TW201024279A - Use of B1 receptor antagonists - Google Patents

Abstract

The present invention is related to a kinin B1 receptor antagonist for use in the treatment of a patient suffering from stricturing Crohn's Disease.

Description

* 201024279 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a kinin B1 receptor antagonist for treating a patient suffering from stricting Crohn's Disease. [Prior Art] Crohn's disease (CD) is a multifactorial disease characterized by chronic inflammation of the intestine produced by complex interactions of genes, immunological and microbial factors. Stenosis in both the small intestine and the colon represents one of the most common complications of the CD, thus defining a particular form or aspect of CD, ie, stricting Crohn's Disease, the stenotic Crohn's disease In addition, the special form or aspect is CD intestinal fibrosis of fibrostenosis, which is also known as fibrosonic Crohn's disease (FCD). More than one-third of CD patients will develop a special fiber stenosis phenotype when there is no luminal inflammatory sign, which leads to recurrent intestinal stenosis as a final product of chronic transmural inflammation. It is a feature of fiber stenosis Crohn's disease. Stenosis Crohn's disease can be defined as the occurrence of persistent chamber narrowing, as evidenced by radiology, endoscopy, or surgical examination, combined with pre-stenosis dilatation and/or obstructive symptoms or signs (Gasche et al ,, Infl Bowel Dis. 2000;6: 8-15). The stenosis is generally asymptomatic until the diameter of the chamber is reduced until it causes a blockage. Not all CD obstruction is caused by fibrotic stenosis; inflammatory edema can also increase stenosis -5 - 201024279 degrees, but can be treated with anti-inflammatory agents. This medication reduces active inflammation, but fiber stenosis will not respond to this. In addition to this, it is now debated whether anti-inflammatory treatment can indeed promote fibrotic stenosis. Patients with fibrous stenotic Crohn's disease who develop a occlusive condition show or suffer from a CD, also known as obstructive fibrotic stenosis, in the form of CD. When fiber stenosis CD does not respond to drug therapy and requires endoscopic or surgical treatment, most CD patients and those with particular fiber stenosis CD require at least one surgical treatment, and more than half of all operations are to reduce bowel Blocking (Van Assche and others Inflamm Bowel Dis. 2004; 1 0 (1): 55-60; Froehlich and others

Digestion. 2007; 76(2): 113-115). Surgery is not effective, as approximately 70% of patients with endoscopy have demonstrated postoperative recurrence at the anastomosis; repeated surgery may be required. Patients undergoing the first surgery are in desperate need of treatment to prevent stenosis and recurrence to avoid repeat surgery. Repeated resections expose these patients to surgical morbidity, significant intestinal loss, and risk of short bowel syndrome (Burke et al., Am J Gastroenterol. 2007; 102:43 9-448). It is said that patients with fibrous stenotic CD (including obstructive fiber® stenotic CD) who have undergone the first surgery to reduce intestinal obstruction suffer or develop recurrent fibrotic stenosis CD and more specifically recurrent obstructiveness. The risk of fiber stenosis CD (RFCD) or the risk. Despite the development of CD therapy, the incidence of stenosis and the requirement for bowel resection have not decreased in the last 25 years (Cosnes and others Gut 2005; 54: 237-24 1). Although a large number of treatment options are available for the treatment of intestinal inflammation of the CD, treatment options for fibrotic stenosis are limited to mechanical methods such as endoscopic-6-201024279 balloon dilatation, stricturoplasty, and surgical resection, and are generally associated High recurrence rate. Specific drug treatments are aimed at preventing or reversing intestinal fibrosis and therefore do not form fibrotic stenosis. In view of these limitations of prior art treatments for stenotic CD, fibrosonic Crohn's disease, obstructive fibrotic stenosis CD, and recurrent fibrotic stenosis CD, the problem underlying the present invention is to provide treatment and/or prevention. Means and methods of CDs in other forms. A further problem constituting the basis of the present invention is to provide means and methods for treating and/or preventing such diseases, whereby the means and methods are highly efficient. An additional problem constituting the basis of the present invention is to provide means and methods for treating and/or preventing such diseases, whereby the means and methods have low side effects. • SUMMARY OF THE INVENTION The problems that form the basis of the present invention are solved by the separate items in the scope of the appended claims. Preferred specific examples are available from the subsidiary of φ in the scope of the patent application. More specifically, in the first aspect, the problem constituting the basis of the present invention is solved in the first specific example by a kinin B1 receptor antagonist for treating a patient suffering from stenotic Crohn's disease. In the second specific example of the first aspect, the second specific example is a specific example of the first specific example of the first aspect, and the stenotic Crohn's disease is a fibrous stenosis Crohn's disease. In the third specific example of the first aspect, the third specific example is a preferred embodiment of the first and second specific examples of the first aspect, and the stenotic Crohn's disease is 201024279 obstructive fibrosis clonality. In a fourth specific example of the first aspect, the fourth specific example is a preferred embodiment of the first, second, and third specific examples of the first aspect, wherein the Crohn's disease is recurrent obstructive fiber stenosis Crohn's disease. In a fifth specific example of the first aspect, the fifth specific example is a preferred embodiment of the first, second, third and fourth specific examples of the first aspect, and the kinin B 1 receptor antagonist is selected From the following:

Ac-Lys-Arg-Pro-Pro-Gly-Phe-Ser-D-Nal-Ile-OH ( R715 )

