JP2001519387A - Inhibitors of farnesyl protein transferase - Google Patents

Abstract

(57) Abstract The present invention provides compounds that result in the inhibition of farnesyl protein transferase, an enzyme involved in ras oncogene expression. The compounds of the present invention also include enantiomers, diastereomers or pharmaceutically acceptable salts, prodrugs or solvates thereof, represented by Formula I or II below. Embedded image (Wherein, m, r, s, t , X, Z, Y, R 1, R 2, R 3, R 4, R 5, R 6, R 8, R, S, T, G, A, B , C and D are as defined in the description)

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to a compound useful as an anticancer agent by inhibiting farnesyl protein transferase and ras protein farnesylation. Such compounds are also useful in the treatment of diseases other than cancer that are associated with signal transduction pathways that function through ras, and other proteins that are post-translationally modified by farnesyl protein transferase. Such compounds also act as inhibitors of other prenyltransferases and are therefore effective in treating diseases associated with other prenyl modifications of proteins.

BACKGROUND OF THE INVENTION The mammalian ras gene family comprises three genes, H-ras and K-ras.
And N-ras. The ras proteins are a family of GTP-linked and hydrolyzed proteins that regulate cell growth and differentiation. Overproduction of a normal ras protein or variant that suppresses GTPase activity can lead to uncontrolled cell division. The transforming activity of ras depends on the localization of the protein to the plasma membrane. This membrane binding occurs by a series of post-translational modifications of the cytosolic Ras protein. The first step in this chain of events is the farnesylation of these proteins. The reaction is catalyzed by farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as a farnesyl group donor for this reaction. rasC
- terminal contains a _{"Cys-Aaa 1 -Aaa 2 -Xaa} " box (CAAX box) and referred are arranged, wherein, Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation is
Occurs on the cysteinyl residue (cys-186) of the CAAX box, whereby the prenyl group is attached to the protein via a thio-ether bond.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, the formula:

Embedded image And their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates are represented by ras
It inhibits farnesyl protein transferase, an enzyme that is involved in oncogene expression. In the above formulas I and II and throughout the present specification, the definitions of the above symbols are as follows. X is selected from the group consisting of carbon, oxygen, NR ⁷ , or X is absent; Z is CHR ⁹ , SO ₂ , CO, CO ₂ , O, NR ¹⁰ , SO ₂ NR ¹¹ , CONR ¹² ,

Embedded image Y is selected from the group consisting of CHR ²³ , SO ₂ , CO, NR ²⁴ , SO ₂ NR ²⁵ , CONR ²⁶ or Y is absent; ^{R 6, R 7, R 9} , R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 24 , R ²⁵ , R ²⁶ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² ,
^{R 33, R 34, R 35} , R 36, R 37, R 38, R 39, R 41, R 42, R 43, R 44, R 45 and R ⁴⁶ is hydrogen, lower alkyl, substituted alkyl, aryl, substituted R ⁴ , R ⁵ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ and R ⁵¹ are selected from the group consisting of hydrogen, halo, nitro, cyano, UR ²⁷ ; Sulfur, oxygen, NR ²⁸ , CO, SO, SO ₂ , CO ₂ , NR ²⁹ CO ₂ , NR ³⁰ CONR ³¹ , NR ³² SO ₂ , NR ³³ SO ₂ NR ³⁴ , SO ₂ NR ³⁵ , NR ³⁶ CO, CONR R ⁴ and R ⁵ are taken together to form a ring; R ¹ , R ² and R ³ are selected from the group consisting of: ³⁷ , PO ₂ R ³⁸ , PO ₃ R ³⁹ or U is absent; Hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g., CONH _2), selected from the group ing substituted carbamyl, said substituted carbamyl is CONH · alkyl, CONH · aryl, CONH R is selected from aralkyl or a group in which two substituents selected from alkyl, aryl or aralkyl are present on nitrogen; R ⁸ and R ²⁷ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl Aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; any ^{two of} R ¹ , R ² and R ³ may be taken together to form a cycloalkyl group Well; R, S and T CR ⁴⁰ is selected from the group consisting of ^{R 41, NR 42 R 43;} R 40 is selected from ^{NR 44 R 45, OR 46,} CN; G is _{-S -, - SO 2 NH -} , - NHSO 2 -,

Embedded image Selected from the group consisting of heterocyclos other than imidazole; A, B, C and D are selected from carbon, oxygen, sulfur, nitrogen or D is absent; R ²⁷ may be hydrogen except when U is SO, SO ₂ , CO ₂ , NR ²⁹ CO ₂ or NR ³² SO ₂ , or Z is SO ₂ , CO ₂ ,

Embedded image 2. except when R ⁸ may be hydrogen, or 3. only one of Y, R, S and T may be nitrogen, or G is -S -, - NHSO ₂ -,

Embedded image 4. Except when, all of Y, R, S and T may be nitrogen, or 5. R ⁶ may be hydrogen except when G is —NHSO ₂ —, or 6. G may be imidazole only if X is oxygen or NR ⁷ , or The condition is that all three of r, s and t must not be 0.

[0004] The definitions of various terms used to describe the present invention are listed below. These definitions apply to the terms used individually or as part of a larger group throughout this specification, unless otherwise specified and otherwise limited. The phrase "alkyl" refers to a straight or branched chain unsubstituted hydrocarbon group having 1 to 20, preferably 1 to 7 carbon atoms. The designation "lower alkyl" refers to an unsubstituted alkyl group having 1 to 4 carbon atoms.

[0005] The phrase "substituted alkyl" includes, for example, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino Aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines (where two amino substituents are selected from alkyl, aryl or aralkyl), alkanoylamino, aroylamino,
Aralcanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralcanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono,
Aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamide (eg, SO ₂ NH ₂ ), substituted sulfonamide, nitro, cyano, carboxy, carbamyl (eg, CONH ₂ ), substituted carbamyl (eg, CONH.alkyl, CONH.OH) Aryl, CONH aralkyl or a group in which two substituents selected from alkyl, aryl or aralkyl are present on the nitrogen), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclo (eg indolyl, imidazolyl, furyl, thienyl, thiazolyl) , Pyrrolidyl, pyridyl, pyrimidyl, etc.).

The terms “halogen” or “halo” refer to fluorine, chlorine, bromine and iodine. The term "aryl" refers to a monocyclic or dicyclic aromatic hydrocarbon group of 6 to 12 carbon atoms in the ring portion, including, for example, phenyl, naphthyl, biphenyl and diphenyl groups, each of which is substituted. Is also good. The phrase "aralkyl" refers to an aryl group bonded directly to an alkyl group, including, for example, benzyl. The phrase “substituted aryl” includes, for example, alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino,
Alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, 1 to 4 such as arylthiono, alkylsulfonyl, sulfonamide, aryloxy
An aryl group substituted with 4 substituents is referred to. The substituent is further halo,
It may be substituted with hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

The term “alkenyl” refers to a straight or branched chain hydrocarbon group having 1 to 4 double bonds and having 2 to 20, preferably 2 to 15, most preferably 2 to 8 carbon atoms. Finger. The phrase “substituted alkenyl” includes, for example, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
Alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamide, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo (eg, indolyl, imidazolyl,
Alkenyl group substituted with one or two substituents such as furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. The term "alkynyl" refers to a straight or branched chain hydrocarbon group having 1 to 4 triple bonds and having 2 to 20, preferably 2 to 15, most preferably 2 to 8 carbon atoms.

