KR101670317B1 - ketonepeptide derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating inflammatory diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a ketone peptide derivative, a process for producing the same, and a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing the same as an active ingredient. The ketone peptide derivative, its optical isomer or its pharmaceutically acceptable Since the salt has an excellent activity of inhibiting the expression of interleukin-6 (IL-6), the salt is useful as an inflammatory bowel disease such as ulcerative colitis, Crohns disease, (Sepsis), and the like can be effectively used as a pharmaceutical composition for preventing or treating inflammatory diseases caused by interleukin-6.

Description

TECHNICAL FIELD The present invention relates to a ketone peptide derivative, a process for preparing the same, and a pharmaceutical composition for preventing or treating an inflammatory disease containing the same as an active ingredient. The present invention relates to a ketone peptide derivative, a preparation method thereof, and a pharmaceutical composition for use in the same. }

The present invention relates to a ketone peptide derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating an inflammatory disease containing the same as an active ingredient.

TGF-β (Transforming Growth Factor-β) is a cytokine that regulates various physiological processes such as cell proliferation, differentiation, apoptosis, migration, and production of extracellular matrix (ECM) (Cytokine). The active form of TGF-beta exists in a dimeric form of 25 kDa. When activated by the cell, it is activated and binds to the serine / threonine receptor kinase of the cell membrane. The TGF-β receptor is composed of type Ⅰ and type Ⅱ. When combined with TGF-β, the two types of receptors form a heterotetrameric complex. The always active type Ⅱ receptors are type Ⅰ receptor Lt; RTI ID = 0.0 > (kinase). ≪ / RTI >

TGF-β signal transduction is a transcription factor called Smad that acts as a mediator of extracellular signaling into the nucleus. Type I receptors phosphorylated by type Ⅱ receptors phosphorylate and activate Smad proteins. The phosphorylated Smad protein enters the nucleus and co-operates with other transcription factors to regulate the expression of various genes (Non-Patent Document 1).

The response of the cells to TGF-β varies depending on the type of the cells and the stimulation conditions, such as promoting or inhibiting proliferation, cell death, differentiation, and the like. Cytokines belonging to the TGF-β family use various type I and type II receptors. Up to now, there have been seven types of type I receptors called activin receptor-like kinase (ALK) and five types of type II receptor. TGF-β uses ALK5 and TR-2 (testicular receptor-2) receptors in most cell types.

Smad proteins are known to be 8 types, depending on their function, receptor-activated Smad (R-Smad, Smad1, Smad2, Smad3, Smad5, Smad8), common mediator Smad (Co- Smad, Smad4), and inhibitory Smad (I-Smad, Smad6, 7). In general, Smad2 and 3 are used in the TGF-β / Activin / Nodal group and Smad1, Smad1 and Smad2 in the BMP / GDF / MIS group. When the ligand binds, the type I receptor directly phosphorylates the SSXS motif at the carboxy terminus of R-Smad, phosphorylated R-Smad binds to Smad4, which is Co-Smad, and enters the nucleus to form Smad binding element SBE) (Non-Patent Document 2). SBE is often a binding site for other transcription factors, and the Smad protein cooperates with other transcription factors to regulate gene expression. Unlike R-Smad and Co-Smad, I-Smad (Smad6, 7) has no carboxy terminus phosphorylated by the type I receptor and inhibits TGF-β signaling. The most well known of the cell responses to TGF- is the growth arrest of the cells. TGF-β induces growth arrest in epithelial cells, endothelial cells, blood cells, and nerve cells. Stimulation of TGF- [beta] induces signal transduction at any stage of the cell cycle but induces arrest of the G1 cell cycle (Non-Patent Document 3).

TGF-beta stimulation in epithelial cells induces transcription of cyclin-dependent kinase inhibitors such as p21Cip1 / WAF1 and p15lnk4b, activating antiproliferative responses and inducing arrest of G1 cell cycle. In addition, TGF-β inhibits the transcription of c-Myc, a growth transcription factor, and ld1, ld2, ld3, a differentiation inhibitor. Furthermore, TGF-β is known to induce various cell death responses.

Thus, TGF-beta and its mediator, Smad, play important roles not only in physiological functions such as cell growth, development and differentiation, but also in cancer, fibrosis, various diseases and disease progression, Studies on active systems and methods for controlling delivery have been actively conducted.

On the other hand, Non-Patent Document 4 discloses that activation of TGF-? 1 promotes the expression of interleukin-6 (IL-6).

The interleukin-6 (hereinafter "IL-6") (aka interferon-β2, B-cell differentiation factor, B-cell stimulating factor-2, hepatocyte stimulating factor, hybridoma growth factor, and plasma cell growth factor) Many biological processes such as modulation of the response, regulation of specific immune responses including B-cell and T-cell differentiation, inflammation reactions arising from bone metabolism, platelet formation, epithelial proliferation, neuronal differentiation, neuroprotection, (Non-Patent Document 5). In addition, IL-6 is a member of the cytokine population that promotes cellular responses through a receptor complex composed of at least one subunit of the signal-transfer glycoprotein gp130 and the IL-6 receptor ("IL-6R") (aka gp80). The IL-6R may be in soluble form ("sIL-6R") and IL-6 binds to IL-6R to duplex the signal-transducing receptor gp130 (non-patent document 6).

In humans, the gene encoding IL-6 is organized into five exons and four introns, and is mapped to the short arm of chromosome 7 at 7p21. Translation and post-translational processing of IL-6 RNA generates 21-28 kDa proteins containing 184 amino acids in mature form (non-patent reference 7).

IL-6 plays an important role in the development of a number of diseases and disorders including but not limited to fatigue, cachexia, autoimmune diseases, skeletal diseases, cancer, heart disease, obesity, diabetes, asthma, Alzheimer's disease and multiple sclerosis . Because of the established relevance of IL-6 in a wide range of diseases and disorders, there is a need for screening methods to identify patients with diseases or disorders associated with IL-6, as well as compositions and methods useful for the prevention or treatment of diseases associated with IL- Are still required in the art. Particularly preferred anti-IL-6 compositions are those that exhibit minimal side effects or minimal side effects when administered to a patient. Compositions or methods that reduce or inhibit a disease or disorder associated with IL-6 are beneficial to a diseased patient.

The function of IL-6 is not limited to the immune response because the IL-6 is involved in the pathogenesis of hematopoiesis, platelet formation, osteoclast formation, C-reactive protein (CRP) and elevation of serum amyloid A Because it acts in the induction of acute phase reactions. Epithelial keratinocytes, kidney angiostatic cells, myeloma and plasma cell types (Non-Patent Document 8). IL-6 is produced by a wide variety of cell types including monocytes / macrophages, fibroblasts, epithelial keratinocytes, vascular endothelial cells, renal vascular mesangial cells, glial cells, chondrocytes, T and B-cells and some tumor cells (Non-Patent Document 9). Except for tumor cells that constitutively produce IL-6, normal cells do not express IL-6 unless appropriately stimulated.

Non-Patent Document 10-12 discloses that IL-6 is directly related to inflammatory bowel disease such as ulcerative colitis, Crohns disease, etc. Also, non-patent document 13 Discloses that plasma concentration of IL-6 is directly related to sepsis. Taken together, these results demonstrate that inhibition of IL-6 is beneficial for the prevention or treatment of inflammatory bowel disease, including sepsis, including ulcerative colitis, Crohns disease, .

Accordingly, the present inventors have made efforts to develop a compound exhibiting the effect of inhibiting the activity of interleukin-6 (IL-6), and have found that the ketone peptide derivative, its optical isomer or its pharmaceutically acceptable The salt acts as an inhibitor of IL-6 activity and can be used as a preventive or therapeutic agent for inflammatory bowel disease such as ulcerative colitis, Crohns disease, or sepsis. And completed the present invention.