Ac-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R892 ),

Ac-Lys-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R9 1 4 ),

Ac-Om-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH ( R954 ), H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic -OH ( B985 8 ), H-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH ( B9958 ), F5c-Lys-Lys-Arg-Pro-Hyp-Gly- Cpg-Ser-D-Tic-Cpg-〇H ( B 1 0324 ), 2-[l - ( 3,4-dichloro-phenylsulfonyl)-3-keto-1,2,3,4- Tetrahydro-quinoxaline-2-yl]-indole {2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-acetamide, -8 - 201024279 >}-{2-[4-(4,5-Dihydro-111-imidazol-2-yl)-phenyl]-ethyl}-2-[1-(naphthalene-2-sulfonate) Mercapto)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamide 3-(3,4-dichloro-phenyl)-indole-{1 -[4-( 4,5-Dihydro-1H-imidazol-2-yl)-benzyl]-2-keto-2-pyrrolidin-1-yl-ethyl}-3-(naphthalene-2 -sulfonylamino)-propanamine, 4'-( 1-{3-[ (2,2-difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridine-2-amine Methyl}-ethyl)-5-methyl-biphenyl-2-carboxylate, N-(4-chloro-2-{1-[3'-fluoro-2'-(3-methyl- [1,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethylamino}-pyridin-3-yl)-3,3,3-trifluoro-propanamide 4'-{1-[4-chloro-3- ( 2- Methyl-ethyl decylamino)-pyridin-2-ylamino]-ethyl}-3-fluoro-biphenyl-2-carboxylic acid, 3-chloro-4'-{l-[4- Methyl-3-(2-cyano-ethenylamino)-pyridin-2-ylamino]-ethyl}-biphenyl-2-carboxylate, N-(4-chloro-2- {1-[3'-Fluoro-2'-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylamino}-pyridin-3-yl)- 2-cyano-acetamide, 3,3'-difluoro-4'-{[5-(4-pyridin-4-yl-piperazin-1-carbonyl)-pyridin-2-ylamino]- Methyl}-biphenyl-2-carboxylic acid methyl ester, 3,3'-difluoro-4'-({[1-(3,3,3-trifluoro-propenylamino)-cyclopropane) Methyl]-amino}-methyl)-biphenyl-2-carboxylic acid methyl ester, 3,3|-difluoro-4'-(1-{[1-(2,2,2-trifluoro-) Methyl decylamino)-cyclopropanecarbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 3-chloro-3^fluoro-4'-(1-{[1-( 2,2,2-trifluoro-ethinylamino)-cyclopropane-9- 201024279 carbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 2,4-dichloro -6-[5-fluoro-6-(1-{[1-(2,2,2-trifluoro-ethinyl))cyclopropanylcarbonyl]-amino}-ethyl)-pyridine-3 -yl]-methyl benzoate, 2-chloro-6-[5-fluoro-6-(1-{[1-(2,2,2-trifluoro-ethenyl) Methyl)-cyclopropanylcarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid methyl ester, 2-chloro-6-[5-fluoro-6-(1-{[1-(2 , 2,2-trifluoro-ethinylamino)-cyclopropanecarbonyl]-aminoethylethyl)-pyridin-3-yl]-benzoic acid ethyl ester, 3-methoxy-isoxanthene-5-carboxylate Acid [1-(1-{5-[3,5-dichloro-2-(2,2-di-ethoxy)-phenyl]-3-gas-chat-2-yl}-B N-(5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] oxadiazole) 3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide, 1- ( 1-butyl-5-cyclohexyl-2-keto-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-[4 -(4-Dimethylamino-piperidin-1-yl)-phenyl]-urea, 1-(1-butyl-2-keto-5-phenethyl-2,3-dihydro- 1H-benzo[e][l,4]di-w-azhen-3-yl)-3-[4-(4-pyridin-4-yl-piperidin-1-yl)-phenyl]-urea, [4-( 2_Benzyl decyl-phenylamine sulfonyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, {4-[2-(pyridine-2-carbonyl)- Phenylamine sulfonyl]-phenyl}-carbamic acid tetrahydro-furan-2-ylmethyl ester, (R)-N- ( 1- ( 5 - ( 5-Chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2-yl)ethyl)-4,4-difluoro 1-hydroxycyclohexane-10-201024279 Carboxylamidine, 3-benzo[1,3]dioxol -5-yl-N-[2-[4-(2,6-dimethyl Benzyl-piperidin-1-ylmethyl)-phenyl]-1-(isopropyl-methyl-amine-mercapto)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonate Mercaptoamine)-propanamide (SSR240612), 1-[4-(2,2-diphenyl-ethylamino)-3-(sodium phenyl-4-carbonyl)-benzenesulfonyl]- Piperidine-4-carboxylic acid bis-(3-dimethylamino-propyl)-decylamine, {2-(2,2-diphenyl-ethylamino)-5-[4- (4 -isopropyl-piperazine-1-carbonyl hydrazino)-piperidine-1-sulfonyl]-phenyl-b-morpholin-4-yl-methanone, {2-( 2,2-diphenyl-B Amino)-5-[4-(4-methyl-piperazin-1-carbonyl)-piperidine-sulfonyl]-phenyl}-morpholin-4-yl-methanone, 3- ( Naphthalene-2-sulfonylamino)-3-phenyl-N-(7-piperidinyl-p-methyl-B- 4-yl)-propanamide, (4-gas! -本基)-N-(7-叫U疋-1-ylmethyl-D--4-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propanamide, φ 1^-[6-(tris-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[1-(3-trifluoromethyl-benzene) Sulfhydryl)-piperidin-2-yl]-acetamide, 2,3-dihydroxy-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalene -1-yl)-4-(3-trifluoromethyl-benzenesulfonyl)-butanamine, 2-((R)-3-buton-1-(phenylsulfonyl)-l, 2,3,4-tetrahydroquinoxaline-p-(2-yl)-N-((R)-7-(piperidin-l-ylmethyl) later-4-yl)acetamidamine > N- [4-( 4,5 -Dihydro-1H-imidazol-2-yl)-benzyl]-2-{2-[ ( 4 -methoxy-2,6-dimethyl-benzenesulfonyl) )-Methyl-amino]-ethoxy}-1 methyl- -11 - 201024279 acetamidine (LF22-0542), 7-chloro-2-[3-(9-pyridin-4-yl-3) ,9-diaza-spiro[5.5]undecyl-3-carbonyl)-phenyl]-2,3-dihydroisoindol-1-one (ELN-44 1 95 8 ), 4-bromo- 5-(2-Chloro-benzylidenylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid [2-( 3,4,5,6-tetrahydro-2H-[1,4 "bipyridyl-4-yl)-ethyl]-decylamine, and 1-benzyl-N-(2-((4-(6-(4,5-dihydro-1H-imidazol-2-) Pyridine 3-Ominoamino)benzyl)(methyl)amino)-2-ketoethyl)-1H-benzo[d]imidazole-2-carboxamide. In the second aspect, the problem constituting the basis of the present invention is solved in the first specific example by using a kinin B1 receptor antagonist for the manufacture of a medicament for treating a patient suffering from a narrow Crohn's disease. In the second specific example of the second aspect, the second specific example is a preferred embodiment of the first specific example of the second aspect, and the stenotic Crohn's disease is fibrosonic Crohn's disease. In the third specific example of the second aspect, the third specific example is a preferred embodiment of the first and second specific examples of the second aspect, and the Crohn's disease is ® occlusive fiber stenosis Crohn's disease. In a fourth specific example of the second aspect, the fourth specific example is a preferred embodiment of the first, second and third specific examples of the second aspect, wherein the Crohn's disease is recurrent obstructive fiber stenosis Crohn's disease. In a fifth specific example of the second aspect, the fifth specific example is a preferred embodiment of the first, second, third and fourth specific examples of the second aspect, wherein the kinin B 1 receptor antagonist is selected From the following: -12- 201024279

Ac-Lys-Arg-Pro-Pro-Gly-Phe-Ser-D- Nal-Ile-OH ( R715)