The phrase “substituted alkynyl” includes, for example, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
Substitutions such as alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamide, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo (such as imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc.) Refers to an alkynyl group substituted with a group. The term "cycloalkyl", preferably 1-3 has a ring and at carbons 3-7 of per ring, optionally condensed with a C ₃ -C ₇ carbocyclic group of unsaturated addition Good,
Refers to an optionally substituted saturated cyclic hydrocarbon group. Specific examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Specific examples of the substituent include one or more alkyl groups described above or one or more groups described above as the alkyl substituent.

The terms “heterocyclo”, “heterocyclic” refer to an optionally substituted, fully saturated or unsaturated aromatic, having at least one heteroatom in at least one carbon atom-containing ring. Or a non-aromatic cyclic group, for example, a 4- to 7-membered monocyclic group, a 7- to 11-membered dicyclic group, or a 10- to 15-membered tricyclic group. Each ring of the heterocyclic group containing a heteroatom is 1,2 selected from nitrogen, oxygen and sulfur.
May have three or four heteroatoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may optionally be quaternized. Is also good. Heterocyclic groups can be linked via any heteroatom or carbon atom.

[0010] Specific examples of the monocyclic heterocyclic group include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, and thiazolidinyl. Isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxyazepinyl, azepinyl, 4-
Piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
Pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, tetrahydrothiopyranyl sulfone, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidini ,
Thietanyl, thiiranyl, triazinyl, triazolyl and the like can be mentioned. Also,
Also included are small heterocyclos, such as epoxides and aziridines.

Specific examples of the dicyclic heterocyclic group include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,
Tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, flopyridinyl (eg, furo [2,3-c] pyridinyl, furo [3,1-b] Pyridinyl or furo [
2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (
For example, 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, Dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl and the like. Can be

Specific examples of the substituent include one or more alkyl groups described above and one or more groups described above as the alkyl substituent. The phrase "heteroatom" includes oxygen, sulfur and nitrogen. An "ABCD" fused ring to a diazepine ring may be monocyclic or dicyclic and includes, for example, naphthyl or quinolyl.

The compounds of the formulas I and II can form salts, which are also within the scope of this invention. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful, for example, for isolating or purifying the compounds of the present invention.

The compounds of formulas I and II include alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, pyridine; and amino acids such as arginine and lysine. It can form salts with. Such salts include, for example, compounds I,
When the carboxylic acid group is contained in II, the carboxylic acid proton can be obtained by exchanging the carboxylic acid proton with a desired ion in a medium in which the salt precipitates or in an aqueous medium, followed by evaporation. Other salts can be formed as known to those skilled in the art.

The compounds of the formulas I and II can form salts with various organic and inorganic acids. Examples of such salts include salts formed with hydrogen chloride, hydroxymethanesulfonic acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, and various other salts ( For example, nitrate,
Phosphate, borate, tartrate, citrate, succinate, benzoate, ascorbate, salicylate, etc.). Such salts form compounds I and II
It can be formed by reacting with an equivalent amount of an acid in a medium in which the salt precipitates or in an aqueous medium, followed by evaporation.

In addition, zwitterions (“inner salts”) may be formed. The compounds of formulas I and II may also have prodrug forms. Any compound that converts in vivo to confer a living agent (ie, a compound of Formulas I and II) is a prodrug within the scope and spirit of the invention. For example, compounds of Formulas I and II can be carboxylate ester components. Carboxylate esters may be conveniently formed by esterifying any of the carboxylic acid functionalities found in the ring structures disclosed above.

[0017] Various forms of prodrugs are well-known in the art. For the specific examples of such prodrug derivatives, see the following documents. a) H. Bundgaard's "Design of Prodrugs" (Elsevier, 1985)
And K. Widder et al., "Methods in Enzymology" (Vol. 42, 309-3).
96, Academic Press, 1985); b) Krosgaard-Larsen and H.S. Bundgaard, "A Textbook of Drug Design and Development" (Chapter 5, pp. 113-191, 1991); Bundgaard, "Design and Application of Prodrugs"; Bundgaard, "Advance Drug Delivery Reviews" ( 8 , 1-38, 1992); Bundgaard et al., "Journal of Pharmaceutical Sciences" ( 77 , 285, 1988); and e. Nakaya et al., "Chem. Phar. Bull." ( 32 , 692, 1984).

It should further be understood that solvates (eg, hydrates) of the compounds of Formulas I-IV also fall within the scope of the invention. Methods of solvation are generally known in the art.

Preferred Components In the case of the compound of the present invention, the following components are preferred. Compounds of Formulas I and II wherein m is 0 More preferred compounds of Formulas I and II are those wherein m is 0 and X is carbon. The most preferred compounds of Formula I are those where m is 0, X is methylene (CH ₂ ) and “AB CD” is a carbocyclic ring, eg, benzo.

Use and Utility The compounds of the formulas I and II are inhibitors of S-farnesyl protein transferase. Therefore, these compounds are useful for treating various carcinomas, including
Without being limited to these, the following may be mentioned. Cancers such as bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), ovary, prostate, testicle, pancreas, esophagus, stomach, gall bladder, neck, thyroid and skin (including squamous cell carcinoma); leukemia Acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,
Hematopoietic tumors of the lymphoid lineage, including T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hair cell lymphoma, and Burkitt lymphoma;

Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; central and central, including astrocytomas, neuroblastomas, gliomas and neurofibromas Tumors of the peripheral nervous system; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; Other tumors, including.

The compounds of the formulas I and II are particularly useful for the treatment of tumors with a high incidence of ras involvement, such as colon, lung and pancreatic tumors, or those in which prenyltransferase contributes to tumor maintenance, tumor growth or tumor development. Useful. Administration of a composition having one (or a mixture of two or more) of the compounds of the present invention results in reduced expression of, or reduced tumor burden, or tumor regression in a mammalian host.

The compounds of formulas I and II may also affect tumor growth by inhibiting tumor angiogenesis. Such anti-angiogenic properties of the compounds of formulas I and II may also be used in the treatment of certain forms of blindness associated with retinal neovascularization. Furthermore, the compounds of the formulas I and II are useful in diseases other than carcinomas which may be involved in signal transduction pathways functioning through ras, such as neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis. It can also be used in the treatment of restenosis after angioplasty or vascular surgery, hyperplastic scar formation, polycystic kidney disease and endotoxin shock.

The compounds of the formulas I and II can induce or suppress apoptosis, a process of physiological cell death that is dangerous for normal development and homeostasis. Alterations in the apoptotic pathway contribute to the pathogenesis of various human diseases. The compounds of Formulas I and II are useful as modulators of apoptosis in the treatment of various human diseases with abnormalities in apoptosis, such as carcinomas (particularly, but not limited to, Alveolar lymphoma, cancer with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenoma polyposis), viral infections (including but not limited to herpes virus, pox virus) , Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases including but not limited to systemic lupus erythema,
Immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus, neurodegenerative disorders including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, muscle Amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndrome,
Aplastic anemia, ischemic injury-related myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-induced liver disease, hematologic diseases, including but not limited to chronic anemia and aplastic anemia ), Degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis),
Aspirin-sensitive sinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer distress.