Masague J, Seoane J, Wotton D. Genes Dev 19: 2783-2810, 2005 Shi Y, Wang YF, Jayaraman L, Yang H, Massague J, Pavletich NP. Cell 94: 585-594, 1998 Massague J, Gomis RR. FEBS Lett 580: 2811-2820, 2006 Oncogene (2003) 22, 4314-4332. doi: 10.1038 / sj.onc.1206478 Papassotiropoulos et al, Neurobiology of Aging, 22: 863-871 (2001) Jones, SA, J. Immunology, 175: 3463-3468 (2005) Papassotiropoulos, et al., Neurobiology of Aging, 22: 863-871 (2001) Grossman et al., 1989 Prot Natl Acad Sci., 86, (16) 6367-6371; Horii et al., 1989, J. Immunol., 143, 12, 3949-3955; Kawano et al., 1988, Nature 332, 6159, 83-85 Akira et al, 1990, FASEB J., 4, 11, 2860-2867 Toxicology and Applied Pharmacology 279 (2014) 311-321 International Immunopharmacology 23 (2014) 294-303 Seminars in Immunology 26 (2014) 75-79 Clin Infect Dis. (2000) 31 (6): 1338-1342.

It is an object of the present invention to provide a ketone peptide derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof having an ability to inhibit interleukin-6 (IL-6) expression.

It is another object of the present invention to provide a process for preparing the ketone peptide derivative.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases containing the above-mentioned ketone peptide derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is -C (= O) R ⁵ , or -C (= O) OR ⁶ ,

Wherein R ⁵ and R ⁶ is a heteroaryl that is independently selected from the group consisting of -H, a C _{1 -10} straight or branched chain alkyl, unsubstituted C _{6 -10} aryl C _{1 -10} of the ring of an alkyl, N, O, and S unsubstituted or substituted 5 to 10 membered heteroaryl-cycloalkyl, or unsubstituted or substituted C _{6 -10} aryl group containing one or more atoms,

), 할로겐, 나이트릴, C_{1 -10}의 직쇄 또는 측쇄 알킬 및 C_{1 -10}의 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-10원자 헤테로사이클로알킬 및 C_{6 -10}의 아릴이고;
The substituted 5 to 10 membered heteroaryl cycloalkyl, and substituted aryl of C _{6 -10} are independently -OH, -Boc (

), Halogen, nitrile, C _{1 -10} linear or branched alkyl, and C _{1 -10} straight or branched alkoxy cycloalkyl of 5 to 10 membered heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl and C _{6 - 10} < / RTI >

R ² And R ³ is independently -H, -OH, halogen, nitrile, aryl or unsubstituted of C _{1 -10} straight or branched chain alkyl, C _{1 -10} linear or branched alkoxy, unsubstituted C _{6 -10} of the ring ≪ / RTI >

R ⁴ is a hetero atom selected from the group consisting of straight or branched chain alkyl, unsubstituted or substituted aryl of C _{6 -10,} unsubstituted or substituted 5 to 10 atom cycloalkyl, N, O and S of C _{1 -10} Or an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S,

The substitution of C _{6 -10} aryl, substituted 5 to 10 atom cycloalkyl, substituted 5-10 membered heteroaryl, and substituted 5-10 membered heteroaryl cycloalkyl is independently -OH, halogen, C _{1 -5} a linear or branched alkyl and C _{1 -5} straight or branched chain alkoxy of C _{6 -10} with one or more substituents selected from the group consisting of substituted aryl, 5 to 10 atom cycloalkyl, 5-10 membered heteroaryl and 5-10 Lt; / RTI > heterocycloalkyl.

The present invention also relates to a process for producing a compound represented by the formula (1)

Preparing a compound represented by the formula (4) through dehydration condensation reaction of the compound represented by the formula (2) and the compound represented by the formula (3) (step 1);

A step of preparing a compound represented by the formula (5) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the formula (4) prepared in the step 1 (step 2); And

(Step 3) of preparing a compound represented by the general formula (1) through dehydration condensation reaction of the compound represented by the general formula (5) and the compound represented by the general formula (6) Of the present invention.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ And R < ⁴ > are independently as defined in the above formula (1).

Further, the present invention relates to a process for the preparation of

(Step 1) of preparing a compound represented by the formula (9) through dehydration condensation reaction of the compound represented by the formula (7) and the compound represented by the formula (8); And

(Step 2) of preparing a compound represented by the formula (2) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the formula (9) prepared in the step 1 to obtain a compound represented by the formula .

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ is the same as defined in the above formula (1).

Also, as shown in the following Reaction Scheme 3,

)를 제거하여 화학식 1b로 표시되는 화합물을 제조하는 단계(단계 1);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.The compound-Boc (

(Step 1), to thereby prepare a compound represented by the formula (1b).

[Reaction Scheme 3]

In Scheme 3,

이고,-Boc

ego,

R ² , R ³ And R < ⁴ > are independently as defined in the above formula (1)

The compounds represented by the general formulas (1a) and (1b) are included in the compounds represented by the general formula (1).

Further, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease containing the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The ketone peptide derivative, its optical isomer, or pharmaceutically acceptable salt thereof according to the present invention is excellent in the activity of inhibiting the expression of interleukin-6 (IL-6), and thus can be used for the treatment of ulcerative colitis, Inflammatory diseases such as inflammatory bowel disease such as Crohn's disease or sepsis, and inflammatory diseases caused by interleukin-6.

1-5 are graphs showing the relative inhibition of interleukin-6 (IL-6) expression inhibitory ability of the compound prepared in Example 1-36.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is -C (= O) R ⁵ , or -C (= O) OR ⁶ ,

Wherein R ⁵ and R ⁶ is a heteroaryl that is independently selected from the group consisting of -H, a C _{1 -10} straight or branched chain alkyl, unsubstituted C _{6 -10} aryl C _{1 -10} of the ring of an alkyl, N, O, and S unsubstituted or substituted 5 to 10 membered heteroaryl-cycloalkyl, or unsubstituted or substituted C _{6 -10} aryl group containing one or more atoms,

), 할로겐, 나이트릴, C_{1 -10}의 직쇄 또는 측쇄 알킬 및 C_{1 -10}의 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-10원자 헤테로사이클로알킬 및 C_{6 -10}의 아릴이고;
The substituted 5 to 10 membered heteroaryl cycloalkyl, and substituted aryl of C _{6 -10} are independently -OH, -Boc (

), Halogen, nitrile, C _{1 -10} linear or branched alkyl, and C _{1 -10} straight or branched alkoxy cycloalkyl of 5 to 10 membered heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl and C _{6 - 10} < / RTI >

R ² And R ³ is independently -H, -OH, halogen, nitrile, aryl or unsubstituted of C _{1 -10} straight or branched chain alkyl, C _{1 -10} linear or branched alkoxy, unsubstituted C _{6 -10} of the ring ≪ / RTI >

R ⁴ is a hetero atom selected from the group consisting of straight or branched chain alkyl, unsubstituted or substituted aryl of C _{6 -10,} unsubstituted or substituted 5 to 10 atom cycloalkyl, N, O and S of C _{1 -10} Or an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S,

The substitution of C _{6 -10} aryl, substituted 5 to 10 atom cycloalkyl, substituted 5-10 membered heteroaryl, and substituted 5-10 membered heteroaryl cycloalkyl is independently -OH, halogen, C _{1 -5} a linear or branched alkyl and C _{1 -5} straight or branched chain alkoxy of C _{6 -10} with one or more substituents selected from the group consisting of substituted aryl, 5 to 10 atom cycloalkyl, 5-10 membered heteroaryl and 5-10 Lt; / RTI > heterocycloalkyl.

