WO2002030873A1

WO2002030873A1 - Mmp inhibitor

Info

Publication number: WO2002030873A1
Application number: PCT/JP2001/008325
Authority: WO
Inventors: Akihiko Sawada; Masahiro Neya
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 2000-10-10
Filing date: 2001-09-25
Publication date: 2002-04-18

Abstract

A novel MMP inhibitor. It is a compound represented by the formula (I) or a salt thereof: (I) wherein R?1 and R2¿ each means optionally substituted aryl, optionally substituted lower arylalkyl, lower arylalkenyl, lower aryloxyalkyl, or an optionally substituted heterocyclic group. The compound is useful as an MMP inhibitor.

Description

Specification

MMP inhibitor technical field

The present invention relates to novel compounds and their pharmaceutically acceptable salts.

More specifically, the present invention relates to novel compounds useful as inhibitors of matrix metaoral protease (hereinafter referred to as MMP) or tumor necrosis factor α (hereinafter referred to as TNF) production, and pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions containing them, their use as medicaments, and methods of using them for the treatment or prevention of ΜΜΡ- or TNFα-mediated diseases.

Background art

ぺ Pirazine compounds useful as inhibitors are known (WO97 / 20824, etc.).

An object of the present invention is to provide a novel and useful compound having a pharmacological activity such as an inhibitory activity against MM- or TNF production, a pharmaceutically acceptable salt thereof, and the novel compound and a salt thereof. Is to provide a method of manufacturing the same.

Another object of the present invention is to provide a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

It is a further object of the present invention to provide a compound of the formula

It is to provide use as a medicament for prophylactic and Z or therapeutic treatment of MP- or TNFa-mediated diseases.

Still further, it is an object of the present invention to provide methods for treating and / or treating MMP- or TNF-I mediated diseases in mammals, especially humans.

The compound of the present invention has inhibitory activity on MMP or TNFa production, and has seizures, arthritis, cancer, tissue ulcer, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and matrix meta Other diseases characterized by oral protease activity It is useful for treating and / or preventing diseases such as AIDS, sepsis, septic shock, and other diseases caused by production of TNFα.

There are a number of structurally related meta-oral proteases that affect the degradation of structural proteins. Matrix-degrading meta-oral proteases such as gelatinases (ΜΜ __2, ΜΜ Ρ-9), stomalisine (ΜΜ Ρ-3) and collagenases (MMP-1, MMP-8, MMP- 13) is involved in tissue matrix degradation and involves many pathologies involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (eg, osteoarthritis and rheumatoid arthritis), cerebral disease (Eg, seizures), tissue ulcers (eg, corneal, epidermal and stomach ulcers), abnormal wound healing, periodontal disease, bone disease (eg, Paget's disease, osteoporosis), tumor metastasis or invasion and It has been linked to HIV infection.

Tumor necrosis factor is recognized to be involved in many infectious and autoimmune diseases. Furthermore, TNF has been shown to be a major mediator of the inflammatory response seen in sepsis and septic shock.

Disclosure of the invention

The target compound of the present invention is novel and can be represented by the following formula (I).

In the formula, R ¹ and R ² each represent an optionally substituted aryl group, an optionally substituted aryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, or an optionally substituted aryl group. Or a salt thereof.

The target compound of the present invention can be produced by the following steps. -OH ☆ -Cl

(II) (III)

100 ml of Trityl Linker Crown (made by Chiron Technologies Pty: Ltd) was placed in a 100 ml wide-mouthed mesh-type bottle, and 50 ml of a 20% acetyl chloride / methylene chloride solution was added. The reaction mixture was allowed to stand for 3 hours. The crown was separated by filtration, and the crown was washed with methylene chloride (50 ml x 5 minutes x 2).

(III) (IV)

N-Hydroxyphthalimide (660 mg) was placed in a 100-ml wide-bottle or bottle, and N, N-diisopropylethylamine (2.8 ml) was added to a mixture suspended in 20 ml of methylene chloride. . The crown (100 pieces) prepared in Production Method 1 was added to the reaction mixture, allowed to stand for 18 hours, and then the crown was filtered off. The crown was washed with methylene chloride (50 ml × 5 minutes × 3 times). The obtained crown was dried.