The compounds of the formulas I and II may also be used as farnesyl transferase substrates other than ras (eg nuclear lamins, transducin, rhodopsin kinase, cGM
P phosphodiesterase, TC21, phosphorylase kinase, Rap2, R
(hoB, RhoE, PRL1), which are also post-translationally modified by farnesyl protein transferase, and may be used in the treatment of diseases associated therewith.

The compounds of Formulas I and II can also act as inhibitors of other prenyltransferases (eg, geranylgeranyltransferases I and II), and therefore, produce proteins (eg, rap, rab, rac, and rho gene products). It is also effective in treating diseases associated with other prenyl modifications (eg, geranylgeranylation). For example, these compounds have been identified as geranylgeranylation of the large isoform of the delta antigen of hepatitis delta virus (HDV), as suggested by recent findings that are required for proliferative virus infection [J . S. Glen et al., "Science" ( 256 , 1331, 1992)] shows that it can be used as a drug against HDV infection.

The compound of the present invention can also be used in combination with a known anticancer agent or cytotoxic agent, and a therapy including radiation. When formulated in a fixed dose, such combination preparation employs a compound of the present invention within the dosage range described below and another pharmaceutically active agent in the approved dosage range. The compounds of the formulas I and II can be used continuously with known anticancer and cytotoxic agents and with therapies including radiation when the combination is inappropriate.

The farnesyl transferase assay is described in It is carried out according to the description of "Drug Development Research" by Manne et al. ( 34 , 121-137, 1995). The compounds of Examples 1 to 17 inhibited farnesyltransferase with IC50 values of 0.1 nM to 100 μM.

The compounds of the present invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraperitoneal, intramuscular, rectal, vaginal or topical administration.
Oral administration requires the use of a slow release formulation, such as a biodegradable polymer or prodrug. Pharmaceutical compositions can be formulated in a conventional manner using solid or liquid vehicles, diluents and additional ingredients appropriate to the desired mode of administration. Such compounds can be administered orally in the form of tablets, capsules, granules, powders and the like. Compounds are administered at about 0.05-200 mg / k once daily or in 2-4 divided doses.
It may be administered in a dose range of up to g / day, preferably up to 100 mg / kg / day.

Production method Reaction formula 1:

Embedded image Note that Step in the reaction formula is translated as "step", and so on. R ₁ is selected from H, halo, NO ₂ , NH ₂ , CN, alkyl, aryl, heteroaryl, substituted alkyl, arylalkyl, alkoxy and substituted amino;
R ₂ , R ₃ and R ₄ are selected from alkyl, substituted alkyl, arylalkyl, aryl, heteroaryl, and R ₂ may be hydrogen; Z is CO, SO ₂ ,
It is selected from CO ₂ , CONR ⁵ and SO ₂ NR ⁵ .

Step 1 The isatoic anhydride 2 comprises reacting the optionally substituted anthranilic acid with a phosgene equivalent, such as phosgene or triphosgene, in a mixed aqueous / organic solvent at a temperature ranging from 0 to 50 ° C. Formed by

Step 2 Isatoic anhydride 2 is reacted with an amino acid ester hydrochloride in pyridine, preferably at reflux at high temperature, to give benzodiazepinedione 3. Compound 3 in which R ₁ is aryl or heteroaryl can be prepared from compound 3 in which R ₁ is bromo at room temperature to 110 ° C. in a mixed aqueous / organic solvent such as THF / DMF / water in the presence of a base such as sodium carbonate. It can be produced by a palladium coupling reaction of an aryl or heteroaryl metalloid derivative such as boronic acid.

Step 3 Thereafter, Compound 3 is placed under an inert atmosphere in an organic solvent such as tetrahydrofuran.
React with a reducing agent such as lithium aluminum hydride or borane at room temperature to reflux temperature.

Step 4 The product is then acylated or sulfonylated at -78 to + 100 ° C under standard conditions (eg in an inert organic solvent such as acetonitrile, or a mixed aqueous / organic solvent such as NaOH / dichloroethane Reaction of R ₃ COX (X is Cl or Br) with an acid halide in an organic solvent such as THF in the presence of a base such as diisopropylethylamine, or a mixed aqueous / organic solvent such as NaOH / C
Reaction with a sulfonyl halide of R ₃ SO ₂ X (X is Cl or Br) in H ₂ Cl ₂ )
. When the compound 5 is sulfonylated with a β-haloalkylsulfonyl halide, the unsaturated sulfone obtained by removing the halide with a base such as diisopropylethylamine and then treating the same in an organic solvent such as THF or dichloromethane at room temperature to reflux temperature. A nucleophile such as dimethylamine is added to the amide.

Step 5 (a) Thereafter, various products are reduced with an aldehyde in an inert organic solvent such as dichloroethane at about room temperature in the presence of an acid such as acetic acid and a reducing agent such as NaBH (OAc) _3. Can form compounds of formulas I and II. The aldehyde can be prepared from a suitable alcohol, for example, oxalyl chloride / DMSO /
It may be prepared by oxidation with triethylamine. They can be prepared from appropriate carboxylic acid derivatives (eg, esters) in an organic solvent such as methylene chloride at -78.
It may be prepared at a temperature of from 0 ° C. to room temperature, for example by reduction with diisobutylaluminum hydride.

(B) Compound 6 may be further processed and reacted with a deprotecting agent such as TFA / triethylsilane in an organic solvent such as dichloroethane to give compounds of Formulas I and II. (C) when compound 6 contains a cleavable group such as chloride, in the case of a hydroxyl group, such group may be changed to a cleavable group such as trifluoromethanesulfonate; Reaction with a nucleophile may provide the desired compound of Formula I or II.

Step 6 Compound 5 is acylated with a acylating agent such as acid chloride in a solvent such as methylene chloride, if necessary, in the presence of a base such as diisopropylethylamine. Compound 5 can be acylated with an isocyanate, and can be sequentially produced with an acyl azide such as nicotinoyl azide. When R ₄ contains a leaving group such as chloride, the compound may be further reacted with a nucleophile such as 2-pyrrolidinone or ammonia to form a compound of formula I or II.

Reaction formula 2:

Embedded image R ₁ is selected from H, halo, NO ₂ , NH ₂ , CN, alkyl, aryl, heteroaryl, substituted alkyl, arylalkyl, alkoxy and substituted amino;
R ₂ , R ₃ and R ₄ are selected from alkyl, arylalkyl, aryl, heteroaryl, R ₂ and R ₄ may be hydrogen and R ₄ may be amino; Z is CO, It is selected from SO ₂ , CO ₂ , CONR ⁵ , and SO ₂ NR ⁵ .

Step 1 Ester 1 prepared according to Step 5 of Reaction Scheme 1 is saponified with a base such as LiOH in a solvent such as aqueous methanol / THF at about room temperature to give acid 2.

Step 2 The acid 2 is then converted to hydroxamic acid 3 with hydroxylamine hydrochloride in the presence of a dehydrating agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and a base such as triethylamine. .

Step 3 Ester 1 can be converted to aldehyde 4 with a reducing agent such as diisobutylaluminum hydride in an organic solvent such as methylene chloride.