Preferably,

R ¹ is -C (= O) R ⁵ , or -C (= O) OR ⁶ ,

Wherein R ⁵ and R ⁶ is a heteroaryl that is independently selected from the group consisting of -H, a C _{1 -5} straight or branched chain alkyl, unsubstituted C _{6 -8} aryl C _{1 -5} in the ring of an alkyl, N, O, and S and unsubstituted or substituted 5-8 membered heteroaryl cycloalkyl, or aryl unsubstituted or substituted C _{6 -8} containing one or more atoms,

), 할로겐, 나이트릴, C_{1 -5}의 직쇄 또는 측쇄 알킬 및 C_{1 -5}의 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-8원자 헤테로사이클로알킬 및 C_{6 -8}의 아릴이고;
The aryl of substituted 5-8 membered heteroaryl cycloalkyl, and a C _{6 -8-substituted} independently -OH, -Boc (

), Halogen, nitrile, with a least one member selected from the group consisting of straight or branched chain alkoxy of C _{1 -5} straight or branched chain alkyl and C _{1 -5} substituents of the optionally substituted 5-8 membered heteroaryl cycloalkyl, and C _{6 - 8} < / RTI >

R ² And R ³ is independently -H, -OH, halogen, nitrile, a C _{1 -5} straight or branched chain alkyl, aryl, or unsubstituted of C _{1 -5} straight or branched alkoxy, unsubstituted C _{6 -8} ring ≪ / RTI >

R ⁴ is a linear or branched C _{1 -5} alkyl, or unsubstituted aryl, substituted or unsubstituted of C _{6 -8} ring atoms, or a substituted 5-8 cycloalkyl,

_Wherein said substituted C _{6 -8} aryl and substituted 5-8 membered cycloalkyl are independently selected from the group consisting of -OH, halogen, C _{1 -5} straight or branched chain alkyl and C _{1 -5} straight or branched alkoxy. At least one substituent of the substituted aryl, and C _{6 -8} is a 5-8 atom cycloalkyl.

More preferably,

,

,

,

,

,

,

, 또는

이고;R ¹ is

,

,

,

,

,

,

, or

ego;

R ² is -H, methyl, tert-butyl, or unsubstituted cyclohexyl;

R ³ is -H, or -OH;

R ⁴ is methyl, n-butyl, unsubstituted phenyl, or unsubstituted cyclopentyl.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) tert-Butyl 2- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;

(2) tert-Butyl 2- (1-oxo-1- (3-oxo-1-phenylheptan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;

(3) tert-Butyl 2- (2-oxo-2- (1-oxo-1,3-diphenylpropan-2-ylamino) ethylcarbamoyl) pyrrolidine-1-carboxylate;

(4) Synthesis of tert-butyl 2- (2- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidin- Carbonyl) pyrrolidine-1-carboxylate;

(5) Synthesis of N- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2- ylamino) propan- Lt; / RTI >2-carboxamide;

(6) tert-Butyl 2- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;

(7) Synthesis of tert-butyl 2- (1- (1-cyclopentyl-1 -oxo-3-phenylpropan-2-ylamino) -1-oxopropane- 2-ylcarbamoyl) pyrrolidine- Rate;

(8) tert-Butyl 2- (2-oxo-2- (3-oxo-1-phenylbutan-2-ylamino) ethylcarbamoyl) pyrrolidine-1-carboxylate;

(9) Synthesis of tert-butyl 2- (2- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan- 2- ylcarbamoyl) pyrrolidine- Pyrrolidine-1-carboxylate;

(10) Synthesis of N- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan- 2-carboxamide;

(11) Synthesis of tert-butyl 2- (2- (1- (1-cyclopentyl-1 -oxo-3-phenylpropan-2-ylamino) 1-carbonyl) pyrrolidine-1-carboxylate;

(12) tert-Butyl 2- (2- (1-cyclopentyl-1-oxo-3-phenylpropan-2-ylamino) -2-oxoethylcarbamoyl) pyrrolidine-1-carboxylate;

(13) 1-acetyl-N- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-yl) pyrrolidine-2-carboxamide;

(14) 1-Acetyl-N- (2-oxo-2- (1-oxo-1,3-diphenylpropan-2-ylamino) ethyl) pyrrolidine-2-carboxamide;

(15) Synthesis of tert-butyl 2- (2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) ) Pyrrolidine-1-carbonyl) pyrrolidine-1-carboxylate;

(16) Synthesis of tert-butyl 2- (2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2- ylamino) -2-oxoethylcarbamoyl) pyrrolidin- Carboxy;

(17) Synthesis of tert-butyl 2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) Di-1-carboxylate;

(18) Synthesis of N- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-carbonyl) pyrrolidine-2-carboxamide;

(19) Synthesis of tert-butyl 2- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-oxoethylcarbamoyl) Lt; / RTI >

(20) Synthesis of tert-butyl 2- (2- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) Yl) pyrrolidine-1-carbonyl) pyrrolidine-1-carboxylate;

(21) Synthesis of N- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan- Di-2-carbonyl) pyrrolidine-2-carboxamide;

(22) Synthesis of tert-butyl 2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) Carboxy;

(23) Synthesis of tert-butyl 2- (2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -1-oxopropane-2-ylcarbamoyl) pyrrolidine -1-carbonyl) pyrrolidine-1-carboxylate;

(24) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) Pyrrolidine-2-carboxamide < / RTI >

(25) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -3,3-dimethyl-1-oxobutan- Lt; / RTI > 2-carbonyl) pyrrolidine-2-carboxamide;

(26) Synthesis of N- (1-cyclohexyl-2- (1- (4-hydroxyphenyl) -3-oxobutan- Carbonyl) pyrrolidine-2-carboxamide;

(27) Synthesis of 1-acetyl-N- (1- (1- (4-hydroxyphenyl) -3-oxobutan- ≪ / RTI >

(28) Synthesis of 1-acetyl-N- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- - yl) pyrrolidine-2-carboxamide;

(29) Synthesis of 1-acetyl-N- (1- cyclohexyl-2- (3- (4-hydroxyphenyl) Carboxamide;

(30) Synthesis of 1-benzoyl-N- (1- (1- (4-hydroxyphenyl) -3-oxobutan- ≪ / RTI >

(31) Benzyl 2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -1-oxopropane- 2-ylcarbamoyl) pyrrolidine- ;

(32) Synthesis of 1-formyl-N- (1- (3- (4- hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- 2-yl) pyrrolidine-2-carboxamide;

(33) Synthesis of N- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-oxoethyl) Carboxamide;

(34) Synthesis of 1-benzoyl-N- (1- cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan- Carboxamide;

(35) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -3,3-dimethyl- 1 -oxobutan- Ylpyrrolidine-2-carboxamide; And

(36) Synthesis of tert-butyl 2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- Ylcarbamoyl) pyrrolidine-1-carboxylate.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-carboxylate, benzenesulfonate, Sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, the present invention encompasses not only the compound represented by the formula (1) and pharmaceutically acceptable salts thereof, but also solvates, optical isomers and hydrates thereof which can be prepared therefrom.

Further, the present invention relates to a process for preparing a compound represented by the following formula 1,

Preparing a compound represented by the formula (4) through dehydration condensation reaction of the compound represented by the formula (2) and the compound represented by the formula (3) (step 1);

A step of preparing a compound represented by the formula (5) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the formula (4) prepared in the step 1 (step 2); And

(Step 3) of preparing a compound represented by the general formula (1) through dehydration condensation reaction of the compound represented by the general formula (5) and the compound represented by the general formula (6) Of the present invention.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ And R < ⁴ > are independently as defined in the above formula (1).

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In the process for preparing a compound represented by the formula 1 according to the present invention, the step 1 is a step for preparing a compound represented by the formula 4 through dehydration condensation reaction of the compound represented by the formula 2 and the compound represented by the formula 3 More specifically, the compound represented by formula (2), the compound represented by formula (3), 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (EDCI), hydroxybenzotriazole Dissolving the base in a solvent and stirring the mixture to prepare a compound represented by the general formula (4).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, and triethylamine is preferably used.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use dichloromethane (DCM).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 12 to 36 hours.