Ac-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R8 92 ),

Ac-Lys-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH (R9 14),

Ac-Orn-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH (R954),

H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH (B9 85 8 ), H-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D -Tic-Cpg-OH (B995 8 ), F5c-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH (B 1 0324 ), 2-[1-(3, 4-Dichloro-benzenesulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[4-( 4,5-di Hydrogen-1H-imidazol-2-yl)-phenyl]-ethyl}-acetamide, N-{2-[4-(4,5-diamino-1H-miso-2-yl)-ben -ethyl}-2-[1-(naphthalene-2-sulfonyl)-3-one-1,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamide 3-(3,4-Dichloro-phenyl)-N-{ 1-[4-( 4,5-dihydro-1H.imidazol-2-yl)-benzyl]-2-indenyl-2 -卩比略 steep-1-yl-ethyl}_3-(Cai-2 - arylamino)-propanamine, 4·- ( 1-{3-[ ( 2,2-difluoro-ring) Propane carbonyl)-amino]-4-methyl-pyridine- -13- 201024279 2-Aminoamino}-ethyl)-5-methyl-biphenyl-2-carboxylic acid methyl ester, N- ( 4 -Chloro-2-{1-[3·-fluoro-2'-(3-methyl-[1,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethyl Amino}-pyridin-3-yl)-3,3,3-trifluoro-propanamide, 4'-{1-[4-chloro-3-(2-cyano-ethenylamino)- Pyridin-2-ylamino]-ethyl Methyl 3-fluoro-biphenyl-2-carboxylate, 3-chloro-4·-{1-[4-chloro-3-(2-cyano-ethenylamino)-pyridin-2-yl Amino]-ethyl}-biphenyl-2-carboxylic acid methyl ester, Ν-(4-chloro-2-{1-[3'-fluoro-2'-(2-methyl-2Η-tetrazole -5-yl)-biphenyl-yl-4-yl]-ethylamino}-pyridin-3-yl)-2-cyano-acetamide, 3,3'-difluoro-4'-{ [5-(4-Pyridin-4-yl·piperazin-1-carbonyl)-pyridin-2-ylamino]-methyl}-biphenyl-2-carboxylic acid methyl ester, 3,3'-di Fluoro-4'-({[1-(3,3,3-trifluoro-propenylamino)-cyclopropanecarbonyl]-amino}-methyl)-biphenyl-2-carboxylic acid methyl ester , 3,3'-difluoro-4'-(1-{[1-(2,2,2-trifluoro-ethylideneamino)-cyclopropanecarbonyl]-amino}-ethyl)-linked Methyl phenyl-2-carboxylate, 3-chloro-3'-fluoro-4'-( 1-{[1-( 2,2,2-trifluoro-ethinyl)-cyclopropane® carbonyl ]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 2,4-dichloro-6-[5-fluoro-6-(1-{[1-(2,2,2) -trifluoro-ethinylamino)-cyclopropenyl]-amino}_ethyl)-p-predated-3-yl]-benzoic acid methyl vinegar '2-chloro-6-[5-fluoro -6-(1-{[1-(2,2,2-trifluoro-ethylideneamino)-cyclopropanecarbonyl]-amino}-ethyl) -pyridin-3-yl]-benzoic acid methyl ester, 2-chloro-6-[5-fluoro-6-(1-{[b (2,2,2-trifluoro-ethinylamino)-) Propane carbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid ethyl ester, -14- 201024279 3 -methoxy-isoxanthene-5-carboxylic acid [1- ( l-{5 -[3,5-Dichloro-2-(2,2-difluoroethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylamine-methylmethyl)-cyclopropyl ]-decylamine, 1^-(1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]-diazol-3-yl)-phenyl] 3-fluoro-pyridin-2-yl}-ethyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide, 1-(1-butyl-5-cyclohexyl -2-keto-2,3-dihydro-1H-benzo[e][l,4]diazol-3-yl)-3-[4-(4-dimethylamino-piperidine) -1-yl)-phenyl]•urea> 1-(1-butyl-2-keto-5-phenethyl-2,3-dihydro-1H-benzo[e][l, 4] Dioxo-3-yl)-3-[4-(4-pyrene than B疋-4-yl-indol-1-yl)-phenyl]-pulse[4-(2-Benzyl) Mercapto-phenylamine sulfonyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, {4-[2-(pyridine-2-carbonyl)-phenylamine sulfonyl]- Phenyl}-carbamic acid tetrahydro-furan-2-ylmethyl ester, ▲ ( R) -N- ( 1- ( 5- ( 5 - chloro-3-fluoro-2- ( 2 ) -methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2-yl)ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide, 3-benzene And [1,3]dioxo-5-yl-N-[2-[4-( 2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-1-(isopropyl) -Methyl-amine-mercapto)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propanamide (SSR2406 1 2 ), 1-[4-( 2,2-diphenyl-ethylamino)-3-(tyrosine-4-carbonyl)-benzenesulfonyl; I-piperidine-4-carboxylic acid bis-(3-dimethylamino- Propyl)-nonylamine, {2-(2,2-diphenyl-ethylamino)-5-[4-(4-isopropyl-piperazin-1-carbonyl-15-201024279)- Piperidine-1-sulfonyl]-phenyl}-morpholin-4-yl-methanone, {2-(2,2-diphenyl-ethylamino)-5-[4- (4- Methyl-piperidin-1-carbonyl)-calliosis-1-expansion base]-phenyl}•味琳-4-yl-jiao' 3- (naphthalene-2-sulfonylamino)-3 -phenyl-> 1-(7-piperidin-1-ylmethyl-[1 gram-4-yl)-propanamide, 3-(4-chloro-phenyl)-N-(7-峨Strep-1-ylmethyl-B gram-4 -yl)-3-( 3-trifluoromethyl-benzenesulfonylamino)-propanamine, N-[6-(tri-butylamino) -methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[l-(3-trifluoro -Benzenesulfonyl)-piperidin-2-yl]-acetamide, © 2,3-dihydroxy-N-(6-piperidin-1-ylmethyl-1,2,3,4- Tetrahydro-naphthalen-1-yl)-4-(3-trifluoromethyl-benzenesulfonyl)-butanamine, 2-((R)-3-keto-1-(phenylsulfonyl) )-1,2,3,4-tetrahydroquinoxaline-2-yl)-N-((R) -7-(Surmine U疋-1-ylmethyl)B gram·4-yl)B Amines » Ν-[4-( 4,5-Dihydro-1 Η-imidazol-2-yl)-benzyl]-2-{2-[ (4-methoxy-2,6-dimethyl -Benzenesulfonyl)-methyl-amino]-ethoxy}-oxime-methyl acetamidine (LF22-0542) , © 7-chloro-2-[3-(9-pyridine-4- 3-,9-diaza-spiro[5.5]undecyl-3-carbonyl)-phenyl]-2,3-dihydro-isoindol-1-one (£1^-44 1 95 8 ) , 4-bromo-5-(2-chloro-benzhydrylamino)-buphenyl-1Η-pyrazole-3-carboxylic acid [2-( 3,4,5,6-tetrahydro-2Η- [1,4']bipyridyl-4-yl)-ethyl]-decylamine> 1-Benzyl-1^-(2-((4-(6-(4,5-dihydro-)- 111-imidazol-2-yl)pyridin-3-ylamino)benzyl)(methyl)amino)-2-ketoethyl)- -16- 201024279 1H-benzo[d]imidazole-2 - Carboxylamamine. In a third aspect, the problem constituting the basis of the present invention is solved by the method of treating a patient suffering from stenotic Crohn's disease in a first embodiment, which comprises administering a pharmaceutically effective amount of kinin B1 The receptor antagonist is administered to the patient. In a second specific example of the third aspect, the second specific example is a preferred embodiment of the first specific example of the third aspect, wherein the stenotic Crohn's disease is selected from the group consisting of fibrosing Crohn's disease, obstructive fibrosis Sexual Crohn's disease, recurrent fibrotic clonal Crohn's disease, and recurrent obstructive fibrostenosis Crohn's disease. The inventors of the present invention have surprisingly discovered that the activity of the antagonistic kinin B1 receptor (also referred to herein as B1R antagonism) is in the treatment of special forms of Crohn's disease such as stenotic CD, fibrostenotic CD, obstructive fiber stenosis. Excellent medical results are provided on CD and recurrent fiber stenosis CD. These special forms of CD will also be referred to herein as "specific forms of CD in accordance with the present invention." With regard to the cd according to the particular form of the invention, it is to be understood that 'if not specifically stated to the contrary', any description and disclosure of a CD relating to a particular form in accordance with the invention may be applied to each of these special forms of CD. And any individual form. Furthermore, the inventors of the present invention have surprisingly found that this B 1R antagonism has an excellent anti-inflammatory and anti-fibrotic effect. In light of the insight and individual contribution to the art, it will be appreciated by those skilled in the art that, in fact, each and every antagonist of the kinin B1 receptor is suitable for the purposes indicated herein and more particularly suitable for use. These forms of CD in accordance with the present invention are treated and/or prevented. In a further aspect -17-201024279 'the invention relates to a patient suffering from the following conditions: suffering from or developing a particular form of CD according to the invention, and more particularly a stenotic CD, a fibrous stenosis CD, In patients with obstructive fibrotic stenosis CD and recurrent fibrostenotic CD risk, the treatment involves administering a B1 receptor antagonist to a patient in need thereof. In a specific embodiment of any aspect of the invention, the use of a B1 receptor antagonist for the treatment of inflammatory stenosis and/or edema of the intestine is preferably excluded from the inflammatory stenosis, whereby the inflammatory stenosis is particularly an intestinal inflammatory stenosis . It will be appreciated by those skilled in the art that the CD system in accordance with the present invention is further characterized by the preamble of this application, which is incorporated herein by reference. In a specific embodiment of any aspect of the invention, the patient to whom the B1 receptor antagonist is administered is different from the patient who has or is at risk of developing an inflammatory stenosis and/or edema of the intestine, preferably inflamed Sexual narrowness is related. Patients who are completely afflicted with inflammatory stenosis are preferably confirmed by a need to achieve a complete response to conventional inflammatory treatments (e.g., steroids or immunomodulators), thereby eliminating the need for surgical resection to reduce intestinal obstruction. With regard to this case ® , the complete response is preferably such that the patient does not substantially react with any symptoms associated with CD and more specifically an obstructive form of CD. It is also known to those skilled in the art that patients suffering from inflammatory stenosis are preferably based on anti-inflammatory treatments (preferably conventional anti-inflammatory and more specifically steroid-based and/or immunomodulatory agents). Treatment) and those whose symptoms are alleviated or who no longer suffer from such symptoms. In another embodiment, the patient to be treated is at risk of suffering from or suffering from one of the intestinal inflammation and edema' and a particular form of CD according to the present invention. It will be appreciated by those skilled in the art that patients treated in accordance with the present invention are either ineffective or unproven as a means of treating inflammatory stenosis. It will be further known to those skilled in the art that patients who can be treated in accordance with the present invention have undergone surgery to remove intestinal stenosis, whereby the patient is preferably positively afflicted with CD and separately for intestinal stenosis. Anti-inflammatory treatment is not responding. Excited B1 receptors are described, for example, in Leeb-Lundberg and others Pharmacol Rev. 2005. 57; 27-77; Regoli and others

Pharmacol Rev. 1980; 32 (1); 1-46; and Regoli and others J

Cardiovasc Pharmacol 1 990; 1 5:6: 5 3 0- 8 ° The term "B 1 R antagonist" is preferably referred to in the conventional sense as a compound that binds to and antagonizes the kinin B1 receptor. The term B1 receptor antagonist or kinin B1 receptor antagonist is used synonymously herein. Unless otherwise indicated by φ, the term "B 1 R antagonist" is preferably intended to include B1 receptor antagonists and their acids, salts, esters, guanamines, prodrugs, active metabolites as specifically disclosed herein. , and other derivatives. Further, it is to be understood that any of its salts, esters, guanamines, prodrugs, active metabolites, and other derivatives are pharmaceutically acceptable and pharmacologically active. Whether or not the compound is suitable as a kinin B1 receptor (B1R) antagonist, if its efficacy and efficacy can be determined by routine experimentation in a suitable assay known to those skilled in the art. Such assays may, for example, be cell-based fluorescence loss (CaM) assays (Ransom and others Eur -19-201024279 J Pharmacol. 2 004; 499: 77-84; Simpson and others Eur J Pharmacol. 2000: 392 : 1 -9 ) or radioligand binding (RLB) test (R ansom and others E ur JP harmac ο 1. 2 0 0 4 ; 4 9 9 ).