(IV) (V)

To the crown prepared in Production Method 2, 2.2 hydrazine hydrazine tylsulfoxyl (50 ml) was added, and the crown was filtered off after standing for 20 hours. The crown was washed with N, N-dimethylhonoleamide (50 ml × 5 minutes × 3 times) and methylene chloride (50 ml × 5 minutes × 3 times), and the obtained crown was dried. Manufacturing method 4

100ml wide-mouthed mess, N-a-Fmoc-β-1 (4,4_dimethinole_2,6-dioxo- 1-cyclohexylidene) ethyl-L-diaminopropionic acid (1.47 g) ), HOBt (1-hydroxybenzotriazole) (450 mg) and diisopropylcarbodiimide (450 / iL) were added, and the mixture was allowed to stand for 20 minutes. The crown obtained in Production Method 3 was added to the reaction mixture, allowed to stand for 45 hours, and then the crown was filtered off. The crown N, N-dimethyl formamidine de (50 ml x 5 minutes x 3 times), washed with salt methylene (50mlx 5 minutes x3 times), dried and the resulting crown _c

After attaching Transron made by Chiron Technologies Pty; Ltd- to the crown obtained in Production, Method 4, add 200ml wide-mouthed meal, calories in Yume bottle, and add 100ml of 20 piperidine / N, N-dimethylformamide solution, After standing for 30 minutes, the crown with Transtem was filtered off. Crown with Transtem ¾r ,, _ _mesh / Lehonore ^ dad (50 ml x 5 minutes χ 3 times): Washed with methylene chloride (50 ml x 5 minutes χ 3 times), and the obtained crown with ranstem was dried. Manufacturing method 6

Carboxylic acid (VIII) was added to a 100 ml wide dome bottle. 1.5% HOB tZN, N-dimethylformamide solution (20 ml) and diisopropylcarbodiimide (300 L) were mixed and left for 20 minutes. Crown with Transtem obtained in Production Method 5 により Divided by 10 minutes using a TranSort system manufactured by Chiron Technologies Pty Ltd., 10 crowns with Transtem were added to each reaction mixture, and the mixture was allowed to stand for 18 hours. After that, 10 kinds of crowns with Transtem were filtered and mixed, and washed with NN-dimethylformamide (50 ml x 5 minutes x 3 times) and methylene chloride (50 ml x 5 minutes x 3 times) to obtain the obtained Transtem. The crown was dried.

Add the crown with Transtem obtained in Production Method 6 to a 200 ml wide-mouthed volume bottle.Add 100 ml of 2% hydrazine hydrate ZN, N-dimethylformamide solution, leave it for 15 minutes, and then allow it to stand for 15 minutes. The furnace was IJ. The crown with Transtem was washed with N, N-dimethylformamide (50 ml × 5 minutes × 3 times) and methylene chloride (50 ml × 3 times 5 minutes), and the obtained crown with Transtem was dried. Manufacturing method 8

The carboxylic acid (XI) was added to a 100 ml wide-mouthed medium bottle. 1. 5% HOBt / N, N-dimethylformamide solution (20 ml) and diisopropylcarbodiimide (300 iL) were added. The crown with Transtem obtained in Production Method 7 was divided into 10 pieces by the TranSort system, and the crown with Transtem (10 pieces) was added to each reaction mixture and allowed to stand for 18 hours. After filtering and mixing 0 kinds of crowns with Transtem, they were washed with N, N-dimethylformamide (50 ml x 5 minutes x 3 times) and methylene chloride (50 ml x 5 minutes x 3 times), and obtained.

The crown with Transtem was dried.

The Transtem-equipped crown obtained in Production Method 8 was placed at a specified position on a pin holder made by Chiron Technologies Pty Ltd. using the ranSort system.

Each was immersed in a 5% trifluoroacetic acid Z methylene chloride solution (1.5 ml) for 1 hour, and the target compound was cut out from the crown with Transtem. The obtained solution was dried in a stream of nitrogen to obtain the target compound. The structure of each target compound was determined using an LCZMS apparatus (ESI + or ESI).