Step 4 Thereafter, the aldehyde 4 is subjected to reductive amination with a hydroxylamine derivative such as O-benzylhydroxylamine and a reducing agent such as sodium cyanoborohydride to obtain a compound 5.

Step 5 Compound 5 can be acylated with an acylating agent such as formic anhydride and deprotected by, for example, hydrogenation to give compound 6.

Next, the present invention will be described more specifically with reference to examples, which are preferred specific examples of the present invention. All temperatures are in degrees Celsius (unless otherwise specified)
° C). These examples are illustrative rather than limiting. Example 1

Embedded image (+,-)-1- (2-amino-3-mercaptopropyl) -2,3,4,5
-Tetrahydro-4- (naphthalenylcarbonyl) -1H-1,4-benzodiazepine monohydrochloride A. 2,3,4,5-Tetrahydro-1H-benzodiazepine-2,5-dione A stirred solution of isatoic anhydride (16.4 g, 0.1 mol) and glycine ethyl ester hydrochloride in 40 ml of pyridine was added to an oil. The mixture is heated under reflux for 7 hours (h). The suspension is cooled to 0 ° C. for 18 h. Collect the precipitate and wash with ethanol and ether to obtain a pale yellow solid (7.0 g, 40%).

B. Compound A (3.5 g, 20 mmol) was added to a stirred suspension of 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine LAH (3.5 g, 90 mmol) / THF (100 ml) at room temperature. ) Is slowly added in small portions under argon. The resulting suspension is heated at reflux for 18 h under argon in oil and cooled to 0 ° C. A solution of concentrated ammonium hydroxide (5 ml) in 30 ml of THF is added with a dropping funnel. The resulting suspension is stirred for 1 h and filtered. The filtrate is concentrated under reduced pressure to give an oil (2.5 g, 84%).

C. 2,3,4,5-tetrahydro-4- (naphthalenylcarbonyl) -1H
Compound B in a mixed solvent of -1,4-benzodiazepine CH ₂ Cl ₂ / 1N—NaOH (1: 1, 150 ml)
(2.0 g, 13.4 mmol) to a stirred solution of 1-CH ₂ Cl ₂ (3 ml).
A solution of naphthoyl chloride (2.0 ml, 13.4 mmol) is added slowly at 0 ° C. Stir the biphasic mixture at 0 ° C. for 2 h. The aqueous phase was washed with CH ₂ Cl ₂ (100 ml
× 2). Dry the combined organic layers over Na ₂ SO ₄ and concentrate to give the title compound (3.6 g, 89%) as a white solid. MS (M + H) 303. Elemental analysis (C ₂₀ H ₁₈ N ₂ O) Calculated values: C89.44, H6.00, N9.26 Found: C89.48, H5.98, N9.14

D. (+,-)-1- (2-amino-3-mercaptopropyl) -2,3,4
Compound C in a mixture of 2,5-tetrahydro-4- (naphthalenylcarbonyl) -1H-1,4-benzodiazepine monohydrochloride dichloroethane (5 ml) and acetic acid (0.5 ml)
To a stirred solution of 102 mg, 0.34 mmol) and N-BOC-S-trityl-cysteine aldehyde (170 mg, 0.38 mmol) was added NaBH (OAc) ₃ (150 mg, 0.68 mmol) in one portion. . The reaction is allowed to proceed for 30 minutes, the mixture is diluted with ethyl acetate (50 ml) and then saturated NaHCO ₃ (5 ml) is added. The resulting mixture is stirred for 2 h, poured into a mixture of ethyl acetate and saturated NaHCO ₃ and shaken well. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 m
Extract in 1). The combined organic extracts are dried over MgSO _{4 and} concentrated under reduced pressure. Flash chromatography of the residue (ethyl acetate / hexane = 1: 2)
To give an oil (220 mg, 88%). This is dissolved in a solvent of TFA / methylene chloride (1: 1, 5 ml). Stir the resulting solution at room temperature for 3 h.
The solvent was removed under reduced pressure and the residue was washed with ether (10 ml) and 10% HCl solution (10 ml).
) To distribute between. The aqueous solution is separated and concentrated under reduced pressure to a small volume. Product H
Purify by PLC (aqueous methanol with 0.1% TFA) to obtain the HCl salt after salt exchange (73 mg, 62%, mp 140 ° C.). MS (M + H) 392.

Embodiment 2

Embedded image (+,-)-1- (2-amino-3-mercaptopropyl) -2,3,4,5
-Tetrahydro-4- (naphthalenylcarbonyl) -7-phenyl-1H-1,
4-benzodiazepine monohydrochloride A. 5 Buromoisato anhydride THF / H ₂ O / conc. HCl (4: 2: 1,350ml) 5- Bed Romo 2-aminobenzoic acid in the mixed solvent (25 g, 0.115 mmol) to a stirred solution of , A phosgene solution (0.23 mmol, 20% toluene solution) is added dropwise. The reaction mixture is stirred at room temperature for 4 h. The precipitate obtained is filtered off, washed with water and dried under reduced pressure to give the title compound (22.5 g, 78%) as a gray solid.

B. 2,3,4,5-tetrahydro-7-bromo-1H-1,4-benzodia
Zepin-2,5-dione The title compound is prepared according to the procedure for preparing compound A of Example 1. C. 2,3,4,5-tetrahydro-7-phenyl-1H-1,4-benzodi
Azepine-2,5-dione Compound B (13.0 g, 5 ml) in a solvent of DMF / THF (1: 2, 250 ml).
1 mmol) with tetrakis (triphenylphosphine) palladium
(O) (10.5 g, 9.1 mmol) is added. After stirring for 0.5 hour, Na _Two CO_Three(8.5 g, 80 mmol) was added, followed by benzeneboronic acid (1
(0.2 g, 83 mmol). Heat the resulting suspension at 105 ° C for 24 hours
And filter. The filtrate is concentrated and H_TwoDilute with O (200 ml). The precipitate is filtered off and H_TwoO (200 ml), CH_TwoCl_Two(50 ml) and washed with ethyl acetate (100 ml) to give the title compound as a yellow solid (10.8 g, 81%). MS (
M + H) 253.

D. 2,3,4,5-Tetrahydro-7-phenyl-1H-1,4-benzodiazepine The title compound is prepared according to the procedure for preparing compound B of Example 1. MS (M +
H) 225. E. FIG. 2,3,4,5-tetrahydro-4- (naphthalenylcarbonyl) -7-
Phenyl-1H-1,4-benzodiazepine The title compound is prepared according to the procedure for preparing compound C of Example 1. MS (M-
H) 379.

F. (+,-)-1- (2-amino-3-mercaptopropyl) -2,3,4
, 5-Tetrahydro-4- (naphthalenylcarbonyl) -7-phenyl-1H-
1,4-Benzodiazepine monohydrochloride The title compound is prepared according to the procedure for preparing compound D of Example 1. MS (M +
H) 468.