The CaM assay measures the ability of a test compound (i.e., a kinin B1 receptor antagonist candidate) to inhibit the increase in free calcium in cells in different cell lines caused by B1R agonists. Endogenous B1R expression can be produced by IL-Ιβ pretreatment of human fetal fibroblasts IMR-90 (

Phagoo and others BiochemSocTrans. 1 997; 25 : 4 3 S ). Several non-human B1Rs (rats, mice, rabbits, dogs, and pigs) can be expressed in a recombinant manner after induction with tetracycline in HEK 293 cells transfected with individual genes with B1R. The radioligand binding assay measures the ability of the test compound to replace the 3H-labeled specific B1 ligand de-arginine kallikrein. The specific combination of B1R is defined as the difference between the total combined and non-specific combined wells. The specificity count in the presence of the compound is plotted against the compound concentration (log Μ ). The IC5D system was calculated by using nonlinear regression (Xlfit, IDBS ID Business Solutions Ltd.) to conform the 4-parameter logic equation to concentration-response data. In a preferred embodiment, the antagonist of the kinin B1 receptor used in accordance with the present invention is a compound having an IC50 S 5 μΜ (preferably S 500 nM). Without wishing to be exhaustive, the scientific teachings that constitute the technical teachings of the present invention are as follows: A general fibrotic disease and a particular form of CD according to the present invention are characterized by excessive scarring due to excessive production, deposition and contraction of extracellular matrices. Tissue fibrosis is generally thought to be caused by the failure of the normal wound healing response to the end of -20-201024279. Although the mechanism of fiber generation is still not fully understood, the basic number of progress has been completed in the past few years. This increased knowledge gains a developmental list of novel mediators and pathways that can be targeted at anti-fibrotic treatment. These include many other chemokines and toll-like receptor (TLR) antagonists, angiogenesis inhibitors, growth factor inhibition/neutralization, and TGF-beta signal modifiers. Table 1 “Anti-fibrosis strategies” (rewritten from Wynn and others J Clin Invest. 2 007; Vol 1 17 (3 ) : Pg5 27 ) and Table 2 “Clinical development of compounds in pulmonary fibrosis” (

The Datamonitor report: Idiopoatliic pulmonary fibrosis: A new hope. Aug 23, 2005) illustrates a number of possible anti-fibrotic strategies discussed in the field.

-21 - 201024279 Table 1: Anti-fibrosis strategies (rewritten from Wynn and others, 2007)

• Various anti-inflammatory/immunosuppressive/cytotoxic agents (including colchicine, azathioprine, cyclophilic amine, prednisone, thalidomide, pentoxifylline) And tea tests) • TGF-β signal modifiers (including relaxin, SMAD7, HGF, and BMP7, and TGF-βΙ' TGFpRI, TGFpRlI, EGR-b, and CTGF inhibit Qi lj_ • Cytokine and cytokine receptor antagonism Agents (IL-Ιβ, IL-5, IL-6, IL-13, IL-2, IL-4R, IL13Ra, GM-CSF 'TNF-α, Oncostatin, WISP-Bu and inhibitors of PDGFs) _ • Cytokines and chemokines (IFN-γ, IFN-α/β, IL-12, IL-10, HGF, CXCL10, and CXCL11) _ • Chemokine antagonists (CXCU, CXCL2, CXCL12, CCL2, CCL3) , inhibitors of CCL6, CCL17, and CCL18) __ . Chemokine receptor antagonists (CCR2, CCR3 'inhibitors of CCR5, CCR7, CXCR2, and CXCR4) _ • TLR antagonists (TLR3, TLR4, and TLR9) Inhibitors) _ • Angiogenesis antagonists (VEGF-specific antibodies and adenosine deaminase replacement therapy) _ • Antihypertensive agents (ANGII, ACE, And beta-blockers and inhibitors of aldosterone)_ • Vasoactive substances (ΕΤ-1 receptor antagonists and bosetan) _ • Inhibitors of enzymes that synthesize and process collagen (ammonium hydroxyl groups) Inhibitors of enzymes) _ • B cell inhibitors (rituximab) _ • Integrin/adhesive antagonists (molecules that block α丨β丨 and ανβ6 integrin, and inhibitors of integrin-linked kinase, and ICAM- 1 and VCAM-1 specific antibodies)_ • Pro-apoptotic agents targeting myofibroblasts ____ • Antimony inhibitors (inhibitors of ΜΜΡ2, ΜΜΡ9, and ΜΜΡ12) _ • ΤΙΜΡ inhibitors (ΤΙΜΡ 专Sexual antibodies) _ • Gene silencing strategy and gene therapy (shRNA of TGF-βΙ and TGFPRII)__ • Dry/source progenitor cell transplantation technology _ • Various combinations of the above __ ACE, ANGI converting enzyme; BMP7, bone forming protein 7; CCL, CC chemokine ligand: CCR, CC chemokine receptor; CTGF, connective tissue growth factor; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor, EGR-1, early growth Reaction 1; ET-1, endothelin-1; HGF, hepatocyte growth factor shRNA, small hairpin RNA; TGFPRI, TGF-β receptor type I; WISP-1, wnt-Ι caused by secreted protein 1 _ 201024279 Table 2: Clinical development of compounds in pulmonary fibrosis (Datamonitor ; 2005 ) mi - ' Company / ' ~ period listing predicts endothelin antagonist bosentan Actelion III 2006 immunomodulator IFN-γ lb InterMune III 2007 PDGFR inhibitor imatinib (imatin ib) Novartis II 2009 TNF-α antagonist ina Ethnercept Wyeth II 2009 Unknown pirfenidone InterMune II ^ 2009 CTGF Mab FG3019 FibroGen/Tashio I 2011 TGF-β Mab GC-1008 Cambridge Antibody Technology I* 2012 /Genzyme INK-Inhibitor AS-602801 Serono I* 2012 * Phase I trial is expected to start at 2H05

From these data, it is evident and immediately understood that the most recent and very well-recognized list of anti-fibrotic strategies (Table 1) does not mention the B1 receptor. Accordingly, although the role of the B1 receptor in inflammation and pain is known and fully documented by a considerable number of publications (for comments, see Leeb-Lundberg and others Pharmacol Rev. 2 0 0 5; 57: 2 7-77) However, it is not a clear anti-fibrosis target for those skilled in the field. The pathogenicity of CD fibrosis is not fully understood and appears to be caused by local inflammatory cells, fibroblasts, smooth muscle cells and cells. The complex interaction of hormones (Rieder and others 2007. Gut· 5 6 : 1 3 0 - 1 3 9 ). An excess of fibrillar collagen occurs in all layers of the intestinal wall. Changes in the number and nature of collagen phenotypes in patients with CD have been reported, but the results conflict with each other (Graham and others Gastroenterology. 1988; 94: -23- 201024279 257-65. Regan MC and others Ann Surgery. 2000 Stallmach and others Gastroenterology. 1 992; 102 : 1920-1929.

McKaig and others AmJCellPhysiol. 2001). Fibrosis pathology is more complicated in the intestine than in other organs because the intestine includes heterogeneous populations of mesenchymal cells, some of which synthesize significant amounts of collagen during physiological conditions (Pucilowska and others Am J Physiol Gastrointest Liver Physiol) 2000; 279 : G65 3 - G659 ). For example, the intestines have a specialized group of specialized mesenchymal activity cells: Intestinal subepithelial myofibroblasts (ISEMF) exhibit ultrafine structural features of fibroblasts from cells and smooth muscle cells. These IS EMFs are located below the basement membrane and become organisms in the fused cells that extend through the lamina propria of the intestine and fuse with the outer cells surrounding the blood vessels (Powell and others AmJPhysiolCellPhysiol. 1 999; 277: 1 83-20 1) ° Compared with liver fibrosis, recurrent fibrosonic Crohn's disease lacks activated fibrogenic mesenchymal cells defined by a specific marker. Mesenchymal intestinal cells producing collagen include fibroblasts, smooth muscle cells, and myofibroblasts. © Furthermore, microbial components are likely to be the most important in intestinal fibrosis. Intestinal flora was injected into the intestinal wall to initiate intestinal TGFbl and collagen synthesis (Mourelle and others Gastroenterology. 1998; 114: 519-5 26). The natural immune system appears to play a special role in the regulation of intestinal fibrosis (Meneghin and Hogaboam. J Clin Invest. 2007; 117: 530-538) ° In summary, fibroproliferative diseases such as intestinal fibrosis, pulmonary fibrosis, all- 24-201024279 Sickness, cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration may share some common mechanisms but also have unique organ-specific fibrogenic pathogenicity (Wynn and others J Clin Invest. 2007; Vol 117 (3): 524-529). In fact, there is very little discussion about the role of the kinin B1 receptor in general fibrosis. Any information currently available is limited to the fibrosis of diseases other than CD, and is therefore limited to tissues and cells, respectively, which differ from C D and more specifically in accordance with the CD of the particular form of the invention. In only three available in vitro studies, the human fetal lung cell line (cell line IMR-90) was studied, and the authors found that the kinin B1 receptor is pre-fibrotic, ie, the receptor is stimulated with collagen. The increase in protein synthesis is carried out together in a test tube, which may be the starting point for fibrosis. Ricupero and others JBiolChem. 2000. 275: 1 2475- 1 2480; Romero and others JBiolChem. 2005. Vol2 8 0 (1 5 ): 14378-14384; and Goldstein and others J Biol Chem. 1 984. Vol 25 9 ( 1 4 ) : 9263 -9268 ). φ Furthermore, it has been described that the upward regulation of B1R in vivo is associated with fibrosis of aortic stenosis (Helske and others Eur Heart J. 2007; 28 (15): 18 94-903), which are again different The cell and tissue type of the CD and the CD in accordance with the particular form of the invention. It is evident that these data from only three in vitro tubes and one in vivo study using the same cell line are not sufficient to conclude that B1R is pre-fibrosis, the paradox is generally CD and in particular according to the invention The pre-fibrosis of the special form of CD. Furthermore, B1R is described in the context of hypertension in cardiac fibrosis (Moniwa and others BioIChem. 2006; 387 (-25-201024279 2): 203-209) and in renal fibrosis (Hagiwara and others)