"Wherein, R ¹ and R ² have the same meaning as described above, Fmoc means 9-fluorenylmethoxycarbonyl, and DDE means 1- (4,4-dimethynole-1,2,6-dioxo-1-1-cyclohexylidene) ethyl."

The salt of the object compound of the present invention or a pharmaceutically acceptable salt may be a conventional non-toxic salt, and may be an organic acid salt (for example, acetate, trifluoroacetate, maleate, tartrate, fumarate) , Methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), inorganic acid (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphoric acid) Salts, etc.), amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.) Magnesium salt, etc., ammonium salt, organic base salt (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexyl) Salts with bases such as luminamine salts, N, N, dibenzylethylenediamine salts and the like.

The target compounds and their pharmaceutically acceptable salts include solvates such as clathrates (eg, hydrates). A description of the appropriate examples and various definitions as included within the scope of the present invention and provided herein above and below is as follows.

Suitable "aryl" in the terms "aryl group" and "optionally substituted aryl group" are, for example, aryl having 6 to 10 carbon atoms such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, etc. Preferably it is phenyl, which may have one or more substituents. Examples of substituted aryl groups include halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, arylo lower alkyl, and preferably aryloxy (eg, phenoxy, etc.). ), Nitro oxaloyl (for example, benzoyl).

Suitable aroyls include aroyl having 6 to 10 carbon atoms, particularly preferably benzoyl.

A suitable “heterocyclic group” in the term “optionally substituted heterocyclic group” is a saturated or unsaturated group containing at least one heteroatom such as an oxygen atom, a sulfur atom, a nitrogen atom and the like. It means a 3- to 8-membered monocyclic or polycyclic heterocyclic group.

More preferred heterocyclic groups are:

one:! An unsaturated 3- to 8-membered, preferably 5- or 6-membered monocyclic monocyclic group containing up to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl; Pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H-tetratolyl) Lazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (for example, 4,5-dihydro-1,2,4_triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.);

one:! A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing up to 4 nitrogen atoms, for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, birazolidinyl, piperazinyl and the like;

Unsaturated condensed 7 to 13 membered, preferably 9 or 10 membered bicyclic heterocyclic group containing one to five nitrogen atoms, e.g., indolyl, isoindolyl, indolizinyl, Benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazopyridyl, tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl, etc.), dihydrotriazolopyridazinyl and the like;

Unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms, for example, oxazolyl, isoxazolyl, oxaziazolyl (for example, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);

A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms, for example, morpholinyl, morpholino and the like;

Unsaturated condensation containing one or two oxygen atoms and one to three nitrogen atoms 7

To 13-membered, preferably 9- or 10-membered bicyclic heterocyclic group, for example, benzoxazolyl, benzoxadiazolyl and the like;

An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two sulfur atoms and one to three nitrogen atoms, for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, Thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.);

A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two sulfur atoms and one to three nitrogen atoms, for example, thiazolidinyl and the like;

An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing a monosulfur atom, for example, phenyl and the like;

An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing a monooxygen atom, for example, furyl and the like;

A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing a monooxygen atom, for example oxolanyl and the like:

Unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered bicyclic heterocyclic group containing one or two sulfur atoms and one to three nitrogen atoms, for example, benzothiazolyl, benzothiaziazolyl Etc .; — An unsaturated condensed 7 to 13 membered, preferably 9 or 10 membered bicyclic heterocyclic group containing one or two oxygen atoms, for example, benzodihydrofuranyl, benzodioxolenyl and the like.

The most preferred heterocyclic group is an unsaturated 5- or 6-membered heterocyclic monocyclic group containing a sulfur atom. '