Embodiment 3

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylsulfonyl) -N-
(3-Pyridinyl) -1H-1,4-benzodiazepine-1-carboxamide 2,3,4,5-tetrahydro-4- (1-naphthalenylsulfonyl)-
1H-1,4-benzodiazepine To a stirred solution of compound B of Example 1 (0.75 g, 5.0 mmol) in methylene chloride / 1N NaOH solution (3: 1, 30 ml) at 0 ° C. with 1-naphthalene Sulfonyl chloride (1.13 g, 5.0 mmol) is added. Mix the mixture at 0 ° C for 30
Stir for minutes and pour into a mixture of methylene chloride and 1 N NaOH solution (50 ml each). Separate the organic layer, wash with NH ₄ Cl solution, dry over MgSO _{4 and} concentrate under reduced pressure. The residue was crystallized from methanol to give a solid (1.3 g, 78%, mp 165-1).
66 ° C). MS (M + H) 339.

B. 2,3,4,5-tetrahydro-4- (1-naphthalenylsulfonyl)-
N- (3-pyridinyl) -1H-1,4-benzodiazepine-1-carboxamide Compound A (160 mg, 0.47 mmol) and 3 in toluene (2 ml)
-A stirred solution of nicotinyl azide (90 mg, 0.61 mmol) at 100 ° C
For 3 h. Cool the mixture to room temperature. The solvent was removed under reduced pressure and the residue was crystallized from ether to give a white solid (150mg, 70%). MS (M + H) 4
59. Elemental analysis (as C ₂₅ H ₂₂ N ₄ O ₃ S.0.30 H ₂ O) Calculated values: C 64.72, H 4.91, N 12.08, S 6.91 Actual values: C 64.63, H 4.89, N11 .86, S6.54

Embodiment 4

Embedded image (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1-[(2-oxo-1-pyrrolidinyl) acetyl] -3- (phenylmethyl) -1H-1 , 4-Benzodiazepine trifluoroacetate A. (R) -2,3,4,5-tetrahydro-7-bromo-3-phenylmethyl-benzodiazepine-2,5-dione Example 2 in the presence of 4-dimethylaminopyridine (2 g) in pyridine (1500 ml). A stirred solution of compound A (150 g, 0.62 mol) and D-phenylalanine methyl ester hydrochloride (127.3 g, 0.59 mol) is heated to reflux under argon for 3 days. The pyridine is removed under reduced pressure and the residue is dissolved in methylene chloride (3L). The solution is washed with 10% HCl solution and brine, dried and concentrated in vacuo to a small volume. The solid so formed is collected and dried to give 152 g of solid (m
p 242-243 ° C, 71%).

B. (R) -2,3,4,5-tetrahydro-7-bromo-3-phenylmethyl-benzodiazepine A stirred solution of compound A (30 g, 87 mmol) in anhydrous THF (870 ml) under argon under borane / tetrahydrofuran complex Solution (440 ml of a 1 M solution,
(440 mmol) at room temperature. The solution is slowly heated to reflux and maintained at reflux for 18 h. The mixture is cooled to 0 ° C. and methanol (150 ml) is added slowly. The resulting solution is concentrated under reduced pressure. Dissolve the residue in methanol (250 ml)
Add 7N HCl solution (50 ml). The mixture is heated in a steam bath for 2 h.
The solid thus formed was collected, resuspended in water (400 ml) and the aqueous suspension
Basify to pH 11 with N-NaOH solution and extract with ethyl acetate (300 ml × 2). The organic extracts were combined, dried and concentrated in vacuo, and the residue was crystallized from methanol and water (9: 1) to give a white solid (mp 135-138 ° C, 2 ° C).
5g, 91%).

C. (R) -2,3,4,5-tetrahydro-7-bromo-4-methanesulfonyl-3-phenylmethyl-benzodiazepine Compound B (1.5 g, 4.73 mmol) in methylene chloride, pyridine (3 m
l) and diisopropylethylamine (1.6 ml, 9.46 mmol) in a stirred solution of methanesulfonyl chloride (0.55 ml, 7.6 ml) at 0 ° C. under argon.
11 mmol). The resulting mixture was stirred at 0 ° C. for 2 h, 1N NaOH
A solution (30 ml) is added and the mixture is stirred for 2 h. Separate the organic layer and add 1N-HC
1 solution (100 ml × 2), dried and concentrated under reduced pressure to give a yellow solid (1.7 g).
, 91%).

D. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1-chloroacetyl-3- (phenylmethyl) -1H-1,4-benzodiazepine in dichloromethane (100 ml) Compound C (2.0 g, 5.06 mmol)
Chloroacetyl chloride (2.0 ml, 25.3 mmol) was added to a stirred solution of and diisopropylethylamine (4.4 ml, 25 mmol) in an ice bath under argon. The mixture was stirred for 30 minutes and 1N aqueous sodium hydroxide solution (200 ml)
And extracted with dichloromethane (100 ml × 2). The organic extracts were combined, washed with 10% HCl solution and brine, dried (MgSO ₄ ) and concentrated in vacuo to an oil which was purified by chromatography (hexane / ethyl acetate = 3: 1). The title compound is obtained as a colorless oil (760 mg, 33%).

E. (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1-[(2-oxo-1-pyrrolidinyl) acetyl] -3- (phenylmethyl) -1H-1 Compound D (50 mg, 0.11 mmol) and 2,4-benzodiazepine trifluoroacetate in dimethylformamide
-To a stirred mixture of pyrrolidinone (0.25 ml, 0.33 mmol) at room temperature under argon at room temperature is added sodium hydride (14 mg, 0.33 mmol). The mixture was stirred at room temperature for 2 h, 1N aqueous hydrochloric acid (75 ml) and ethyl acetate (75 ml)
Pour into the mixture. The organic layer is separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue is purified by preparative HPLC (aqueous methanol containing 1.0% trifluoroacetic acid). The product fractions were combined and lyophilized to give the title compound as a white solid (15 mg
, 26%). MS (M + H) 521.

Embodiment 5

Embedded image (R) -7-bromo-4-[[2- (dimethylamino) ethyl] sulfonyl]
-2,3,4,5-tetrahydro-b-oxo-3- (phenylmethyl) -1H
-1,4-benzodiazepine-1-ethanesulfonamide A. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (ethenylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine of Example 4 in dichloromethane (120 ml). To a stirred solution of compound B (10 g, 31.5 mmol) at 0 ° C. was added dropwise a solution of 2-chloroethanesulfonyl chloride (3.2 ml, 30 mmol) in dichloromethane (10 ml), followed by DI
PEA (5.2 ml, 30 mmol) is added dropwise. After stirring for 15 minutes, 2-chloroethanesulfonyl chloride (1.5 ml, 15 mmol) followed by DIPEA (
10.4 ml, 60 mmol). The mixture was warmed to room temperature and water (80 m
pour into l). The organic layer was separated, washed with 1N HCl and saturated aqueous NaHCO ₃ (80 ml each), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a yellowish foamy solid (15.2 g) Get in. MS (M + H) 406.

B. (R) -7-bromo-2,3,4,5-tetrahydro-4-[[2- (dimethylamino) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4
-Benzodiazepine A solution of compound A (7 g) and dimethylamine in THF (2 g) was placed in a round bottom flask at room temperature.
M, 20 ml). The flask is stoppered with a glass stopper and the mixture is stirred for 18 h. Concentrate the mixture and purify by chromatography (20% acetone / chloroform) to give the title compound (3.25 g, 48% over compound B of Example 4).
MS (M + H) 451.