In the method for preparing the compound represented by the formula (1) according to the present invention, the step (2) may be carried out by replacing the methoxycarbonyl group of the compound represented by the formula (4) with the carboxy group to obtain the compound represented by the formula More specifically, it is a step of dissolving a compound represented by the formula (4) in a solvent, adding a base and stirring to prepare a compound represented by the formula (5).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride, and sodium hydroxide is preferably used.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use tetrahydrofuran (THF).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but it is preferable to carry out the reaction for 0.5 to 12 hours.

In the process for preparing the compound represented by the formula (1) according to the present invention, the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the above step 2 are dehydrated and condensed, More specifically, the compound represented by Chemical Formula 5 is dissolved in a solvent, and then the compound represented by Chemical Formula 6, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ( EDCI), hydroxybenzotriazole (HOBt) and a base are added and stirred to prepare a compound represented by the formula (1).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, and triethylamine is preferably used.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use dichloromethane (DCM).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 12 to 36 hours.

The present invention also relates to a process for producing a compound represented by the formula

(Step 1) of preparing a compound represented by the formula (9) through dehydration condensation reaction of the compound represented by the formula (7) and the compound represented by the formula (8); And

(2), which is a starting material of Reaction Scheme 1, comprising the step of preparing a compound represented by the general formula (2) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the general formula (9) A method for producing a compound to be displayed is provided.

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ is the same as defined in the above formula (1).

Hereinafter, the method for preparing the compound represented by Formula 2 according to the present invention will be described in detail.

In the process for preparing the compound represented by the formula 1 according to the present invention, the step 1 is a step for preparing a compound represented by the formula (9) by dehydration condensation reaction between a compound represented by the formula (7) and a compound represented by the formula More specifically, the compound represented by the general formula (8), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), hydroxybenzotriazole (HOBt) and a base are added and stirred to prepare a compound represented by the formula (9).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, and triethylamine is preferably used.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use dichloromethane (DCM).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 12 to 36 hours.

In the method for preparing the compound represented by Formula 1 according to the present invention, in Step 2, the methoxycarbonyl group of the compound represented by Formula 9 is replaced with a carboxy group to obtain the compound represented by Formula 2 More specifically, it is a step of dissolving a compound represented by the formula (9) in a solvent, adding a base, and stirring to prepare a compound represented by the formula (2).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride, and sodium hydroxide is preferably used.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use tetrahydrofuran (THF).

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but preferably 12-24 hours.

Also, as shown in the following Reaction Scheme 3,

)를 제거하여 화학식 1b로 표시되는 화합물을 제조하는 단계(단계 1);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.The compound-Boc (

(Step 1), to thereby prepare a compound represented by the formula (1b).

[Reaction Scheme 3]

In Scheme 3,

이고,-Boc

ego,

R ² , R ³ And R < ⁴ > are independently as defined in the above formula (1)

The compounds represented by the general formulas (1a) and (1b) are included in the compounds represented by the general formula (1).

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

)를 제거하여 화학식 1b로 표시되는 화합물을 제조하는 단계이며, 보다 구체적으로는, 화학식 1a로 표시되는 화합물을 용매에 용해시킨 후, 산을 첨가하고 교반하여 화학식 1b로 표시되는 화합물을 제조하는 단계이다.In the process for preparing the compound represented by the formula (1) according to the present invention, the step 1 is a step of reacting the compound represented by the formula (1a) with -Boc

) Is removed to prepare a compound represented by the formula (1b). More specifically, the compound represented by the formula (1b) is dissolved in a solvent, and then an acid is added and stirred to prepare a compound represented by the formula to be.

At this time, hydrochloric acid (HCl) is preferably used as the acid.

The solvent may include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonasene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenyl Propionate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, mandelate, sulphate, Etc., and it is preferable to use ethyl acetate.

Further, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but it is preferable to carry out the reaction for 0.5 to 12 hours.

The present invention also provides a pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases containing the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Herein, the pharmaceutical composition is characterized by inhibiting the expression of interleukin-6 (IL-6), and the inflammatory diseases include inflammatory diseases such as ulcerative colitis, Crohns disease, Inflammatory bowel disease and sepsis.

Thus, in order to evaluate the ability of the compound of Example according to the present invention to inhibit the expression of interleukin-6 (IL-6), the compound prepared in Example 1-36 was found to have an interleukin- 6 as well as Smaducin-6 and Transforming Growth Factor Beta (TGF-b), which are known to have the ability to inhibit IL-6, IL-6, (See FIG. 1-5 of Experimental Example 1).

Accordingly, the ketone peptide derivative, its optical isomer, or pharmaceutically acceptable salt thereof according to the present invention is excellent in the activity of inhibiting the expression of interleukin-6 (IL-6), and thus Ulcerative inflammatory diseases caused by interleukin-6, such as inflammatory bowel disease such as colitis and Crohns disease, or sepsis.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 / day, based on adult patients weighing 70, and may be administered once to several times per day It may be administered in divided doses.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto. In addition, since it is difficult to identify the structure of the peptide structure through nuclear magnetic resonance (Nuclear Magnetic Resonance) peaks, the actual molecular weight and the observed molecular weight were compared to confirm the synthesis of the compound of the Example.

< Example  1> tert -Butyl 2- (1-oxo-1- (3-oxo-1- Phenylbutane -2- Amino ) Propan-2-yl Carbamo Work) Pyrrolidine -One- Carboxy  Produce

Step 1: tert -Butyl 2- (1- Methoxy -One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

(Tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution dissolved in dichloromethane was added 2.95 g of methyl 2-aminopropanoate hydrochloride, 1.95 g of 1-ethyl-3- Aminopropyl) carbodiimide, 2.85 g of hydroxybenzotriazole, and 10.7 mL of triethylamine to prepare a reaction mixture, which was then stirred at room temperature for one day. The reaction mixture was concentrated in vacuo, diluted with aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The collected organic layer was washed with brine and washed three times with 1N hydrochloric acid solution. The organic layer was washed again with brine, dried over anhydrous MgSO ₄ , concentrated, and purified by medium pressure liquid chromatography (MPLC) to obtain 7.1 g of the title compound.

Step 2: 2- (1- ( tert - Butoxycarbonyl ) Pyrrolidine -2- Carbox amido ) Propanoic acid  Produce

To 3.20 g of the compound prepared in the above step 1 dissolved in tetrahydrofuran was added NaOH (644 mg, 16.1 mmol) dissolved in water, followed by stirring at room temperature for one day. The reaction mixture was concentrated, and the pH (PH) was adjusted to 1 using 1N hydrochloric acid solution (aq.). The aqueous layer was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous MgSO ₄ and concentrated to obtain 2.4 g of the desired compound.

Step 3: tert -Butyl 2- (1-oxo-1- (3-oxo-1- Phenylbutane -2- Amino ) Propan-2-ylcarbamoyl) Pyrrolidine -One- Carboxy  Produce

A solution of 264 mg of the compound prepared in the above step 2, 120 mg of 3-amino-4-phenylbutan-2-one hydrochloride, 396 mg of 1-ethyl- 3- (3- dimethylaminopropyl) carbodiimide, 279 mg of the sol and 0.76 mL of triethylamine were added to a round bottom flask containing dichloromethane and stirred at room temperature for one day. The reaction mixture was concentrated in vacuo, diluted with aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The collected organic layer was washed with brine and washed three times with 1N hydrochloric acid solution. The organic layer was washed again with brine, dried over anhydrous MgSO ₄ , concentrated, and purified by medium pressure liquid chromatography (MPLC) to obtain 220 mg of the target compound.

Exact Mass (M): 431.2

Observed (M + H & lt ^; + & gt ^; ): 431.8

< Example  2> tert -Butyl 2- (1-oxo-1- (3-oxo-1- Phenyl heptane -2- Amino ) Propan-2-yl Carbamo Work) Pyrrolidine -One- Carboxy  Produce

Amino-1-phenylheptan-3-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride in the same manner as in Example 1 (Yield: 80%).