These heterocyclic groups may have one or more substituents. Examples of the substituent of the substituted heterocyclic group include halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, and optionally substituted. Heterocyclic group, haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroarylole, biphenyl, aryloxyaryl, trihaloalkylaryl, cyano (lower) alkoxyaryl, cyanoaryl, cyano (lower) Alkylaryl, lower alkanoyloxyl, lower alkanoyloxy (lower) alkylaryl, di (lower) alkylaminosulfonylaryl, hydroxy (lower) alkylaryl, lower alkoxycarbonyl Aryl, lower alkoxycarbonyl (lower) alkoxyl, lower alkoxysulfoninoleoxyl, aryl substituted with halogen and hydroxy, aryl and halogen substituted alkoxy, halogen and lower alkoxy Aryl, a lower alkyl-heterocyclic group and an aryl substituted with a lower alkoxy, a lower alkyl-heterocyclic group and an aryl-heterocyclic group, preferably a halogen; Halophenyl; hydroxyphenyl; lower alkoxyphenyl; lower alkylphenyl; nitrophenyl; biphenylinole; phenoxyphenyl; torino, mouth (lower) alkylphenyl; cyano (lower) alkoxyphenyl; cyanophenyl; Lower) alkylphenyl; lower alkanoyloxyphenyl; lower alkanoyloxy (lower) alkylphenyl; di (lower) alkylaminosulfonylphenyl; lower anolexoxycarbonyl (lower) anolexoxyphenyl; lower alkoxy Sulfenyloxyphenyl; phenyl substituted by halogen and hydroxy; phenyl substituted by halogen and lower alkanoyloxy; phenyl substituted by halogen and lower alkoxy. A suitable "aryl lower alkyl" in the term "substituted or more aryl lower alkyl" is a straight-chain or branched alkyl having 1 to 6 carbon atoms, which is substituted by the above aryl, and is methyl, ethynole, propyl. Isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Preferred aryl lower alkyls are phenylmethyl and naphthylmethyl. The aryl group may be substituted by one or more substituents, and examples of the substituent include halogen, cyano, nitro, acylamino, carbamoyl, hydroxy, lower alkoxy, lower alkenyl carbamoyl, and carboxy. Protected carboxy, di (lower) alkylamino, lower alkylamino, protected amino, arylcarbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di (lower) alkylaminosulfol-amino, and the like. Preferably, it includes naphthylmethyl or chloro off We methylpropenylmethyl group as a 1 ¹ or 1 ^ ^2.

A suitable "aryl lower alkenyl" in the term "aryl lower alkenyl" is a straight-chain or branched alkenyl having 2 to 6 carbon atoms, which is substituted by aryl, and is selected from the group consisting of bier, 1-propenyl, and 2-propane. Nyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl and the like are exemplified, and preferably a butyl. Preferred examples of lower alkenyl include phenylbutyl.

Preferable examples of "aryloxy lower alkyl" include phenoxymethyl, phenoxethyl, naphthoxymethyl, naphthoxethyl, and preferably phenoxethyl.

The term "lower" means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.

Suitable "norogens" include fluorine, bromine, and chlorine iodine. BEST MODE FOR CARRYING OUT THE INVENTION Of the target compound (I),

(1) Preferred are

Wherein R ¹ and R ² are an aryloxyaryl group, an aryloylyl group, a nitroaryl group, an aryl lower alkyl group, a haloaryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, Or an unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms. "

(2) More preferred are:

R ¹ and R ² are each a phenoxyphenyl group, a benzoylphenyl group, a ditrophenyl group, a naphthyl lower alkyl group, a halophenyl lower alkyl group, a phenyl lower alkenyl group, a phenoxy lower alkyl group, or a phenyl group; 'The compound according to the above (1),

(3) Most preferred is

R ¹ and R ² are each, 3- or 4-Fuenokishifue two Honoré group, 4-Benzo Irufueniru group, 4-nitrophenyl group, 1-naphthylmethyl group, 2-chlorophyll Enirumechiru group, 2-phenylene Rubiniru group, 1- Or the compound according to the above (2), which is a 2-phenoxethyl group or a 2-phenyl group.

The compound obtained by the above-mentioned production method can be separated and purified by a conventional method, for example, pulverization, recrystallization, column chromatography, reprecipitation and the like. The target compound can be converted to a salt thereof by a conventional method.

The target compound may include one or more stereoisomers due to asymmetric carbon, and all such isomers and mixtures thereof are included in the scope of the present invention.