The in vivo results of the anti-fibrotic role of Hypertens. Res. 2004. 27 (6): 399-408) conflict with the pre-fibrotic activity expected by those skilled in the art from the results of the above in vitro test. In addition to the prior art unrecognized kinin B1 receptor system as a possible target for any anti-fibrotic strategy, even those familiar with the field will use kinin B1 receptor antagonists as a starting point for fibrosis due to the role and fibrosis of B1R (recommendation) There is limited knowledge of the in vitro profibrotic activity associated with only test cell lines and in vivo anti-fibrotic activity (which therefore clearly conflicts with the in-tube results), and those skilled in the art will have no reason to assume: The anti-fibrotic strategy in the treatment of CD may be based on B1R. Furthermore and as described above, as found in the specific form of CD according to the present invention and in particular RFCD, gastrointestinal fibrosis is more complicated than fibrotic diseases of other organs to successfully treat CD and provide a kinin B1 receptor. The reasonable expectation of a particular form of CD of the invention does not facilitate the experimentation of anyone familiar with the field. By Burke and others (Burke and others Am J Gastroenterol. 2007; 1 02; 43 9-448 ), it is known that the prior art does not believe that the kinin B1 is affected by the system as an entry point for stenotic Crohn's disease.

Burke and others commented on possible entry points for stenotic Crohn's disease, as summarized in Table 3 of Figure 4, and did not specify the kinin B1 receptor. -26- 201024279 Table 3: Possible treatment entry points for stenotic Crohn's disease (rewritten from Burke and others ^ j Gastroenterol. 2007; 102 * pg. 444) CTGF inhibition ___ Angiotensin I-> Inhibition of sputum transformation (downstream TGFb inhibition)_

Ca縦 blocker _ TGF-β - Ras/MEK/ERK pathway inhibition _ TGF-β antagonism _ ❹ 丨 HMG CoA reductase inhibition · > CTGF transcriptional inhibition In view of this, the inventor of the present invention credited It has been determined that the stimulatory B1 receptor is not only involved in the pathogenicity of fibrosis associated with CD and more particularly in accordance with the particular form of CD of the present invention, but is even a target or starting point for anti-fibrotic strategies associated with these diseases. As can be seen from the results of prior art, it may not be motivated by those skilled in the art that the B1R antagonists will be suitable means for the treatment of CDs and their particular forms of CD, respectively. φ Many kinin B1 receptor antagonists are well known in the art. Due to the mode of action, i.e., inhibition of the activity of the kinin B1 receptor, and the pathological mechanism of CD according to the particular form of the invention as described above, it is apparent that any kinin B1 receptor antagonist can be used to treat any A CD according to a special form of the invention. More preferred B1 receptor antagonists are disclosed in the following International Patent Publications, the disclosures of which are hereby incorporated by reference in its entirety herein by reference in the the the the the the the the the the the the the the the the the the the the the the the W000075 1 07 , WOO 1 005 78 3 , W002017958 , -27- 201024279 W020020535 1 6 WO02076964 WO02092 5 56 W0020993 88 W02003007958 WO03 065 7 89 WO03 0665 77 WO03093245 WO03 1 06428 US20040116353 US20040034064, US20040063 76 1 US20040198666 W00401 9868 WO04033 436 WO040 545 84 W0040563 1 9 W004083 1 73 W004092 1 1 6 W02004087700 W004092 1 64 WO0409 8 5 8 9 W004098590 W004099 1 55 W0050048 1 0 US20050020591 US20050084463 US20050085667 US20050124654 W0050 1 6886 US20050215470 US20050234044 , US2005026 1 327 ' WO05 03 7994 US20050288305 W02005042027 W005063690 W02005061 467 W0200508 5 。 。 。 。 。 。 。 。 。 。 。 。 0060 1 9975 US200602 1 73 62 , US20060247229 , US2006028 1 73 3 , W02006041 888 US20060293332 , W0200603 6664 WO060443 5 5 , W0060444 12 , W006048209 , W00607 1 775 WO06 1 1 3 1 40 WO06 1 32 8 3 7 US06908921 US20070032475 US06919343 US06919347 US20070093485 , US20070123531, US20070161633, -28-201024279 US20070189865, US07041785, US07056937, WO07067629, W007072092, US07074783, US0709 1 3 8 0, WO07 1 0 1 007, US 07 1 0 9203, W007 1403 83, US07157454, US07163951, US07183281, US07211566 , US07291642, US07332499, US07393873, US20080064642, W00801 1 1 68, WO08024692, WO08033 73 9, WO080465 73, W008050 1 67 'W008050 1 68 , W02008068540 ° Φ More preferred B1 receptor antagonists that can be used in accordance with the present invention are as follows By Ac-Lys-Arg-Pro-Pro-Gly-Phe-Ser-D- Nal-Ile-OH ( R715)

Ac-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH (R 8 9 2 ), and

Ac-Lys-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH (R914), as described in Gobeil, F., Jr. and others

1999, 33, 823-9;

Ac-Orn-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH (R954), as described in Gabra, BH; Sirois, P. 2003, 24, 1131-9; H-Lys- Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH (B 9 8 5 8 ), and H-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D- Tic-Cpg-OH (B 9 9 5 8 ) as described in Stewart, J. Μ. et a 1.;

Immunopharmacology 1996,3 3, 5 1 -60 ; -29- 201024279 F5c-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH ( B 1 0 3 2 4 ), such as Described in Gera, L. et al.; International Immunopharmacology 2008, 8, 289-92;

2-[l-(3,4-Dichloro-benzenesulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[ 4-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-acetamide, as described in Su, D.-S. et al; ··· CAew. Soc · 2003, i2_5, 7516-7;

〇=s^0

N-{2-[4-( 4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-2-[l-(naphthalene-2-sulfonyl)-3- Keto-1,2,3,4-tetrahydro-quinoxin-2-yl]-acetamide

3-(3,4-Dichloro-phenyl)-^^-{1-[4-(4,5-dihydro-1-imidazol-2-yl-30- 201024279 )-benzyl]- 2-keto-2-pyrrolidin-1-yl-ethyl}_3-(naphthalene-2-sulfonylamino)-propanamide

4'-(1-{3-[(2,2-Difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridin-2-ylamino}-ethyl)-5-methyl- Methyl biphenyl-2-carboxylate,

>^(4-Chloro-2-{1-[3'-fluoro-2'-(3-methyl-[1,2,4]oxadiazol-5-yl)·biphenyl-4- ]]-ethylamino}-pyridin-3-yl)-3,3,3-trifluoro-propanamide as described in Hess, JF et al.; P/zarmaco/. 2004, 310, 488-97 ;

4'-{1-[4-Chloro-3-(2-cyano-ethenylamino)-pyridin-2-ylamino]-ethyl}-3-fluoro-biphenyl-2-carboxylate Methyl ester,

-31 - 201024279 3-Chloro-4'-{l-[4-chloro-3-(2-cyano-ethenylamino)-yl]-ethyl}-biphenyl-2-carboxylic acid ester,

N-(4-Chloro-2-{1-[3,-fluoro-2'-(2-methyl-2H-tetrazol-5yl-4-yl]-ethylamino}-pyridine-3- Benzyl-2-cyano-acetamidine 1 as described in Kuduk, SD et al.; J. Med. Chem 6439-42;

o 3,3'-Difluoro-4'-{[5-(4-pyridin-4-yl-piperidin-1-carbonyl)amino]-methyl}-biphenyl-2-carboxylic acid methyl ester , as described in Kuduk, SD et ai.; Bioorg. Med. 2006, 16, 2791-5;

3, difluoro-41-({[1-( 3,3,3-trifluoro-propenylamino)-amino}-methyl)-biphenyl-2-carboxylic acid methyl ester, earth Pyridin-2-ylamine-yl)-biphenyl, .2004, 4 7, φ -D ratio D -2 -yl Chem. Lett. e )-cyclopropane carbonyl

-32- 201024279 3,3·-Difluoro-4'-( 1-{[1-( 2,2,2-trifluoro-ethylideneamino)cyclopropanylcarbonyl]-amino}-ethyl )-biphenyl-2-carboxylic acid methyl ester,

