][2，3]Benzodiazepine *	148-150	87-705.0°(c＝0.5，CHCl3)
Method A	MS：EI(70eV)：[M]+.：405，m/z：280，245，134，83，77CI：[M+H]+：406
				192	(R) -5- (4-aminophenyl) -8-methyl-7- (2-methyl-3-oxo-2, 3-dihydro-1, 2, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxoleno- [4, 5-H][2，3]Benzodiazepine *	185-190	60-45.0°(c＝0.47，CHCl3)
Method A	1H NMR(DMSO-d6)d 1.19(3H，d，6.5Hz)，2.69(1H，dd，14.0Hz，10.0Hz)，3.00(1H，dd，14.0Hz，4.5Hz)，3.05(3H，s)，4.89(1H，m)，5.81(2H，s，br)，6.05(1H，s)，6.08(1H，s)，6.58(2H，d，8.5Hz)，6.59(1H，s)，7.06(1H，s)，7.26(2H，d，8.5Hz)MS：EI(70eV)：[M]+.：409，m/z：279，252CI：[M+H]+：410，[M]+.：409
				193	(±) -5- (4-aminophenyl) -8-methyl-7- (5, 5-dimethyl-4-oxo-4, 5-dihydrothiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H][2，3]Benzodiazepine *	124-130 amorphous	75
Method A	MS：EI(70eV)：[M]+.：422，m/z：407，279，252CI：[M+H]+：423

Example 194

(R) -7- (4, 5-dihydro-thiazol-2-yl) -5- (4-chlorophenyl) -8-methyl-8, 9-dihydro -7H-1，3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -7- (tert-Butoxycarbonyl) -5- (4-chlorophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

According to the literature (Anderson et al, j.am.chem.soc.117: 12358(1995)) except that t-butyl carbazate and 4-chlorobenzaldehyde were used instead of acethydrazide and 4-nitrobenzaldehyde, respectively. The title product was isolated as a foam and used in the next step.

Step B

(R) -5- (4-chlorophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

11.0g (28.2mmol) of the product obtained in step A were dissolved in 120ml of ethyl acetate containing 10% hydrochloric acid and stirred for 3 hours, and then the solution was washed with sodium carbonate and water. After drying and evaporation, the crude product was recrystallized from ethyl acetate to yield 5.07g (57%) of the title compound. Melting point: 185-187 deg.C; [ alpha ] to]_D：+241.0°(c＝0.5；CHCl₃).

Step C

(R) -5- (4-chlorophenyl) -8-methyl-7-thiocarbamoyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *

A mixture containing 1.57g (5.0mmol) of the product obtained in step B, 0.73g (7.5mmol) of potassium thiocyanate and 16ml of acetic acid was stirred at 110 ℃ for 3 hours. After cooling, water was added and the precipitated crystals were filtered off, washed with water and dried to yield 1.73g (92%) of the title compound. Melting point: 208 ℃ and 212 ℃.

Step D

The compound obtained in step C (1.0g, 2.66mM) was reacted with 2.20g (10.7mmol) of 2-bromoethylamin hydrobromide in 5ml of dimethylformamide according to the method described in example 9. The product was isolated by column chromatography with the addition of recrystallization from ethyl acetate to yield 0.26g (25%) of the title compound. Melting point: 216-219 ℃; [ alpha ] to]_D：+326.7°(c＝0.5；CHCl₃).

¹H NMR(DMSO-d₆)δ1.11(3H，d，5.7Hz)，2.79(1H，dd，14.7Hz，6.4Hz)，3.16(1H，dd，14.7Hz，1.7Hz)，3.25(2H，m)，4.16(2H，m)，4.28(2H，m)，5.25(1H，m)，5.99(2H，s)，6.59(1H，s)，6.71(1H，s)7.34(2H，d，8.0Hz)，7.53(2H，d，8.0Hz)

Example 195

(R) -5- (4-chlorophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

The compound obtained in step C of example 194 (0.55g, 1.47mmol) was reacted with 0.22ml (1.47mmol) of bromoacetaldehyde diethyl acetal according to the method described for example 1. The crude product was purified by column chromatography using a mixture of n-hexane-ethyl acetate (2: 1) as eluent. After concentration of the fractions containing the title compound, the residue was treated with water to yield 0.40g (68%) of the title compound. Melting point: 116 ℃ and 117 ℃; [ alpha ] to]_D：+118.6°(c＝0.5；CHCl₃).