C. (R) -7-bromo-4-[[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-b-oxo-3- (phenylmethyl)-
1H-1,4-benzodiazepine-1-ethanesulfonamide To a stirred solution of compound B (90 mg, 0.2 mmol) in dichloromethane (1 ml) at 0 ° C. under argon at 0 ° C., was added chlorosulfonylacetyl chloride (0.063 ml, 0
. 6 mmol). The mixture is stirred for 8 h, cooled to -78 C and the mixture is condensed with liquid ammonia (2 ml). The stirred mixture is warmed to room temperature over 1 h, diluted with chloroform (20 ml) and shaken with water (20 ml). The aqueous layer is carefully adjusted to pH 6-7 by adding 1N HCl. The organic layer was separated, dried (K ₂ CO ₃₎ and concentrated. The residue was chromatographed (10% i-Pr
Purify with oOH / chloroform to give the title compound (51 mg, 44%). MS (M + H) 573.

Embodiment 6

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-
Compound C of Example 1 (100 mg, 0.33 mmol) in a mixture of (2-thienylmethyl) -1H-1,4-benzodiazepine dichloroethane (2 ml) and acetic acid (1.0 ml), 2-thiophenecarboxaldehyde ( To a stirred solution of 56 mg (0.5 mmol) NaBH (OAc) ₃ (190 mg) is added in one portion. The mixture is stirred for 30 minutes, diluted with ethyl acetate (25 ml) and then with concentrated NH ₄ OH (3 ml). The resulting mixture is stirred at room temperature for 18 h and poured into a mixture of ethyl acetate (50 ml) and saturated NaHCO ₃ (50 ml). Shake this enough. Separate the organic layer and extract the aqueous layer with ethyl acetate (50 ml). The combined organic extracts are dried (MgSO ₄ ) and concentrated under reduced pressure. The residue thus obtained is chromatographed (hexane / ethyl acetate = 3: 1).
To give a solid (40 mg, 30%). MS (M + H) 399.

Embodiment 7

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1- (3-pyridinylmethyl) -7-phenyl-1H-1,4-benzodiazepine hydrochloride nicotinaldehyde and Example 2 The title compound is produced from the compound E according to the production procedure described in Example 6. MS (M + H) 470.

Embodiment 8

Embedded image From 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1- (3-thienylmethyl) -1H-1,4-benzodiazepine 3-thiophenecarboxaldehyde and compound C of Example 1 The title compound is prepared according to the procedure described in Example 6. MS (M + H) 475.

Embodiment 9

Embedded image 2,3,4,5-tetrahydro-1- [2- (3-hydroxy-2-oxo-1 (2H) -pyridinyl) ethyl] -4- (1-naphthalenylcarbonyl) -1H
-1,4-benzodiazepine dihydrochloride A. Ethyl 3-hydroxy-2-oxo-1 (2H) -pyridinyl acetate 2,3-dihydroxypyridine (11.1 g, 0.10 mol) and ethyl bromoacetate (55.4 ml, 0.5 mol) The stirred mixture is refluxed for 12 h, cooled and concentrated. The residue was recrystallized from ethyl acetate / hexane to give the title compound as a white solid (1
9.5 g). MS (M-H) 196.

B. Compound A (1.0 g, 5.1 mmol) in ethyl 3- [dimethyl- (1,1-dimethyl) ethylsiloxy] -2-oxo-1 (2H) -pyridinyl acetate dimethylformamide (5 ml) And a stirred solution of imidazole (863 mg, 12.7 mmol) was added t-butyldimethylmethylchlorosilane (920 mg, 6.1 mmol). The resulting solution is stirred for 1 h and poured into water (100 ml). The aqueous solution is extracted with ethyl acetate. Water the organic layer,
Wash with 10% aqueous lithium chloride, dry (MgSO ₄ ), filter and concentrate to give the title compound as a clear oil (1.5 g). MS (M + H) 312.

C. 3- [Dimethyl- (1,1-dimethyl) ethylsiloxy] -2-oxo-1 (2H) -pyridinylethanal Dispersion of compound B (450 mg, 1.44 mmol) in dry methylene chloride (5 ml). To the stirred solution at -78 ° C, diisobutylaluminum hydride (1M in methylene chloride,
2.2 ml, 2.2 mmol) are added dropwise over 5 minutes. Mixture at -78 ° C for 1 h
Stir and warm to room temperature. Water was added and the methylene chloride layer was separated, washed with water, dried (MgSO ₄ ), filtered and concentrated to give the title compound as a clear oil (385mg). MS (M + H) 268.

D. 2,3,4,5-tetrahydro-1- [2- (3-hydroxy-2-oxo-1 (2H) -pyridinyl) ethyl] -4- (1-naphthalenylcarbonyl)-
1H-1,4-Benzodiazepine dihydrochloride The title compound is prepared from compound C and compound C of Example 1 according to the preparation procedure described in Example 6. Dissolve the product in methanol, add 1N HCl / ether and remove the solvent to give the title compound. MS (M + H) 440.

Embodiment 10

Embedded image 2,3,4,5-tetrahydro-1- [2- (3-hydroxy-2-oxo-1 (2H) -pyridinyl) ethyl] -4- (1-naphthalenylcarbonyl) -7-
Phenyl-1H-1,4-benzodiazepine dihydrochloride The title compound is prepared from compound C of Example 9 and compound E of Example 2 according to the preparation procedure described in Example 6. Dissolve the product in methanol and add 1N-HC
Add l / ether and remove the solvent to give the title compound. MS (M + H) 516.

Embodiment 11

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-[(5-oxo-2-pyrrolidinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine methylene chloride ( To a stirred solution of pyroglutamic acid (400 mg, 3.1 mmol) in 6 ml) was added thionyl chloride (4 ml) at room temperature with one drop of pyridine. The reaction mixture is stirred for 2 h and concentrated. The residue is dissolved in 2 ml of methylene chloride. To this stirred solution is added compound E of Example 2 (40 mg, 0.106 mmol) and diisopropylethylamine (0.5 mL, 3 mmol) / methylene chloride (5 mL). The mixture is stirred for 16 h and concentrated. The residue is dissolved in ethyl acetate (50ml). The resulting solution is washed successively with 1N aqueous potassium bisulfate, saturated aqueous sodium bicarbonate and brine. The organic layer is dried (MgSO ₄ ), filtered and concentrated. The residue is purified by preparative HPLC (aqueous methanol containing 0.1% TFA) to give 15 mg of the title compound as a white solid. _{MS (M + NH 4) 507} .

Example 12

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3- (2-pyridinylamino) propyl] -1H-1,4-benzodiazepine dihydrochloride Salt A. 3- [dimethyl (1,1-dimethylethyl) siloxy] -propanol 1,3-propanediol (4.8 ml, 66 mmol) in THF (100 ml).
To a stirred solution of was added sodium hydride (60% dispersion in mineral oil, 2.6 g, 66 mmol), followed by t-butyldimethylchlorosilane. The solution was stirred for 16 h and concentrated to an oily residue. Chromatography (40% ethyl acetate / hexane)
To give the title compound (12.3 g). MS (M + H) 191.