Exact Mass (M): 473.3

Observed (M + H & lt ^; + & gt ^; ): 473.9

< Example  3> tert -Butyl 2- (2-oxo-2- (1-oxo-1,3- Diphenyl propane -2- Amino ) Ethyl carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-aminoacetate hydrochloride was used,

Amino-1,3-diphenylpropan-1-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride in the same manner as in Example 1 To obtain the target compound (yield: 61%).

Exact Mass (M): 479.2

Observed (M + H & lt ^; + & gt ^; ): 479.9

< Example  4> tert -Butyl 2- (2- (1-oxo-1- (1-oxo-1,3- Diphenyl propane -2- Amino ) Propane-2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

Step 1: tert -Butyl 2- (2- ( Methoxycarbonyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

To a solution of 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (10.0 g, 46.5 mmol) dissolved in dichloromethane was added methyl pyrrolidine-2-carboxylate hydrochloride (8.44 g, 51.1 mmol) (9.80 g, 51.1 mmol), hydroxybenzotriazole (6.90 g, 51.1 mmol) and triethylamine (25.8 mL, 186 mmol) were added to a solution of 1- After the reaction mixture was prepared, it was stirred at room temperature for one day. The reaction mixture was concentrated in vacuo, diluted with aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The collected organic layer was washed with brine and washed three times with 1N hydrochloric acid solution. The organic layer was washed again with brine, dried over anhydrous MgSO ₄ , concentrated, and purified by medium pressure liquid chromatography (MPLC) to give the desired compound (15.3 g).

Step 2: 1- (1- ( tert - Butoxycarbonyl ) Pyrrolidine -2- Carbonyl ) Pyrrolidine -2-carboxylic acid

To the solution of the compound prepared in the above step 1 (10.0 g, 30.7 mmol) dissolved in tetrahydrofuran was added NaOH (2.45 g, 61.3 mmol) dissolved in water and stirred at room temperature for one day. The reaction mixture was concentrated, and the pH (PH) was adjusted to 1 using 1N hydrochloric acid solution (aq.). The aqueous layer was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous MgSO ₄ and concentrated to obtain 8.9 g of the desired compound.

Step 3: tert -Butyl 2- (2- (1- Methoxy -One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -1-carbonyl) Pyrrolidine -One- Carboxy  Produce

To a solution of 1- (1- (tert-butoxycarbonyl) pyrrolidine-2-carbonyl) pyrrolidine-2-carboxylic acid (6.00 g, 19.2 mmol) dissolved in dichloromethane was added methyl 2-aminopropanoate (2.85 g, 21.1 mmol) and triethylamine (2.95 g, 21.1 mmol) were added to a solution of the compound (10.7 mL, 76.8 mmol) to prepare a reaction mixture, which was then stirred at room temperature for one day. The reaction mixture was concentrated in vacuo, diluted with aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The collected organic layer was washed with brine and washed three times with 1N hydrochloric acid solution. The organic layer was washed again with brine, dried over anhydrous MgSO ₄ , concentrated, and purified by medium pressure liquid chromatography (MPLC) to obtain 6.2 g of the target compound.

Step 4: 2- (1- (1- ( tert - Butoxycarbonyl ) Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carbox amido ) Propanoic acid  Produce

To the solution of the compound prepared in the above step 3 (3.20 g, 8.05 mmol) dissolved in tetrahydrofuran was added NaOH (644 mg, 16.1 mmol) dissolved in water and stirred at room temperature for one day. The reaction mixture was concentrated, and the pH (PH) was adjusted to 1 using 1N hydrochloric acid solution (aq.). The aqueous layer was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous MgSO ₄ and concentrated to obtain 4.9 g of the title compound.

Step 5: tert -Butyl 2- (2- (1-oxo-1- (1-oxo-1,3- Diphenyl propane -2- Amino ) Propane-2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

(264 mg, 0.69 mmol), 2-amino-1,3-diphenylpropan-1-one hydrochloride (120 mg, 0.46 mmol) (396 mg, 2.06 mmol), hydroxybenzotriazole (279 mg, 2.06 mmol) and triethylamine (0.76 mL, 5.50 mmol) were added to a round bottom flask containing dichloromethane, Lt; / RTI &gt; for one day. The reaction mixture was concentrated in vacuo, diluted with aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The collected organic layer was washed with brine and washed three times with 1N hydrochloric acid solution. The organic layer was washed again with brine, dried over anhydrous MgSO ₄ , concentrated, and purified by medium pressure liquid chromatography (MPLC) to give the target compound as a white solid (yield: 89%).

Exact Mass (M): 590.3

Observed (M + H & lt ^; + & gt ^; ): 591.3

< Example  5> N- (1-oxo-1- (1-oxo-1,3- Diphenyl propane -2- Amino ) Propan-2-yl) -1- ( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

4N hydrochloric acid solution dissolved in dioxane was added to the compound prepared in Example 4 (80.0 mg, 0.14 mmol) dissolved in ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 490.3

Observed (M + H & lt ^; + & gt ^; ): 491.8

< Example  6> tert -Butyl 2- (1-oxo-1- (1-oxo-1,3- Diphenyl propane -2- Amino ) Propane-2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Amino-1,3-diphenylpropan-1-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride in the same manner as in Example 1 To obtain the target compound (yield: 79%).

Exact Mass (M): 493.3

Observed (M + H & lt ^; + & gt ^; ): 493.9

< Example  7> tert -Butyl 2- (1- (1- Cyclopentyl -1-oxo-3- Phenylpropane -2- Amino )-One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Example 1 was repeated except that 2-amino-1-cyclopentyl-3-phenylpropan-1-one hydrochloride was used instead of 3-amino- (Yield: 64%).

Exact Mass (M): 485.3

Observed (M + H & lt ^; + & gt ^; ): 485.8

< Example  8> tert -Butyl 2- (2-oxo-2- (3-oxo-1- Phenylbutane -2- Amino ) Ethyl carbamoyl ) Pyrrolidine -One- Carboxy  Produce

The procedure of Example 1 was repeated except that methyl 2-aminoacetate hydrochloride was used instead of methyl 2-aminopropanoate hydrochloride to give the target compound (yield: 68%). .

Exact Mass (M): 417.2

Observed (M + H & lt ^; + & gt ^; ): 417.9

< Example  9> tert -Butyl 2- (2- (1-oxo-1- (3-oxo-1- Phenylbutane -2- Amino ) Propane-2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

Amino-4-phenylbutan-2-one hydrochloride was used instead of 2-amino-1,3-diphenylpropan-1-one hydrochloride in the same manner as in Example 4 To give the desired compound (yield: 49%).

Exact Mass (M): 528.3

Observed (M + H & lt ^; + & gt ^; ): 528.9

< Example  10> N- (1-oxo-1- (3-oxo-1- Phenylbutane -2- Amino ) Propan-2-yl) -1- (P &lt; Loridine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

4N hydrochloric acid solution dissolved in dioxane was added to 80.0 mg of the compound prepared in Example 9 dissolved in ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 428.2

Observed (M + H & lt ^; + & gt ^; ): 428.8

< Example  11> tert -Butyl 2- (2- (1- (1- Cyclopentyl -1-oxo-3- Phenylpropane -2- Amino )-One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

Except that 2-amino-1-cyclopentyl-3-phenylpropan-1-one hydrochloride was used instead of 2-amino-1,3-diphenylpropan- (Yield: 74%). &Lt; / RTI &gt;

Exact Mass (M): 582.3

Observed (M + H & lt ^; + & gt ^; ): 583.3

< Example  12> tert -Butyl 2- (2- (1- Cyclopentyl -1-oxo-3- Phenylpropane -2- Amino )-2- Oxoethylcarbamoyl ) Pyrrolidine -One- Carboxy  Produce

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-aminoacetate hydrochloride was used,

Example 1 was repeated except that 2-amino-1-cyclopentyl-3-phenylpropan-1-one hydrochloride was used instead of 3-amino- (Yield: 57%).