3-Chloro-3'-fluoro-4'-(1-{[1-(2,2,2-trifluoro-ethinyl)-cyclopropanecarbonyl]-amino}-ethyl)-linked Methyl phenyl-2-carboxylate, as described in Kuduk, SD et al_; J. Med. C hem. 2007, 50, β 272-82;

Cl

2,4-Dichloro-6-[5-fluoro-6-(1-{[1-(2,2,2-trifluoro-ethinylamino)·cyclopropanecarbonyl]-amino}-B Methyl)-pyridin-3-yl]-benzoate,

-cyclopropane 2-chloro-6-[5-fluoro-6-((2,2,2-trifluoro-ethinylaminocarbonyl)-amino}-ethyl)-pyridin-3-yl] -methyl benzoate,

Ethylcarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid ethyl ester is as described in Kuduk, SD et al.; 5z'oorg. Met/. C/zem. Ze". -33- 201024279 2007, 17, 3608-12

3-methoxy-isoxamidine-5-carboxylic acid [1-(1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]- 3-Fluoro-pyridin-2-yl}-ethylaminemethanyl)-cyclopropyl]-nonylamine, as described in Feng, D.-M. et al.; Met/. Le". 2008, 1 8, 6 82-7 ;

, cf3 ΌΗ N-( l-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-3·chloro -U ratio B-but-2-yl}-ethyl)-3,3,3.dioxy-2. oxyl-2-methyl-propanamide, as described in Wood, MR et al.; Bioorg. Med. Chem. Lett. 2008, i<?, 716-20;

1-( 1_ butyl-5-cyclohexyl-2-keto-2,3·dihydro-1H_benzo[e][l,4]二201024279 气呼-3·基)-3-[4- (4-methylamino-pyridin-1-yl)-phenyl]

P

® 1-(1-Butyl-2-keto-5-phenethyl-2,3-dihydro-1H-benzo[e][l,4]dioxo-3-yl)-3- [4-(4-indolyl-4-yl-indol-1-yl)-phenyl]-mai] as described in Wood, MW et al.; J. Med. Chem. 2003, 46, 1803 -6 ;

-phenyl]-carbamic acid tetrahydro-furan [4-(2-benzylidene-phenylamine sulfonyl)-2-ylmethyl ester, -35- 201024279

{4-[2-(Pyridin-2-carbonyl)-phenylamine sulfonyl]-phenyl-p-butylamine tetrahydro-furan-2-ylmethyl ester, as described in Su, D.-S. et al ·; J. Mec/. Ckw· 2 008, 3946-52;

(R)-N-(1-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3)- 卩-卩2-yl)ethyl)-4,4-oxo-1-yl-based cycloheximide carboxamide, 2008 >printing;

3-Benzo[1,3]dioxo-5-yl-N-[2-[4-( 2,6-dimethyl-piperidin-1-yl 201024279 methyl)-phenyl]-1 -(isopropyl-methyl-aminocarbamimido)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propanamide (SSR2406 1 2 ), as described In Gougat, J. et al.; J. Pharmacol. Exp. Ther. 2004, 309, 661-9;

1-[4-(2,2-Diphenyl-ethylamino)-3-(sodium benzo-4-carbonyl)-benzenesulfonyl]-piperidine-4-carboxylic acid bis-(3-di Methylamino-propyl)-guanamine,

{2-( 2,2-Diphenyl-ethylamino)-5-[4-(4-isopropyl-piperidin-1-carbonyl-yl)-piperidine-1-sulfonyl]- Phenyl}-morpholin-4-yl-methanone,

{2-(2,2-Diphenyl-ethylamino)-5-[4-(4-methyl-piperazin-1-carbonyl)-piperidine-1-sulfonyl]-phenyl} - tyrosine-4-yl-methanone, as described in Ritchie, TJ et al.; J. Met/. CAe 777. 2004, 莩 7, 4 6 4 2-4, and by Fox, A. et al.; Br. J. Pharmacol. 2005, -37-201024279 144, 889-99;

3-(naphthalene-2-sulfonylamino)-3-phenyl-N-(7-piperidin-1-ylmethyl-indol-4-yl)-propanamide, as described in D' Amico, DC· et al·; Med_ C/iem. 2 007,50, 607-1 0 ; β

F 3 - ( 4 -Gas-phenyl)-N-( 7-indole-1-ylmethyl-4-yl)-3-( 3-trifluoromethyl-benzenesulfonylamino)- Propylamine, as described in Biswas, K. et al.; J. Med. Che m. 2007, 50, 2200-12;

N-[6-(tris-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[l-(3-trifluoromethyl-benzenesulfonate Mercapto) piperidin-2-yl]-acetamide, as described in Fotsch, C. et al.; Bioorg. Med. Chem. Lett. 2006, 16, 2071-5;

38- 201024279 2,3-Dihydroxy-N-(6-piperidinyl-p-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-4-(3-trifluoromethyl - Benzenesulfonylbutyramine, as described in Donga, H. et al.; Mwma/ 〇/

Me tho ds 2008, 1 68^ 7 6-8 7 i

2-( (R) -3 -keto-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)-indole ( ( R ) -7- (piperidin-1-ylmethyl) gram-4-yl) acetamamine as described in Chen, JJ et al.; Bioorg. Med. Chem. Lett. 2008, 18, 4477-81;

N-[4-(4,5-Dihydro-lH-imidazol-2-yl)-benzyl]-2-{2-[(4-methoxy- 2,6-dimethyl-benzenesulfonate) Mercapto)-methyl-amino]-ethoxy}-N-methyl-acetamide (LF22-0542), as described in Poicreca, F. et a.., J. Pharmacol. Exp. The r. 2006, 195-205, and Sevcik, MA et al.; J. Pain 2005, 6, 771-5; -39- 201024279

7-Chloro-2-[3-(9-pyridin-4-yl-3,9-diaza-spiro[5.5]undecyl-3-carbonyl)-phenyl]-2,3-dihydro-iso吲哚-buxone (ELN-44 1 95 8 ) - as described in Hawkinson, JE et al.; ·/· r/ie/*. 2007, 322, 619-30;

4-bromo-5-(2-chloro-benzhydrylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid [2-(3,4,5,6-tetrahydro-211- [1,4']bipyridyl-4-yl)-ethyl]-decylamine

As described in D r e s s eη, D. et al ·; human Me i /. C / z e m · 2 0 0 7, 5 0, 5161-7;

1-Benzyl-:(2-((4-(6-(4,5-dihydro-1}1-imidazol-2-yl)pyridin-3-ylamino)phenyl)) Amino)-2-ketoethyl)-1H-benzo[d]imidazol-2-carboxamide, -40- 201024279 as described in Guo, Q. et al.; 5ioorg. Mei/· ie&quot The invention will now be further illustrated by the following figures and examples, whereby other features, specific examples and advantages are obtained, from which Figure 1 shows a representation showing a B1R antagonist reference. The peptide JPE-1697 (2 mg/kg, ip d35-d49) significantly reduced fibrotic collagen deposition, whereby colon collagen content was reduced to near baseline levels, as seen in the largest possible reduction in collagen as measured The control group of ethanol and TNBS + anti-TGF-β cohort, however, JPE-ctrl represents the group treated with the control group peptide, which has no activity on B 1 R acting as a negative control group; Figure 2 shows an illustration , which demonstrates that the B1R antagonist JPE-1 697 reduces pre-fibrotic IL 1 3 and TGF-β secretion from lamina propria monocytes from TNB S-treated mice;

Figure 3 shows a diagram showing that the B1R antagonist JPE-1697 reduces the secretion of proinflammatory TNF-ct, IFN-γ and TH17 pathways IL23, IL17 and IL25 from lamina propria mononuclear cells from TNBS-treated mice. . The abbreviations used herein for amino acids correspond to the three letter codes of the peptide chemistry tradition described by Eur. Jf. Biochem 1 3 8,9 (1 9 8 4 ). Other abbreviations used are shown below: TF A 2,2,2-trifluoroacetic acid

Cpg cyclopentylglycine

Nal 2-naphthylpropylamine oxime 0 i c cis, intrinsic octahydroquinone 卩 2 2 - ore base

Occ octanoic acid -41 - 201024279

Tic 1,2,3,4-tetrachloroisosalinyl F5c 2,3,4,5,6-pentafluorocinnamic acid Hyp trans-4-hydroxy-L-proline acid Ac Ethyl Orn bird Amino acid Igl α-(2-dihydroindenyl)glycine Phe phenylalanine NMePhe Ν-methylphenylalanine G1 y glycine lie isoleucine Lys lysine Pro valine Gin Brassic acid Arg arginine S er serine Val guanidine hydrate [Examples] Example 1: Effect and principle of B1R antagonist JPE-1 697 in a rat model with colitis and intestinal fibrosis