B. 3- [Dimethyl (1,1-dimethylethyl) siloxy] -propanal To a stirred solution of oxalyl chloride (504 mg, 4 mmol) in 20 ml of methylene chloride under argon at -63 DEG C. was added dimethyl sulfoxide (1.0 g, 2.0 g). 6 mmol) / methylene chloride (5 ml). Thereafter, compound A (1.0 g, 2.6 mmol) / methylene chloride (5 ml) was added over 15 minutes, during which the reaction temperature was raised to -50 ° C.
It is kept below. The resulting solution was stirred at -63 ° C for 30 minutes, then a solution of triethylamine (1.2 g, 11.9 mmol) / methylene chloride (5 ml) was added over 15 minutes while the solution was kept below -50 ° C. Hold. The reaction was stirred for 30 minutes and quenched by the addition of 1M potassium bisulfate (4.5 ml), water (20 ml) and ethyl ether (200 ml). Separate the layers, basify the aqueous layer with saturated aqueous sodium bicarbonate, and extract with ethyl acetate (3 x 50 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated to give the title compound (1.0 g). MS (
M + H) 189.

C. 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3-dimethyl (1,1-dimethylethyl) siloxypropyl] -1H-1,4-benzodiazepine The title compound is prepared from compound B and compound E of Example 2 according to the preparation procedure described in Example 6. MS (M + H) 552. D. 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3-hydroxypropyl] -1H-1,4-benzodiazepine Compound C (300 mg, 0.54 (Mmol) / dioxane (6 ml) and 4N-HCl aqueous solution were stirred for 1 h and concentrated. The residue is triturated with diethyl ether to give 230 mg of the title compound as a white solid. MS (M + H) 437.

E. 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3- (2-pyridinylamino) propyl] -1H-1,4-benzodiazepine dihydrochloride dry To a stirred solution of compound D (50 mg, 0.11 mmol) in methylene chloride (5 ml) at -40 ° C was added di (t-butyl) methylpyridine (23 mg, 0.11 mmol),
Then triflic anhydride (0.19 ml, 0.11 mmol) is added.
The solution was stirred at -40 ° C for 30 minutes and 2-aminopyridine (16 mg, 0.17 mmol) was added. The mixture is stirred at −40 ° C. for 30 minutes and warmed to room temperature over 2 h. The reaction is concentrated and purified by preparative HPLC (aqueous methanol containing 0.1% TFA). Dissolve the product in methanol, add 1N HCl / ether and remove the solvent to give the title compound as a solid (20 mg). MS (M + H) 513.

Embodiment 13

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3- (3-pyridinylamino) propyl] -1H-1,4-benzodiazepine dihydrochloride Example 1 except that 3-aminopyridine was used in place of the salt 2-aminopyridine.
According to the production procedure described in 2, the title compound is produced. MS (M + H) 513.

Example 14

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3- (1H-pyrazol-3-ylamino) propyl] -1H-
1,4-Benzodiazepine dihydrochloride The title compound is prepared according to the procedure described in Example 12 except that 3-aminopyrazole is used instead of 2-aminopyridine. MS (M + H) 502.

Embodiment 15

Embedded image 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1- [3- (2-pyrimidinylamino) propyl] -1H-1,4-benzodiazepine di The title compound is prepared according to the procedure described in Example 12 except that 3-aminopyrimidine is used instead of 2-aminopyridine. MS (M + H) 514.

Embodiment 16

Embedded image (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (3-pyridinylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine hydrochloride The title compound is prepared from compound C of Example 4 and nicotinaldehyde according to the preparation procedure of Example 6. MS (M + H) 486.

Example 17

Embedded image (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (1-oxo-3-pyridinylmethyl) -3- (phenylmethyl) -1
H-1,4-benzodiazepine hydrochloride Example 16 compound in methylene chloride in the presence of sodium bicarbonate (25 mg, 0.0
MCPBA (50 mg) at 0 ° C. to a stirred solution of 5 mmol). The mixture is stirred for 3 h and treated with aqueous potassium carbonate. The suspension is stirred, filtered and concentrated.
The residue was dissolved in methanol, 1N HCl / ether was added, and the solvent was removed to give the title compound as a solid (22 mg). MS (M + H) 502.

Example 18

Embedded image (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (2-pyridinylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine hydrochloride From compound C of Example 4 and 2-pyridylcarboxaldehyde, Example 6
The title compound is prepared according to the procedure described in the above. MS (M + H) 486.

Example 19

Embedded image (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (4-pyridinylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine hydrochloride From compound C of Example 4 and 4-pyridylcarboxaldehyde, Example 6
The title compound is prepared according to the procedure described in the above. MS (M + H) 486.

Example 20

Embedded image (R) -7-Bromo-2,3,4,5-tetrahydro-N-hydroxy-4- (methylsulfonyl) -1H-1,4-benzodiazepine-1-acetamide hydrochloride A. Ethyl (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1H-1,4-benzodiazepine-1-acetate Compound C of Example 4 and ethylglyoxalate To produce the title compound according to the production procedure of Example 6. MS (M + H) 481.

B. (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1H-1,4-benzodiazepine-1-acetic acid Compound A (480 mg, 1 mg) in THF in the presence of aqueous methanol. (0.0 mmol), LiOH.H ₂ O (210 mg, 5.0 mmol) was added. The mixture is stirred for 3 h and acidified with 1N HCl solution. The mixture is concentrated under reduced pressure and partitioned between ethyl acetate and 1N HCl solution. Separate the organic layer, dry and concentrate to give the title compound (400 mg, 89%). MS (M-H) 451.

C. (R) -7-Bromo-2,3,4,5-tetrahydro-N-hydroxy-4- (methylsulfonyl) -1H-1,4-benzodiazepine-1-acetamide hydrochloride Compound B (230 mg) in DMF , 0.5 mmol) in a stirred solution of hydroxylamine hydrochloride (350 mg, 5.0 mmol), triethylamine (0.07 ml,
0.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg, 0.5 mmol). The mixture is stirred for 18 h and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and 1N HCl solution. Separate the organic layer, dry and concentrate. The residue is purified by chromatography (ethyl acetate / hexane = 1: 1). Dissolve the resulting oil in methanol, add 1N HCl and remove the solvent to give the title compound. MS (M + H) 468.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 401/06 C07D 401/06 401/12 401/12 403/06 403/06 403/12 403/12 409 / 06 409/06 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor John T. Hunt United States 08540 Skyfield Drive 7th, Princeton, NJ (72) Inventor Katerina Lefseris 08558 Skillman, New Jersey Richmond, NJ Drive No. 92 (72) Inventor Rajiv S. bide United States 19047 Burnsbury Road, Langhorne, PA 156 F-Term (reference) 4C063 AA01 BB09 CC37 CC92 DD03 DD12 DD25 DD29 DD37 EE01 4C086 AA01 AA02 AA03 BC56 GA04 GA07 GA08 MA01 MA04 NA14 ZA02 ZA15 ZA16 ZA33 ZA34 ZA36 ZA39 ZA40 ZA45 ZA55 ZA59 ZA75 ZA81 ZA89 ZAB ZA96

Claims (10)