Exact Mass (M): 471.3

Observed (M + H & lt ^; + & gt ^; ): 472.0

< Example  13> 1-acetyl-N- (1-oxo-1- (1-oxo- Diphenyl propane -2- Amino ) Propan-2-yl) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-acetylpyrrolidine-2-carboxylic acid solution was used,

Amino-1,3-diphenylpropan-1-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride in the same manner as in Example 1 To give the desired compound (yield: 47%).

Exact Mass (M): 435.2

Observed (M + H & lt ^; + & gt ^; ): 436.2

< Example  14> 1-acetyl-N- (2-oxo-2- (1-oxo- Diphenyl propane -2- Amino )ethyl) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-acetylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-aminoacetate hydrochloride was used,

Amino-1,3-diphenylpropan-1-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride in the same manner as in Example 1 (Yield: 62%). &Lt; / RTI &gt;

Exact Mass (M): 421.2

Observed (M + H & lt ^; + & gt ^; ): 422.2

< Example  15> tert -Butyl 2- (2- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane -2 days army No) -1- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

Amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 2-amino- The procedure of Example 4 was repeated to obtain the target compound (yield: 73%).

Exact Mass (M): 606.3

Observed (M + H & lt ^; + & gt ^; ): 607.0

< Example  16> tert -Butyl 2- (2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane Ylamino) -2- Oxoethylcarbamoyl ) Pyrrolidine -One- Carboxy  Produce

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-aminoacetate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the target compound (yield: 75%).

Exact Mass (M): 495.2

Observed (M + H & lt ^; + & gt ^; ): 495.9

< Example  17> tert -Butyl 2- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane Ylamino) -1- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 81%).

Exact Mass (M): 509.3

Observed (M + H & lt ^; + & gt ^; ): 510.0

< Example  18 > N- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane -2- Amino ) -1-ox Sopro 2-yl) -1- ( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

4N hydrochloric acid solution dissolved in dioxane was added to 80.0 mg of the compound prepared in Example 15 dissolved in ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 506.3

Observed (M + H & lt ^; + & gt ^; ): 507.1

< Example  19> tert -Butyl 2- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Neil Pro Edition-2 Amino )-2- Oxoethylcarbamoyl ) Pyrrolidine -One- Carboxy  Produce

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-2-cyclohexyl acetate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 79%).

Exact Mass (M): 577.3

Observed (M + H & lt ^; + & gt ^; ): 578.1

< Example  20> tert -Butyl 2- (2- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane -2- Amino )-2- Oxoethylcarbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -1-carboxylate

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-2-cyclohexyl acetate hydrochloride was used,

Amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 2-amino- , The target compound was prepared (yield: 71%).

Exact Mass (M): 674.4

Observed (M + H & lt ^; + & gt ^; ): 675.2

< Example  21 > N- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane -2- Amino )-2- Oxoethyl )-One-( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

4N hydrochloric acid solution dissolved in dioxane was added to 80.0 mg of the compound prepared in Example 20 dissolved in ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the target compound in the form of a white powder (yield: 79%).

Exact Mass (M): 574.3

Observed (M + H & lt ^; + & gt ^; ): 575.3

< Example  22> tert -Butyl 2- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino )-One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride. 1 (yield: 89%).

Exact Mass (M): 447.2

Observed (M + H & lt ^; + & gt ^; ): 448.1

< Example  23> tert -Butyl 2- (2- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino )-One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carbonyl ) Pyrrolidine -One- Carboxy  Produce

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 2-amino-1,3-diphenylpropan-1-one hydrochloride. (Yield: 85%) by carrying out the same processes as in the above Example 4.

Exact Mass (M): 544.3

Observed (M + H & lt ^; + & gt ^; ): 545.1

< Example  24> N- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino )-One- Oxopropane Yl) -1- ( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

4N hydrochloric acid solution dissolved in dioxane was added to 80.0 mg of the compound prepared in Example 23 dissolved in ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 444.2

Observed (M + H & lt ^; + & gt ^; ): 445.1

< Example  25> N- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino ) -3,3-dimethyl-1- Oxobutane Yl) -1- ( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

The procedure of Example 23 was repeated except that methyl 2-amino-3,3-dimethylbutanoate hydrochloride was used instead of methyl 2-aminopropanoate hydrochloride to obtain compound A ).

Then, 80.0 mg of the compound (A) prepared above was dissolved in ethyl acetate, 4N hydrochloric acid solution dissolved in dioxane was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 486.3

Observed (M + H & lt ^; + & gt ^; ): 487.3

< Example  26> N- (1- Cyclohexyl -2- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino )-2- Oxoethyl )-One-( Pyrrolidine -2- Carbonyl ) Pyrrolidine -2- Carboxamide  Produce

(B) was prepared in the same manner as in Example 23, except that methyl 2-amino-2-cyclohexyl acetate hydrochloride was used instead of methyl 2-aminopropanoate hydrochloride instead of methyl 2- Respectively.

Then, 80.0 mg of the compound (B) thus prepared was dissolved in ethyl acetate, and a 4N hydrochloric acid solution dissolved in dioxane was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white powder (yield: 99%).

Exact Mass (M): 512.3

Observed (M + H & lt ^; + & gt ^; ): 513.3

< Example  27> 1-Acetyl-N- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino ) -1-ox Sopro 2-yl) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-acetylpyrrolidine-2-carboxylic acid solution was used,

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride. 1, the target compound was prepared (yield: 57%).

Exact Mass (M): 389.2

Observed (M + H & lt ^; + & gt ^; ): 389.9

< Example  28> 1-acetyl-N- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane Ylamino) -3,3-dimethyl-l- Oxobutane -2 days) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-acetylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-3,3-dimethyl butanoate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 62%).

Exact Mass (M): 493.3

Observed (M + H & lt ^; + & gt ^; ): 494.2

< Example  29> 1-Acetyl-N- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Neil Pro Edition-2 Amino )-2- Oxoethyl ) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-acetylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-2-cyclohexyl acetate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 44%).

Exact Mass (M): 519.3

Observed (M + H & lt ^; + & gt ^; ): 520.2

< Example  30> 1- Benzoyl -N- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino ) -1-ox Sopro 2-yl) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-benzoylpyrrolidine-2-carboxylic acid solution was used,

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride. 1 (yield: 87%).

Exact Mass (M): 451.2

Observed (M + H & lt ^; + & gt ^; ): 452.2

< Example  31> benzyl 2- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino )-One- Oxopropane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Except that a solution of 1- (benzyloxycarbonyl) pyrrolidine-2-carboxylic acid was used instead of the solution of 1- (tert-butoxycarbonyl) pyrrolidine-

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride. 1 (yield: 72%).

Exact Mass (M): 481.2

Observed (M + H & lt ^; + & gt ^; ): 482.3

< Example  32> 1- Formyl -N- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane Ylamino) -3,3-dimethyl-l- Oxobutane -2 days) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-formylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-3,3-dimethyl butanoate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 69%).

Exact Mass (M): 479.2

Observed (M + H & lt ^; + & gt ^; ): 480.1

< Example  33> N- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane -2- Amino )-2- Oxoethyl )-One- Formylpyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-formylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-2-cyclohexyl acetate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 71%).

Exact Mass (M): 505.3

Observed (M + H & lt ^; + & gt ^; ): 506.3

< Example  34> 1- Benzoyl -N- (1- Cyclohexyl -2- (3- (4- Hydroxyphenyl ) -1-oxo-1- Neil Pro Edition-2 Amino )-2- Oxoethyl ) Pyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-benzoylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-2-cyclohexyl acetate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 89%).