Jerini is dedicated to investigating the anti-fibrotic properties of B1R antagonists in a good reference mouse model with experimental chronic colitis and intestinal fibrosis. Repeated treatment with increasing doses of TNBS (2,4,6·trinitrobenzenesulfonic acid), -42-201024279 over 7 weeks, resulted in increased collagen deposition and high fibrosis. As described herein, Jerini found in particular that B1R antagonism significantly reduces fibrotic collagen deposition in this model. The purpose of this study was to determine the agonist B 1 receptor antagonist as an exemplary kinin. The P 1 R antagonist JPE-1 697 of the peptide improves the ability of chronic colitis and intestinal fibrosis in this mouse model associated with fibrosis, including its effect on collagen deposition in the colon, by intestinal immune cells (more specific Pre-fibrotic and pro-inflammatory factors are released from the lamina propria mononuclear cells. This widely used model shows transmural inflammation and fibrosis caused by TNBS, as seen in the stenosis of Crohn's disease (Lawrance and others Gastroenterology. 2 0 0 3 ; 1 25 : 1 750- 1 76 1; Fichtner -Feigl and others J Clin Invest. 2005; 115: 3057-3071; Wu and others J Immunol. 2007; 1 79 : 6988-7000 ). This recurrent TNB S pattern represents only available patterns, including chronic intestinal inflammation, subsequent development of fibrosis, and extremely characterized pathophysiology, including the amount of cytokines over the course of 49 days. Effective relationship. The first 1-2 weeks are characterized by massive inflammatory infiltration of the mucosal lamina propria, epithelial division, and secretion of sputum 1 cytokines. Weeks 3 - 5 showed a regression of acute inflammation, an appearance of edema, a decrease in sputum 1 cytokine (in addition to TNF-α, which remained upward for up to 7 weeks) and a development toward the TH1 7 cytokine model. During the 4th-6th week, a slow increase in collagen deposition and pre-fibrotic mediator IL1 3 and TGF-β was observed to be regulated on -43-201024279. Finally, from the 6th to 7th week, the animal's large intestine develops a large amount of collagen deposition (Fichtner-Feigl and others j Immunol. 2007; 178: 5859-5870) ° Materials and methods of colitis-induced chronic TNBS (2, 4 , 6-trinitrobenzenesulfonic acid) colitis is administered weekly by dose of TNBS (Sigma-Aldrich) (1.5-2.5 mg in 45% ethanol) until the 49th day (week 7) And caused. The rats were slightly anesthetized with isofluorane and then administered TNBS/ethanol/rectal via a 3.5 F catheter fitted with a 1 ml syringe; the catheter was moved forward to the rectum until the tip was closest to the anal edge 4 cm. At this point, a total volume of 150 μΐ of TNBS was administered. Rats were treated with R-954 or JPE-ctrl (i.p. 2 mg/kg/d) and anti-TGF-β Ab (i.p. lmg/kg/week) treatment was started on day 35 until day 49. Collagen test The colon of the mouse was obtained on day 49 of the study and homogenized in 0.5 Μ acetic acid (in a concentration of 10 mg tissue/10 ml acetic acid solution) containing 1 mg of gastric gas. The resulting mixture was then incubated and stirred at 4 ° C for 24 hours. The total amount of soluble collagen in the mixture was then determined using a Sircol Collagen Assay Kit (Biocolor). An acid-soluble type I collagen with a kit was used to generate a standard curve (Kitani and others JExpMed. 2003; 1 98: 1 1 79-1 1 8 8 ). 201024279 Cell isolation and culture of isolated colon lamina propria mononuclear cells (LPMC) are isolated from colon tissue as described (Boirivant and others *^\?)^4·1998; 188: 1929-1939), and then Cultivate for 48 hours. The lxlO6 cultured LPMC was stimulated with plate-bound anti-CD3 Ab and soluble anti-CD28 Ab (BD Pharmingen) to determine IFN-γ, IL13, IL25 and IL17 protein secretions. To determine IL12p70, TNFa protein secretion LPMC was stimulated with IFN-γ/LPS. To determine IL23 protein secretion m, LPMC was stimulated with bacterial peptide peptidoglycan (Sigma Aldrich), and to determine TGF-β release, LPMC was stimulated with IL1 3/TNF-a. The cytokine concentration of the liquid on the LPMC was measured by ELISA according to the manufacturer's instructions. The kinin B 1 receptor antagonist, also known as JPE-1697, is a high-efficiency, good reference peptide antagonist of the B1 subtype of kinin receptor, which has the following structure Ac-Orn-Arg-Oic- Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH 2xHCI. In the isolated organ preparation, R954 inhibited the contraction caused by de-arginine, and the PA2値 of the human umbilical artery was 8.64, and the pA2 値 of the rabbit aorta was 8.46 ( Neugebauer et al.,

CanJPhysiolPharmacol. 2 0 0 2 8 0 : 2 8 7-2 92 ) ° R954 has been shown to be effective in pain, extravasation and inflammatory patterns in various rodents (Gabra and others EurJPharmacol. 2005; 61-67; Gabra and others Human Neuropeptides. 2003; 37: 36-44; Eric and others Br J -45- 201024279

Pharmacol. 2003; 138: 1589-1597; Simard and others Can J Physiol Pharmacol. 2002; 80 (12): 1 203 - 1 207 ) ° R954 is also described and claimed in US Patent # US72 1 1 566B2 (Regoli and others May 1 2007; patent application scope 5): R9 54 is a selective peptide B 1 receptor antagonist, which is quite resistant to catalytic degradation in vitro and in vivo, and has good pharmacokinetic properties. And in vivo effects of diabetic microvascular leakage, diabetic hyperalgesia, and allergic asthma patterns that have been shown in rodents (Regoli and others US #72 1 1 566B2. 2007) ° R954 was also characterized and displayed by the inventor of the present case Antagonistic activity against human B1R (IC50 = 15 nM in calcium shift assay CaM; IC50 = 3 nM in radioligand binding assay RLB) and antagonistic activity against B1R in mice (IC50 = 800 nM CaM; IC 5 0 = 5 70 nM) RLB). Up to 10 μΜ, no partial stimuli were detected in human, rat, mouse or rabbit B 1 R. Up to 30 μΜ, no inhibitory activity against B2R in mice was detected. Data analysis A two-tailed Student t-test was used to compare the test and vehicle groups. At P<0.01, the difference was considered significant. RESULTS AND CONCLUSIONS Compared with ethanol (TNBS vector), JPE-ctrl (negative control group) and anti-TGF-β treatment (positive control group), the effect of jpe-1 697 on intestinal collagen deposition induced by TNBS-201024279 In Figure 1. Animals treated with ethanol alone (without TNBS) developed some degree of colonic fibrosis 'which could not be prevented by anti-TGF-β treatment, indicating that the ethanol and anti-TGF-β groups indicate that minimal collagen can be achieved in this model. Content (1 〇〇% reduction). Because treatment with the B1R antagonist JPE-1 697 was not statistically significantly different from anti-TGF-[beta] or ethanol treatment, B1R antagonism caused a reduction in TNBS-induced fibrosis to near baseline. Control group peptide JAL-1 3 6 4 Occ-Ala-Phe-Arg-Leu-Hyp-Oic-Asp-Arg-Ile-NH2 ® lxTFA showed no effect on colonic fibrosis, thus demonstrating the observed by B1R antagonism The beneficial effect is specificity. The effect of JPE-1697 on the profibrotic IL 13 and TGF-β secretion from the intestinal immune cells LPMC (hereditary mononuclear cells) from TNBS-treated mice is shown in Figure 2. After 7 weeks of treatment with TNBS or ethanol, LPMC was obtained, pooled and cultured from 10 animals on day 49 (d4 9). After stimulation, LPMC from ethanol treated animals showed no increase in IL1 3 or TGF-β, thus confirming that collagen deposition observed in this cohort was the result of atypical fibrotic mechanisms. LPMC from TNBS-treated mice showed a dramatic increase in IL13 and TGF-β production in response to stimulation. This response was greatly reduced on animals treated with the B1R antagonist JPE-16997. This shows that B 1 R antagonism drastically alters the number of LPMCs after 49 days in TNBS-treated mice. The control group peptide JPE-ctrl showed no effect on colonic fibrosis, thus demonstrating that the beneficial effect observed with B1R antagonism is specificity. JPE-1 697 treatment of intestinal immune cells from TNBS-treated mice-47- 201024279 LPMC (prolaminar mononuclear cells) pre-inflammatory TH1 (IL12, IFN-γ, TNF-α) and TH17/TH2 (IL23, The effect of cytokine secretion by IL17, IL25) is shown in Fig. 3. After 7 weeks of treatment with TNBS or ethanol, LPMC was obtained, pooled, and cultured from 1 animal on day 49 (d49). After stimulation, LPMC from TNBS-treated mice showed a dramatic increase in TH1 and TH17/TH2 cytokine production. This response was greatly reduced in animals treated with the B1R antagonist JPE-1697. This was determined: B1R antagonism significantly altered the number of LPMCs after 49 days in TNBS-treated mice. The control group peptide JPE-ctrl showed no effect on colonic fibrosis, thus demonstrating that the beneficial effect observed with B1R antagonism is specificity. It will be appreciated by those skilled in the art that the results/conclusions obtained with the B1R antagonist R954 (JP E - 1 6 9 7) apply to any B 1 R antagonism characterized by appropriate functional and binding assays. Agent. The features of the invention disclosed in the specification, the scope of the invention, and/or the drawings may be individually and in any combination thereof for the materials of the invention for understanding various forms. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a diagram showing that the B1R antagonist reference peptide -1^ 697 (2 mg/kg, ip d3 5-d49) significantly reduces fibrotic collagen deposition, thereby using the colon Collagen levels were reduced to near baseline levels, as seen in the positive control group of ethanol and TNBS + anti-TGF-β groups as the largest possible reduction in collagen determination, however, JPE-ctrl indicates that the control group was successful in 201024279 treatment. a group that does not have any activity on B 1 R acting as a negative control group; Figure 2 shows a diagram showing that the B1R antagonist JPE-1 697 is reduced #Pre-fiber of lamina propria mononuclear cells from TNBS-treated mice Il13 and TGF-β secretion; Figure 3 shows a graphical representation showing that the B1R antagonist JPE-1697 reduces the pre-inflammatory τΝίτ-α, IFN-γ and the lamina propria mononuclear cells from TNBS-treated mice. Secretion of TH17 pathways IL23, IL17 and IL25. Reference