[Claims] 1. The enzyme inhibits farnesyl protein transferase, which is an enzyme involved in ras oncogene expression, and has the formula: Wherein m, r, s and t are 0 or 1; X is selected from the group consisting of carbon, oxygen and NR ⁷ , or X is absent; Z is CHR ⁹ , SO ₂ , CO, CO ₂ , O, NR ¹⁰ , SO ₂ NR ¹¹ , CONR ¹² , Y is selected from the group consisting of CHR ²³ , SO ₂ , CO, NR ²⁴ , SO ₂ NR ²⁵ , CONR ²⁶ or Y is absent; ^{R 6, R 7, R 9} , R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 24 , R ²⁵ , R ²⁶ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² ,
^{R 33, R 34, R 35} , R 36, R 37, R 38, R 39, R 41, R 42, R 43, R 44, R 45 and R ⁴⁶ is hydrogen, lower alkyl, substituted alkyl, aryl, substituted R ⁴ , R ⁵ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ and R ⁵¹ are selected from the group consisting of hydrogen, halo, nitro, cyano, UR ²⁷ ; Sulfur, oxygen, NR ²⁸ , CO, SO, SO ₂ , CO ₂ , NR ²⁹ CO ₂ , NR ³⁰ CONR ³¹ , NR ³² SO ₂ , NR ³³ SO ₂ NR ³⁴ , SO ₂ NR ³⁵ , NR ³⁶ CO, CONR R ⁴ and R ⁵ are taken together to form a ring; R ¹ , R ² and R ³ are selected from the group consisting of: ³⁷ , PO ₂ R ³⁸ , PO ₃ R ³⁹ or U is absent; Hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g., CONH _2), selected from the group ing substituted carbamyl, said substituted carbamyl is CONH · alkyl, CONH · aryl, CONH R is selected from aralkyl or a group in which two substituents selected from alkyl, aryl or aralkyl are present on nitrogen; R ⁸ and R ²⁷ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl Aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; any ^{two of} R ¹ , R ² and R ³ may be taken together to form a cycloalkyl group Well; R, S and T CR ⁴⁰ is selected from the group consisting of ^{R 41, NR 42 R 43;} R 40 is selected from ^{NR 44 R 45, OR 46,} CN; G is _{-S -, - SO 2 NH -} , - NHSO 2 -, - Chemical formula 3] Selected from the group consisting of heterocyclos other than imidazole; A, B, C and D are selected from carbon, oxygen, sulfur, nitrogen or D is absent; R ²⁷ may be hydrogen except when U is SO, SO ₂ , CO ₂ , NR ²⁹ CO ₂ or NR ³² SO ₂ , or Z is SO ₂ , CO ₂ , 2. except when R ⁸ may be hydrogen, or 3. only one of Y, R, S and T may be nitrogen, or G is -S-, -NHSO _2- , 4. Except when, all of Y, R, S and T may be nitrogen, or 5. R ⁶ may be hydrogen except when G is —NHSO ₂ —, or 6. G may be imidazole only if X is oxygen or NR ⁷ , or with the proviso that all of r, s and t must not be 0), or an enantiomer, diastereomer or pharmaceutically acceptable salt, prodrug or solvate thereof. 2. The compound according to claim 1, wherein A, B, C, D and X are carbon and are 2,3,4,5-tetrahydrobenzodiazepine compounds. 3. The compound according to claim 1, wherein m is 0. 4. (+,-)-1- (2-amino-3-mercaptopropyl)
-2,3,4,5-tetrahydro-4- (naphthalenylcarbonyl) -1H-1
, 4-Benzodiazepine monohydrochloride; (+,-)-1- (2-amino-3-mercaptopropyl) -2,3,4,5
-Tetrahydro-4- (naphthalenylcarbonyl) -7-phenyl-1H-1,
4-benzodiazepine monohydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylsulfonyl) -N-
(3-pyridinyl) -1H-1,4-benzodiazepine-1-carboxamide; (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1-[(2-oxo -1-pyrrolidinyl) acetyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine trifluoroacetate; (R) -7-bromo-4-[[2- (dimethylamino) ethyl] sulfonyl]
-2,3,4,5-tetrahydro-b-oxo-3- (phenylmethyl) -1H
-1,4-benzodiazepine-1-ethanesulfonamide; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-
(2-thienylmethyl) -1H-1,4-benzodiazepine; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-
(3-pyridinylmethyl) -7-phenyl-1H-1,4-benzodiazepine
Hydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-
(3-thienylmethyl) -1H-1,4-benzodiazepine; 2,3,4,5-tetrahydro-1- [2- (3-hydroxy-2-oxo-
1 (2H) -pyridinyl) ethyl] -4- (1-naphthalenylcarbonyl) -1
H-1,4-benzodiazepine dihydrochloride; 2,3,4,5-tetrahydro-1- [2- (3-hydroxy-2-oxo-
1 (2H) -pyridinyl) ethyl] -4- (1-naphthalenylcarbonyl) -7
-Phenyl-1H-1,4-benzodiazepine dihydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1-
[(5-oxo-2-pyrrolidinyl) carbonyl] -7-phenyl-1H-1,
4-benzodiazepine; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-
Phenyl-1- [3- (2-pyridinylamino) propyl] -1H-1,4-benzodiazepine dihydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-
Phenyl-1- [3- (3-pyridinylamino) propyl] -1H-1,4-benzodiazepine dihydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-
Phenyl-1- [3- (1H-pyrazol-3-ylamino) propyl] -1H
-1,4-benzodiazepine dihydrochloride; 2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-
Phenyl-1- [3- (2-pyrimidinylamino) propyl] -1H-1,4-
Benzodiazepine dihydrochloride; (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (3-pyridinylmethyl) -3- (phenylmethyl) -1H-1, 4
-Benzodiazepine hydrochloride; (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (1-oxo-3-pyridinylmethyl) -3- (phenylmethyl)-
1H-1,4-benzodiazepine hydrochloride; (R) -7-bromo-2,3,4,5-tetrahydro-N-hydroxy-4-
(Methylsulfonyl) -1H-1,4-benzodiazepine-1-acetamide hydrochloride; (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (2- Pyridinylmethyl) -3- (phenylmethyl) -1H-1,4
-Benzodiazepine hydrochloride; (R) -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1- (4-pyridinylmethyl) -3- (phenylmethyl) -1H-1, 4
The compound according to claim 1, which is selected from the group consisting of benzodiazepine hydrochloride. 5. A method of inhibiting farnesyl protein transferase comprising administering to a mammalian subject an amount of the compound of claim 1 effective to inhibit farnesyl protein transferase. 6. A method of inhibiting prenyltransferase, comprising administering to a mammalian subject an amount of the compound of claim 1 effective to inhibit prenyltransferase. 7. A method for inhibiting a tumor, comprising administering to a mammalian subject an effective amount of the compound of claim 1 for inhibiting the tumor. 8. A method of treating a disease associated with a signal transduction pathway that functions through Ras, comprising administering to a mammalian subject an effective amount of the compound of claim 1 for treating such disease. Treatment method. 9. A method for treating a disease associated with a protein that is post-translationally modified by farnesyl protein transferase, comprising administering to a mammalian subject an effective amount of the compound of claim 1 for treating such disease. Treatment. 10. A method for treating a disease associated with a protein that is post-translationally modified by geranylgeranyl protein transferase, comprising administering to a mammalian subject an effective amount of the compound of claim 1 for the treatment of such disease. Treatment.