¹H NMR(CDCl₃)δ1.22(3H，d，6.4Hz)，2.83(1H，dd，14.6Hz，7.2Hz)，3.18(1H，dd，14.6Hz，3.4Hz)，5.38(1H，m)，6.01(2H，s)，6.61(1H，s)，6.69(1H，d，3.7Hz)，6.78(1H，s)，7.32(1H，d，3.7Hz)，7.38(2H，d，8.6Hz)，7.58(2H，d，8.6Hz)

Example 196

(R) -5- (4-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine *

Step A

(R) -5- (4-chlorophenyl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * -7-carbosulfanyl chloride

The compound obtained in step B of example 194 (2.20g, 7.0mmol) was reacted according to the method described for starting compound XI. The crude product was purified by column chromatography using a mixture of n-hexane-ethyl acetate (4: 1) as eluent to yield 1.38g (49%) of the title compound as a solid foam.

Step B

The title compound was prepared according to the method described for example 28 method B, using 1.0g (2.48mmol) of the product obtained in step A. The product was isolated by column chromatography and solidified with water to yield 0.42g (52%). Melting point: 105 ℃ and 108 ℃; [ alpha ] to]_D：+103.2°(c＝0.5；CHCl₃).

¹H NMR(CDCl₃)δ1.25(3H，d，6.2Hz)，2.61(3H，s)，2.84(1H，dd，14.3Hz，7.1Hz)，3.18(1H，dd，14.3Hz，3.6Hz)，5.35(1H，m)，6.02(2H，s)，6.57(1H，s)，6.79(1H，s)，7.38(2H，d，8.2Hz)，7.52(2H，d，8.2Hz)

Example 197

(R) -5- (4-acetylamino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4- Thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzene and its derivatives Diaza *

The compound of example 119 was acetylated according to the general procedure described in example 120-131. Melting point: 267-. Yield: 67%; [ alpha ] to]_D：-121.0°(c＝0.5；CHCl₃).

¹H NMR(DMSO-d₆)δ1.16(3H，d，6.1Hz)，2.10(3H，s)，2.25(3H，s)，2.50(3H，s)，2.79(1H，dd，14.0Hz，8.2Hz)，3.09(1H，dd，14.0Hz，4.0Hz)，5.08(1H，m)，6.07(1H，s)，6.09(1H，s)，6.55(1H，s)，7.07(1H，s)，7.31(1H，d，8.3Hz)，7.38(1H，8，br)，7.59(1H，d，br，8.3Hz)，9.36(1H，s)

Example 198

(R) -1-methyl-3 { 2-methyl-4- [ 8-methyl-7- (5-methyl-1, 3, 4-thiadiazole-2- Radical) -8, 9-dihydro-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -5-yl]} -phenylureas

The material obtained in example 119 (1.03g, 2.53mmol) was reacted with 0.75ml (12.6mmol) of methyl isocyanate in 20ml of dichloromethane at room temperature for 6 days. Evaporation of the solvent gave a crude product which was purified by column chromatography using a mixture of hexane-ethyl acetate (2: 1) as eluent to give 0.67g (57%) of the title compound. Melting point: 237-242 ℃; [ alpha ] to]_D：-140.0°(c＝0.5；CHCl₃).

¹H NMR(DMSO-d₆)δ1.17(3H，d，6.4Hz)，2.21(3H，s)，2.51(3H，s)，2.66(3H，d，4.6Hz)，2.71(1H，dd，14.2Hz，9.4Hz)，3.04(1H，dd，14.2Hz，4.5Hz)，5.02(1H，m)，6.05(1H，d，0.9Hz)，6.08(1H，d，0.9Hz)，6.55(1H，s)，6.56(1H，q，4.6Hz)，7.07(1H，s)，7.30(1H，dd，8.4Hz，2.0Hz)，7.34(1H，d，2.0Hz)，7.82(1H，s)，8.00(1H，d，8.4Hz)

Example 199

(R) -2-methyl-4- [ 8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-di Hydrogen-7H-1, 3-Meta-dioxacyclopenteno[4，5-h][2，3]Benzodiazepine * -5-yl]-benzene Carbamic acid ethyl ester

The substance obtained in example 119 (0.90g, 2.21mmol) was reacted with ethyl chloroformate (0.30ml, 3.15mmol) in dichloromethane at room temperature in the presence of 0.40ml (2.88mmol) of triethylamine for 6 hours. The solution was washed with dilute hydrochloric acid and sodium bicarbonate solution, dried and evaporated to dryness. A mixture of hexane-ethyl acetate (2: 1) was used asEluent, and the residue was purified by column chromatography to yield 0.45g (42%) of the title product. Melting point: 241-244 ℃; [ alpha ] to]_D：-180.0°(c＝0.5；CHCl₃).