Exact Mass (M): 581.3

Observed (M + H & lt ^; + & gt ^; ): 582.3

< Example  35> N- (1- (1- (4- Hydroxyphenyl ) -3- Oxobutane -2- Amino ) -3,3-dimethyl-1- Oxobutane Yl) -1- Pivaloylpyrrolidine -2- Carboxamide  Produce

Instead of using a 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid solution, a 1-pivaloylpyrrolidine-2-carboxylic acid solution was used,

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-3,3-dimethyl butanoate hydrochloride was used,

Except that 3-amino-4- (4-hydroxyphenyl) butan-2-one hydrochloride was used instead of 3-amino-4-phenylbutan-2-one hydrochloride. 1 (yield: 47%).

Exact Mass (M): 473.3

Observed (M + H & lt ^; + & gt ^; ): 474.4

< Example  36> tert -Butyl 2- (1- (3- (4- Hydroxyphenyl ) -1-oxo-1- Phenylpropane Ylamino) -3,3-dimethyl-l- Oxobutane -2- Il carbamoyl ) Pyrrolidine -One- Carboxy  Produce

Instead of using methyl 2-aminopropanoate hydrochloride, methyl 2-amino-3,3-dimethyl butanoate hydrochloride was used,

Except that 2-amino-3- (4-hydroxyphenyl) -1-phenylpropan-1-one hydrochloride was used instead of 3-amino- , The procedure of Example 1 was repeated to produce the desired compound (yield: 87%).

Exact Mass (M): 551.3

Observed (M + H & lt ^; + & gt ^; ): 552.2

The chemical structures of the compounds prepared in Examples 1-36 are summarized in Table 1 below.

Example Chemical structural formula Example Chemical structural formula One

19

2

20

3

21

4

22

5

23

6

24

7

25

8

26

9

27

10

28

11

29

12

30

13

31

14

32

15

33

16

34

17

35

18

36

< Experimental Example  1> interleukin-6 ( Interleukin -6, IL -6) expression inhibition ability evaluation

In order to evaluate the ability of the compound of Example according to the present invention to inhibit the expression of interleukin-6 (IL-6), the following experiment was conducted.

First, RAW 264.7 cells (macrophage cell line) is American Type Culture Collection (Manassas, VA) from the obtained, 10 × culture medium under 37 ℃ 5% CO ₂ environment [1% Protea agarose peptone (proteose peptone), 0.2% glucose, And cultured on a glass slide surface in 0.1% yeast extract, 0.003% ethylenediaminetetra acetic acid (EDTA) ferric sodium salt.

RAW 264.7 macrophages were divided into 6-well plates. After 24 hours, the compound prepared in Example 1-36 and Smaducin-6 were incubated for 30 minutes at 100 nM and the Transforming Growth Factor Beta (TGF-b) at 5 ng / ml For 2 hours and then treated with Lipopolysaccharides (LPS) for 2 hours. The cells were harvested using trizol to extract RNA (ribonucleic acid). CDNA (complementary deoxyribonucleic acid) was synthesized using 2 μg of extracted RNA, and reverse transcription polymerase chain reaction (RT-PCR) and real-time polymerase chain reaction (Real-Time Polymerase Chain Reaction Chain Reaction, Real-Time PCR). The RT-PCR sample after the measurement was confirmed by hanging on a gel, and the amount thereof was quantified using a densitometer. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene was used as a loading control for the IL-6 gene. The results are shown in Figs. 1-5.

1-5 are graphs showing the relative inhibition of interleukin-6 (IL-6) expression inhibitory ability of the compound prepared in Example 1-36.

As shown in Figs. 1-5, the compounds prepared in Example 1-36 were found to be effective in suppressing the expression of interleukin-6 (IL-6), Smaducin-6 and Smaducin- The expression of IL-6 was effectively inhibited similarly to that of Transforming Growth Factor Beta (TGF-b).

Accordingly, the ketone peptide derivative, its optical isomer, or pharmaceutically acceptable salt thereof according to the present invention is excellent in the activity of inhibiting the expression of interleukin-6 (IL-6), and thus Ulcerative inflammatory diseases caused by interleukin-6, such as inflammatory bowel disease such as colitis and Crohns disease, or sepsis.

< Formulation example  1> Preparation of pharmaceutical preparations

1-1. Manufacture of Powder

2 g of the compound of formula 1 according to the invention

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

1-2. Manufacture of tablets

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

1-3. Preparation of capsules

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

1-4. Manufacture of granules

The compound of formula 1 according to the present invention, 150 mg

Soybean extract 50 mg

Glucose 200 mg

Starch 600 mg

After mixing the above components, 100 μl of 30% ethanol was added and the mixture was dried at 60 ° C to form granules, which were filled in a capsule.

Claims (11)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is -C (= O) R ⁵ , or -C (= O) OR ⁶ ,
Wherein R ⁵ and R ⁶ is a heteroaryl that is independently selected from the group consisting of -H, a C _{1 -10} straight or branched chain alkyl, unsubstituted C _{6 -10} aryl C _{1 -10} of the ring of an alkyl, N, O, and S unsubstituted or substituted 5 to 10 membered heteroaryl-cycloalkyl, or unsubstituted or substituted C _{6 -10} aryl group containing one or more atoms,
The substituted 5 to 10 membered heteroaryl cycloalkyl, and substituted aryl of C _{6 -10} are independently -OH, -Boc (

), Halogen, nitrile, C _{1 -10} linear or branched alkyl, and C _{1 -10} straight or branched alkoxy cycloalkyl of 5 to 10 membered heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl and C _{6 - 10} &lt; / RTI &gt;

R ² And R ³ is independently -H, -OH, halogen, nitrile, aryl or unsubstituted of C _{1 -10} straight or branched chain alkyl, C _{1 -10} linear or branched alkoxy, unsubstituted C _{6 -10} of the ring &Lt; / RTI &gt;

R ⁴ is a hetero atom selected from the group consisting of straight or branched chain alkyl, unsubstituted or substituted aryl of C _{6 -10,} unsubstituted or substituted 5 to 10 atom cycloalkyl, N, O and S of C _{1 -10} Or an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S,
The substitution of C _{6 -10} aryl, substituted 5 to 10 atom cycloalkyl, substituted 5-10 membered heteroaryl, and substituted 5-10 membered heteroaryl cycloalkyl is independently -OH, halogen, C _{1 -5} a linear or branched alkyl and C _{1 -5} straight or branched chain alkoxy of C _{6 -10} with one or more substituents selected from the group consisting of substituted aryl, 5 to 10 atom cycloalkyl, 5-10 membered heteroaryl and 5-10 Lt; / RTI &gt; heterocycloalkyl).
The method according to claim 1,
R ¹ is -C (= O) R ⁵ , or -C (= O) OR ⁶ ,
Wherein R ⁵ and R ⁶ is a heteroaryl that is independently selected from the group consisting of -H, a C _{1 -5} straight or branched chain alkyl, unsubstituted C _{6 -8} aryl C _{1 -5} in the ring of an alkyl, N, O, and S and unsubstituted or substituted 5-8 membered heteroaryl cycloalkyl, or aryl unsubstituted or substituted C _{6 -8} containing one or more atoms,
The aryl of substituted 5-8 membered heteroaryl cycloalkyl, and a C _{6 -8-substituted} independently -OH, -Boc (

), Halogen, nitrile, with a least one member selected from the group consisting of straight or branched chain alkoxy of C _{1 -5} straight or branched chain alkyl and C _{1 -5} substituents of the optionally substituted 5-8 membered heteroaryl cycloalkyl, and C _{6 - 8} &lt; / RTI &gt;

R ² And R ³ is independently -H, -OH, halogen, nitrile, a C _{1 -5} straight or branched chain alkyl, aryl, or unsubstituted of C _{1 -5} straight or branched alkoxy, unsubstituted C _{6 -8} ring &Lt; / RTI &gt;