Collagenase initiates the degradation of vertebrate collagen and, in addition to their normal function in connective tissue metabolism and wound healing, a number of pathologies, such as joint rupture in rheumatoid arthritis, periodontal disease, corneal ulcers , Tumor metastasis, osteoarthritis, pressure ulcer, restenosis after percutaneous coronary lumen dilatation, osteoporosis, psoriasis, active chronic hepatitis, self The compounds of the present invention are useful for the treatment and Z or prevention of such conditions, as they have been implicated in autoimmune keratitis and the like.

For therapeutic purposes, the compounds of the present invention and their pharmaceutically acceptable salts are suitable for oral, parenteral or topical administration of a pharmaceutically acceptable carrier, for example, an organic or inorganic solid or liquid. The compound can be used in the form of a preparation containing one of the compounds as an active ingredient by mixing with an excipient. Formulations may include capsules, tablets, dragees, granules, solutions, suspensions, emulsifiers, sublingual tablets, suppositories, ointments and the like. If necessary, these preparations may contain auxiliary substances, stabilizers, wetting agents, emulsifiers, buffers and other commonly used additives.

The dose of the compound varies depending on the age and condition of the patient, but the daily dose is 0.01 to 100 mg per kg of human body weight for intravenous administration, and human for intramuscular administration. Daily dose of 0.05 to 100 mg / kg of human body weight, or 0.1 to 100 mg / day of human body weight per oral administration of active ingredient MMP or TNF α mediated by oral administration Generally administered for the treatment of disease.

Industrial applicability

In order to show the usefulness of the target compound, data of pharmacological tests of representative compounds are shown below.

MMP inhibitory activity: ·

1. Test method

The inhibitory activity of MMP-13 was measured using Arthrogen-CIA MMP-13 Kit (Chondrex) according to the prescription of Chondrex according to the following procedure. 100 μl of the human recombinant MMP-13 solution activated with Activator_l, 10 μl of Buffer B solution containing various concentrations of the test sample, and 10-fold dilution with Buffer A solution ΐ Substrate Stock Solution 100 μΐ The reaction was started by excluding calo, left at room temperature for 2 hours, and stopped by adding Stop Solution (10 mM o-phenanthroline) at 10 μΐ. The amount of Substrate released by the enzymatic reaction was measured using a fluorometer (SPECTRAFLUOR PLUS: TECA) at an excitation wavelength of 360 nm and a fluorescence wavelength of 465 nm. IC _5. Values are shown as the concentration of each sample required for 50% inhibition. 2. Test compound

Example 19 Compound of 9

3. Test results

The following examples are provided for purposes of illustrating the invention in detail, but are not intended to limit the invention in any way.

The target compound having the following structural formula was synthesized by the method shown in the above-mentioned Production method 9.

The combinations of R ¹ and R ^{2 in} the above structural formula are described in the following table.

Claims

The scope of the claims

Formula:

(In the formula, R ¹ and R ² each represent an optionally substituted aryl group, an optionally substituted aryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, or an optionally substituted aryl group. A compound represented by the formula: or a salt thereof.

2. Formula:

(Wherein, R ¹ and R ² are an aryloxyaryl group, an arylyl group, a nitraryl group, an aryl lower alkyl group, a haloaryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, Or an unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms.).

3. In the formula, R ¹ and R ² are each a phenoxyphenyl group, a benzoylphenyl group, a nitrophenyl group, a naphthyl lower alkyl group, a halophenyl lower alkyl group, a phenyl lower alkenyl group, a phenoxy lower alkyl group, or a phenyl group. 3. The compound according to claim 2, which represents a phenyl group.

4. In the formula, R ¹ and R ² are each a 3- or 4- 1-phenoxyphenyl group-4-benzoylphenyl group, 4-12 trophenyl group, 1-naphthylmethyl group, 2-phenylmethylmethyl group , 2-phenylvinyl group, 1- or 2-phenoxy 4. The compound according to claim 3, which represents an ethyl group or a 2-phenyl group.

5. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof.

6. An MMP- or TNFα production-inhibitor containing the compound according to claim 1 or a salt thereof.

7. Use of the compound according to claim 1 or a salt thereof for the manufacture of a medicament for treating MMΡ- or TNFα-mediated disease.

8. A method for treating ΜΜΡ- or TNFa-mediated disease, comprising administering the compound according to claim 1 or a salt thereof to a mammal including human.