¹H NMR(DMSO-d₆)δ1.15(3H，d，6.1Hz)，1.25(3H，t，7.0Hz)，2.25(3H，s)，2.51(3H，s)，2.78(1H，dd，14.3Hz，8.7Hz)，3.05(1H，dd，14.3Hz，4.3Hz)，4.13(2H，q，7.0Hz)，5.07(1H，m)，6.06(1H，d，0.7Hz)，6.08(1H，d，0.7Hz)，6.55(1H，s)，7.07(1H，s)，7.31(1H，dd，8.3Hz，2.0Hz)，7.36(1H，d，2.0Hz)，7.53(1H，d，8.3Hz)，8.96(1H，s)

Further results for the compounds of the invention are gathered in the following table, illustrating the AMPA antagonist activity of the compounds of formula (I). (corresponding in vitro and in vivo research methods and related documents are described and cited in the preamble of the present application.)

Table 13 (continuation table 1)

Inhibition of "spreading depression" in chicken retina

Compounds (example numbers)/IC50μM
						119	165	166	167	168	182
0.069	0.113	0.201	0.064	0.082	0.020

Table 14 (continuation table 2)

Inhibition of ionic current caused by 5 μ M AMPA by whole cell patch clamp method System for making

Compounds (example numbers)/IC50μM
						119	165	166	167	168	182
0.026	0.024	0.028	0.070	0.011	0.031

Table 15 (continuation table 3)

Study of anticonvulsant Activity in mice

Method of producing a composite material	Compounds (example numbers)/ED50mg/kg po.
							119	165	166	167	168	182
	MES 60’	2.87	3.99	4.01	5.85	4.49							6.17
MES 30’							2.15	2.39	4.54	4.78	2.21	5.08
	Penta tetra nitrogen	5.00	10.10	9.18	9.66	6.90							8.37
Strychnine							8.40	10.20	7.29	10.50	10.00	5.90
	Beimege	5.70	10.00	7.77	8.33	6.70							7.94
Dicentrine							2.50	5.79	13.30	12.70	10.60	8.44
	Nicotine	6.30	18.60	21.80	10.80	17.70							24.20
4-AP							2.68	8.60	6.81	10.80	4.60	5.44
	3-MPA	3.37	8.53	9.92	10.30	4.62							7.57

Abbreviations: MES ═ maximal electroshock onset; 4-AP ═ 4-aminopyridine; 3-MPA ═ 3-mercapto-propionic acid

Table 16 (continuation table 4)

Muscle relaxant activity in mice

Compounds (example No.)	Inclined sieve ED50Intraperitoneal (mg/kg)	RotarodED50Intraperitoneal (mg/kg)
			119	2.49	0.51
165	2.94	0.91
			166	3.27	0.86
167	4.24	0.80
			168	3.58	0.80
182	5.84	2.61

TABLE 17 (continuation Table 5)

Inhibition of ischemia in rats

Compounds (example No.)	Dose mg/kg intravenous (6X, every 30 minutes)	Reduction in infarct size compared to control group%
						30 minutes	120 minutes	180 minutes	240 minutes
		Time to first treat after occlusion
						119	0.5		7
	1.0		38
							1.5		51*	21
	2.0		56*	44**	21

P < 0.05; p < 0.01; dunnett's test calculation by ANOVA

(Dunnett J.Amer.Statist.Ass. 50：1096(1955))

As described earlier in the specification, except that 10 animals weighing 140-160g (Lewis rats, females) were used in each group, the compounds of the present invention were further studied in a rat autoimmune encephalomyelitis model. The results are shown in tables 19 and 20.