R ⁴ is a linear or branched C _{1 -5} alkyl, or unsubstituted aryl, substituted or unsubstituted of C _{6 -8} ring atoms, or a substituted 5-8 cycloalkyl,
_Wherein said substituted C _{6 -8} aryl and substituted 5-8 membered cycloalkyl are independently selected from the group consisting of -OH, halogen, C _{1 -5} straight or branched chain alkyl and C _{1 -5} straight or branched alkoxy. Wherein at least one of the substituents is C _{6 -8} aryl and 5-8 atomic cycloalkyl which is substituted, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ¹ is

,

,

,

,

,

,

, or

ego;
R ² is -H, methyl, tert-butyl, or unsubstituted cyclohexyl;
R ³ is -H, or -OH;
R ⁴ is methyl, n-butyl, unsubstituted phenyl, or unsubstituted cyclopentyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(1) tert-Butyl 2- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;
(2) tert-Butyl 2- (1-oxo-1- (3-oxo-1-phenylheptan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;
(3) tert-Butyl 2- (2-oxo-2- (1-oxo-1,3-diphenylpropan-2-ylamino) ethylcarbamoyl) pyrrolidine-1-carboxylate;
(4) Synthesis of tert-butyl 2- (2- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidin- Carbonyl) pyrrolidine-1-carboxylate;
(5) Synthesis of N- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2- ylamino) propan- Lt; / RTI &gt;2-carboxamide;
(6) tert-Butyl 2- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-ylcarbamoyl) pyrrolidine-1-carboxylate;
(7) Synthesis of tert-butyl 2- (1- (1-cyclopentyl-1 -oxo-3-phenylpropan-2-ylamino) -1-oxopropane- 2-ylcarbamoyl) pyrrolidine- Rate;
(8) tert-Butyl 2- (2-oxo-2- (3-oxo-1-phenylbutan-2-ylamino) ethylcarbamoyl) pyrrolidine-1-carboxylate;
(9) Synthesis of tert-butyl 2- (2- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan- 2- ylcarbamoyl) pyrrolidine- Pyrrolidine-1-carboxylate;
(10) Synthesis of N- (1-oxo-1- (3-oxo-1-phenylbutan-2-ylamino) propan- 2-carboxamide;
(11) Synthesis of tert-butyl 2- (2- (1- (1-cyclopentyl-1 -oxo-3-phenylpropan-2-ylamino) 1-carbonyl) pyrrolidine-1-carboxylate;
(12) tert-Butyl 2- (2- (1-cyclopentyl-1-oxo-3-phenylpropan-2-ylamino) -2-oxoethylcarbamoyl) pyrrolidine-1-carboxylate;
(13) 1-acetyl-N- (1-oxo-1- (1-oxo-1,3-diphenylpropan-2-ylamino) propan-2-yl) pyrrolidine-2-carboxamide;
(14) 1-Acetyl-N- (2-oxo-2- (1-oxo-1,3-diphenylpropan-2-ylamino) ethyl) pyrrolidine-2-carboxamide;
(15) Synthesis of tert-butyl 2- (2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) ) Pyrrolidine-1-carbonyl) pyrrolidine-1-carboxylate;
(16) Synthesis of tert-butyl 2- (2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2- ylamino) -2-oxoethylcarbamoyl) pyrrolidin- Carboxy;
(17) Synthesis of tert-butyl 2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) Di-1-carboxylate;
(18) Synthesis of N- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-carbonyl) pyrrolidine-2-carboxamide;
(19) Synthesis of tert-butyl 2- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-oxoethylcarbamoyl) Lt; / RTI &gt;
(20) Synthesis of tert-butyl 2- (2- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) Yl) pyrrolidine-1-carbonyl) pyrrolidine-1-carboxylate;
(21) Synthesis of N- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan- Di-2-carbonyl) pyrrolidine-2-carboxamide;
(22) Synthesis of tert-butyl 2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) Carboxy;
(23) Synthesis of tert-butyl 2- (2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -1-oxopropane-2-ylcarbamoyl) pyrrolidine -1-carbonyl) pyrrolidine-1-carboxylate;
(24) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) Pyrrolidine-2-carboxamide &lt; / RTI &gt;
(25) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -3,3-dimethyl-1-oxobutan- Lt; / RTI &gt; 2-carbonyl) pyrrolidine-2-carboxamide;
(26) Synthesis of N- (1-cyclohexyl-2- (1- (4-hydroxyphenyl) -3-oxobutan- Carbonyl) pyrrolidine-2-carboxamide;
(27) Synthesis of 1-acetyl-N- (1- (1- (4-hydroxyphenyl) -3-oxobutan- &Lt; / RTI &gt;
(28) Synthesis of 1-acetyl-N- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- - yl) pyrrolidine-2-carboxamide;
(29) Synthesis of 1-acetyl-N- (1- cyclohexyl-2- (3- (4-hydroxyphenyl) Carboxamide;
(30) Synthesis of 1-benzoyl-N- (1- (1- (4-hydroxyphenyl) -3-oxobutan- &Lt; / RTI &gt;
(31) Benzyl 2- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -1-oxopropane- 2-ylcarbamoyl) pyrrolidine- ;
(32) Synthesis of 1-formyl-N- (1- (3- (4- hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- 2-yl) pyrrolidine-2-carboxamide;
(33) Synthesis of N- (1-cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -2-oxoethyl) Carboxamide;
(34) Synthesis of 1-benzoyl-N- (1- cyclohexyl-2- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan- Carboxamide;
(35) Synthesis of N- (1- (1- (4-hydroxyphenyl) -3-oxobutan-2-ylamino) -3,3-dimethyl- 1 -oxobutan- Ylpyrrolidine-2-carboxamide; And
(36) Synthesis of tert-butyl 2- (1- (3- (4-hydroxyphenyl) -1-oxo-1-phenylpropan-2-ylamino) -3,3-dimethyl- Ylcarbamoyl) pyrrolidine-1-carboxylate.
As shown in Scheme 1 below,
Preparing a compound represented by the formula (4) through dehydration condensation reaction of the compound represented by the formula (2) and the compound represented by the formula (3) (step 1);
A step of preparing a compound represented by the formula (5) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the formula (4) prepared in the step 1 (step 2); And
(Step 3) of preparing a compound represented by the formula (1) by dehydration condensation reaction between the compound represented by the formula (5) and the compound represented by the formula (6) prepared in the step 2 Lt; RTI ID = 0.0 &gt;
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ , R ² , R ³ And R &lt; ⁴ &gt; are independently as defined in formula (1) of claim 1).
As shown in Reaction Scheme 2 below,
(Step 1) of preparing a compound represented by the formula (9) through dehydration condensation reaction of the compound represented by the formula (7) and the compound represented by the formula (8); And
(Step 2) of preparing a compound represented by the formula (2) by substituting a carboxy group for the methoxycarbonyl group of the compound represented by the formula (9) prepared in the step 1 to obtain a compound represented by the formula Manufacturing method:
[Reaction Scheme 2]

(In the above Reaction Scheme 2,
R ¹ is as defined in formula (I) of claim 1).
As shown in Scheme 3 below,
The compound-Boc (

(Step 1): &lt; EMI ID = 15.0 &gt; (wherein R &lt; 1 &gt;
[Reaction Scheme 3]

(In the above scheme 3,
-Boc

ego,
R ² , R ³ And R &lt; ⁴ &gt; are independently as defined in formula (1)
The compound represented by the general formula (Ia) or (Ib) is included in the compound represented by the general formula (1).
A pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases containing the compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The method of claim 8,
Wherein said pharmaceutical composition inhibits the expression of interleukin-6 (IL-6).
9. The method of claim 8,
Wherein the inflammatory disease is sepsis, or an inflammatory bowel disease.
11. The method of claim 10,
Wherein the inflammatory bowel disease is Ulcerative colitis or Crohns disease.

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