Table 18 (continuation table 6)

2, 3-benzodiazepine * having AMPA antagonist Activity in Lewis rats Effect of clinical symptoms of autoimmune encephalomyelitis

Compounds (example No.)	Dosage form		Neurological symptoms (vs. control)Change in comparison,%) female rats
					mg/kg intraperitoneally	mg/kg p.o.	0-8 days	0-14 days
	119	3.751.8751.00.50.2	3.751.8751.00.5	-97***-72*-75**-33-36-64***-50**-20+2					-90**-71**-72**-35-37-61***-50**-23-1
166						7.53.75	-51*-6	-53*-9
	168		7.53.75	-55*-16					-56*-23

See table 20 for statistics.

Table 19 (continuation table 7)

2, 3-benzodiazepine * derivatives with AMPA antagonist characteristics were administered 24 days after immunization Effect of histological and clinical symptoms of autoimmune encephalomyelitis in Lewis rats

Compounds (example No.)	Dosage form		Histopathological symptoms (% change)	Neurological symptoms (% change)
					mg/kg intraperitoneally	mg/kgp.o.	Female rat
	119	3.751.8751.00.50.2	3.751.8751.00.5	+3-8-3-13+2-32-42-21-16					-90**-71**-72**-35-37-61***-50**-23-1

P < 0.05; p < 0.01; p < 0.001(Mann-Whitney test).

Table 20 (continuation table 8)

2, 3-benzodiazepine * derivatives with AMPA antagonist characteristics for different chemistries Effect of agent-induced tremor in CD1 mice

Compounds (example No.)	ED50(mg/kg po.)
			Oxygradixin 1mg/kg intraperitoneal	GYKI 2003910mg/kg intraperitoneal
	119	1.38(0.80-2.38)			2.21(1.37-3.56)
165			4.63(3.66-5.85)	5.34(3.90-7.31)
	166	2.74(1.97-3.00)			4.54(3.69-5.58)
167			4.81(3.45-6.72)	7.73(4.99-11.98)
	168	3.29(2.63-4.12)			4.11(3.22-5.45)
182			2.66(1.24-5.72)	3.64(2.37-5.57)

Table 21 (continuation table 9)

The compound described in example 119 was sensitized to ovalbumin and by inhalation Bronchial hyperreactivity and eosinophilia in the airways of antigen-challenged BN-rats Using (mean ± sd, N ═ 10, p was determined by Student's t-test).

			Compounds (example No.)
				Parameter(s)	Control	Attack of	1193.0mg/kg po
ED50*	5.19±0.07	5.97±0.29	4.35±0.36
				p	0.001		0.001
MAX**	100±0	154±21	82±7
				p	0.001		0.009
Eosinophil	0.15±0.03	1.17±0.18	1.16±0.24
				p	0.001		NS*

Concentration of acetylcholine (Ach) (-log M) causing 50% contraction compared to control

Relative contraction at maximum Ach concentration compared to control

Basf eosinophil number (× 10)⁶/ml)

^*Not significant (p > 0.05)

Equivalent scheme

Although the claimed invention has been described in detail with reference to specific embodiments, those skilled in the art will appreciate that various changes and modifications can be made to the claimed invention without departing from the spirit and scope thereof. Thus, for example, those of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific materials and methods described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

Claims (24)

1. A compound of formula (I), wherein

R³Represents a substituted or unsubstituted 5-or 6-membered aromatic, saturated or partially saturated heterocyclic ring containing at least 2 heteroatoms, which may be oxygen, sulphur or nitrogen atoms, and when the heterocyclic ring contains 2 heteroatoms, one of which is not nitrogen;

R⁴，R⁵，R⁶and R⁷Independently of one another, represents a hydrogen atom, a halogen atom, C₁-C₃Alkyl, nitro, amino, wherein the amino groups can be substituted independently of one another by 1 or 2 of the following groups: c₁-C₃Alkyl radical, C₂-C₅Acyl or C₂-C₅Alkoxycarbonyl, or aminocarbonyl, or C₂-C₅An alkylaminocarbonyl group; and is

R⁹Represents C₁-C₃An alkoxy group or a halogen atom, or a salt thereof,

R¹⁰represents a hydrogen or halogen atom or

R⁹And R¹⁰Together form C₁-C₃An alkylenedioxy group; and

stereoisomers and acid addition salts of said compounds.

2. A compound according to claim 1, wherein R³The heterocyclic ring of (a) may be further substituted with one or more of the following substituents: c₁-C₅Alkyl radical, C₂-C₃Alkenyl radical, C₃-C₇Cycloalkyl, trifluoromethyl, C₁-C₃Alkoxy or phenyl, oxo, formyl, carboxy or C₂-C₄Alkoxycarbonyl radical, C₁-C₃Alkoxymethyl, halogen atoms, hydroxymethyl, in which the hydroxyl group may be alkylated or acylated, C₁-C₃Alkylthiomethyl, cyanomethyl or aminomethyl, where the amino group may be alkylated or acylated.

3. A compound according to claim 1, wherein R³Is selected from: substituted and unsubstituted isoxazole, isothiazole, thiazole, thiazoline, 4-thiazolinone, oxazole, oxazoline, 1, 2, 3-thiadiazole, 1, 3, 4-thiadiazolin-2-one, 1, 2, 4-thiadiazolin-3-one, 1, 4, 2-oxathiazoline, 1, 3, 4-oxadiazole, 1, 2, 3-triazole, 1, 3, 4-triazole, 1, 2,3, 4-thiatriazole, tetrazole, 1, 3-thiazin-4-one, and 1, 3, 4-thiadiazin-4-one rings.

4. A compound according to claim 1, wherein R³Is a substituted or unsubstituted 1, 3, 4-thiadiazol-2-yl, 4, 5-dihydro-thiazol-2-yl, 2-thiazolyl or 1, 3, 4-oxadiazolyl group, R⁵Is a hydrogen atom or a methyl group, R⁶The substituent is an amino group, and R⁹And R¹⁰Together represent methylenedioxy, or R⁹Is a chlorine atom or a methoxy group, and R¹⁰Is a hydrogen or chlorine atom.

5. A compound according to claim 1, selected from: (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (2-thiazolyl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (4, 5-dihydro-thiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-aminophenyl) -8-methyl-7- (5-methyl-1, 3, 4-oxadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-propyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- {5- [1- (1E) -propen-1-yl ] -1, 3, 4-thiadiazol-2-yl } -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine *; (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine *; and (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methoxy-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * and acid addition salts thereof.

6. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine * or an addition salt thereof.

7. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -7- (5-ethyl-1, 3, 4-thiadiazol-2-yl) -8-methyl-8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

8. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-propyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

9. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

10. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

11. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-methylphenyl) -8-methyl-7- {5- [1- (1E) -propen-1-yl ] -1, 3, 4-thiadiazol-2-yl } -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

12. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo- [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

13. The compound according to claim 1, wherein said compound is (R) -5- (4-amino-3-chlorophenyl) -8-methyl-7- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) -8, 9-dihydro-7H-1, 3-dioxolo [4, 5-H ] [2,3] benzodiazepine * or an acid addition salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 14 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

15. A method of treating glutamate dysfunction associated with acute or chronic neurodegenerative diseases, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

16. The method of claim 8, wherein the neurodegenerative disease is selected from the group consisting of: cerebral ischemia (stroke), brain and spinal cord injury, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, essential tremor, Parkinson's disease, multiple sclerosis and urinary incontinence.

17. A method for treating epilepsy comprising administering to a subject in need of such treatment a therapeutically effective antiepileptic amount of a compound of claim 1.

18. A method of reducing muscle spasm comprising administering to a subject in need of such treatment a therapeutically effective muscle relaxing amount of a compound of claim 1.

19. A method of treating acute and chronic inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective anti-inflammatory amount of a compound of claim 1.

20. The method of claim 19, wherein the inflammatory disease treated is an allergic inflammatory disease of the airways.

21. The method of claim 20, wherein said allergic inflammatory disease of the airways is selected from the group consisting of: allergic rhinitis, intrinsic or extrinsic bronchial asthma, acute or chronic bronchitis, chronic obstructive pulmonary disease and pulmonary fibrosis.

22. A method of alleviating pathological pain comprising administering to a subject in need of such treatment a pain-reducing therapeutically effective amount of a compound of claim 1.

23. A method of treating glutamate dysfunction in an acute or chronic disease of the eye associated with glutamate dysfunction comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

24. The method of claim 23 wherein the disease treated is selected from glaucoma or diabetic retinopathy.