-49-

Claims (1)

.201024279 VII. Scope of application for patents: 1 - A kinin B 1 receptor antagonist for the treatment of patients with stenotic Crohn's disease. 2. A kinin B1 receptor antagonist according to claim 1, wherein the fibrostenotic Crohn's disease is fibrosinotic Crohn's disease. 3. A kinin B1 receptor antagonist according to claim 1, wherein the stenotic Crohn's disease is an obstructive fibrostenotic Crohn's disease. The stomach peptide 4 is a kinin B receptor receptor according to any one of claims 1 to 3, wherein the stenotic Crohn's disease is recurrent obstructive fibrotic narrow Crohn's disease. 5. The kinin B1 receptor antagonist according to any one of claims 1 to 3, wherein the kinin B1 receptor antagonist is selected from the group consisting of: Ac-Lys-Arg-Pro-Pro-Gly-Phe -Ser-D- Nal-Ile-OH ( R715) Ac-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R8 92 ), Ac-Lys-Lys-Arg-Pro -Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R914 ), Ac-Orn-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH ( R9 54 ), H- Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH (B9 8 5 8 ), H-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D- Tic-Cpg-OH ( -50- 201024279 B995 8 ), F5c-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH ( B 1 03 24 ) - _ 2-[ 1-(3,4-Dichloro-benzenesulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxaline-2-yl]-N-{2-[4- ( 4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-acetamide, N-{2-[4-( 4,5-dihydro-1H-imidazole-2- -phenyl]-ethyl}-2-[1-(naphthalene-2-sulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl] -acetamide, 3-(3,4-dichloro-phenyl)-indole-{1-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]-2 -keto-2-pyrrolidin-1-yl-ethyl}-3-(naphthalene-2-sulfonylamine ))-propionamide, 4'-( 1-{3-[ ( 2,2 -- 萧(-3⁄4丙院羯基)-amino]-4 -methyl-la 11 疋_ 2-amine Methyl}-ethyl)-5-methyl-biphenyl-2-carboxylate, N-(4-chloro-2-{1-[3'-fluoro-2'-(3-methyl-) [1,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethylamino}-pyridin-3-yl)-3,3,3·trifluoro-propanamide > 4'-{1-[4-Chloro-3-(2-cyano-ethenylamino)-pyridin-2-ylamino]-ethyl}-3-fluoro-biphenyl-2 -Methylcarboxylate, 3-chloro-4'-{l-[4-chloro-3-(2-cyano-ethenylamino)-pyridin-2-ylamino]-ethyl}-linked Methyl phenyl-2-carboxylate, N-(4-chloro-2-{1-[3'-fluoro-2'-(2-methyl-2H-tetrazol-5-yl)-biphenyl 4-yl]-ethylamino}-indole ratio D疋-3-yl)-2-mercapto-ethazamine, 3,3'- one-4'-{[5- (4- batch D疋-4-yl-哄哄-1-mercapto)-batch-2 -yl group 201024279 Amino]-methyl}-biphenyl-2-carboxylic acid methyl ester, • 3,3'-two Fluoro-4'-({[1-(3,3,3-trifluoro-propenylamino)-cyclopropanecarbonyl]-amino}-methyl)-biphenyl-2-carboxylic acid methyl ester , 3,3'-difluoro-4'-(1-{[1-(2,2,2-trifluoro-ethenylamino)- Propane carbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 3-chloro-3'-fluoro-4'-(1-{[1-(2,2,2-three) Fluoro-acetamidoamino)-cyclopropanecarbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 2,4-dichloro-6-[5-fluoro-6-( 1-{[1-(2,2,2-Trifluoro-ethinylamino)-® cyclopropanecarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid methyl ester, 2 -Chloro-6-[5-fluoro-6-(1-{[1-(2,2,2-trifluoro-ethinyl)-cyclopropanecarbonyl]-amino}-ethyl)-pyridine Methyl-3-yl]-benzoate, 2-chloro-6-[5-fluoro-6-((2,2,2-trifluoro-ethenylamino)-cyclopropanecarbonyl]-amino} -ethyl)-pyridin-3-yl]-benzoic acid ethyl ester, 3-methoxy-isoxazin-5-cyanic acid [1-(1-{5-[3,5-dichloro-2- (2,2-Difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylaminecarbazyl)-cyclopropyl]-nonylamine, ^ ^1-(1 -{5-[5-Chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl }-Ethyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide, 1-( 1-butyl-5-cyclohexyl-2-keto-2,3- Dihydro-1H-benzo[e][l,4]diazepin-3-yl)-3-[4-(4-dimethylamino-piperazine 0 -1-yl)-phenyl]-urea, 1-(1-butyl-2-indolyl-5-phenethyl-2,3-amino-1H-benzo[e][l,4] Dioxo-3-yl)-3-[4-(4-D 比Π定-4-yl-哄哄-1.-yl)-phenyl]-pulse, -52- 201024279 [4- (2 -benzimidyl-phenylamine sulfonyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, {4-[2-(pyridine-2-carbonyl)-phenylamine sulfonate Tetraamino-furan-2-ylmethyl ester, (R)-N-( 1-( 5-( 5-chloro-3-fluoro-2-(2-methyl-2H) -tetrazol-5-yl)phenyl)-3-gas batch D疋-2-yl)ethyl)-4,4 - one gas-1- via cycline carboxy guanamine, 3-benzo[1] ,3]dioxol -5-yl-N-[2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-1-(isopropyl) Benzyl-methyl-amine-mercapto)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propanamide (SSR240612), 1-[4-(2 ,2-diphenyl-ethylamino)-3-(tyrosolin-4-carbonyl)-benzenesulfonyl]-piperidine-4-carboxylic acid bis-(3-dimethylamino-propyl )-decylamine, {2-(2,2-phenyl-ethylamino)-5-[4-(4-isopropyl-indole-1-3-yl)-piperidine-sulfonate ]]-phenyl}-morpholin-4-yl-methanone, {2-( 2,2-Diphenyl-ethylamino)-5-[4·( 4 -methyl-piperidin-1-carbonyl)-indole-1-mineral base]-benton }-味琳-4-基-甲嗣, 3-(蔡-2-矿酸amino)-3-phenyl-Ν- ( 7 -峨D-den-1-ylmethyl-Β克· 4 -yl)-propanamine, 3-(4-phenyl-phenyl)-indole-(7-indol-1-ylmethyl-indol-4-yl)-3-(3-trifluoromethyl) -Benzenesulfonylamino)-propionamide, 1[6-(tri-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[ 1-(3-Trifluoromethyl·benzenesulfonyl)-piperidin-2-yl]-acetamide, 2,3-dihydroxy-1(6-piperidinyl-p-methyl-1,2 ,3,4-tetrahydro-naphthalen-1-yl)--53- 201024279 4-(3-Trifluoromethyl-benzenesulfonyl)-butanamine, 2-((R)-3-keto 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)-N-((R)-7-(piperidin-1-ylmethyl)indole克-4-yl)acetamide N-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]-2-{2-[(4-methoxy-2) ,6-Dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}-!^-methyl-acetamide (LF22-0542), 7-chloro-2-[3- ( 9-Pyridin-4-yl-3,9-diaza-spiro[5·5:indole-alkyl-3-carbonyl Φ)-phenyl]-2 ,3-dihydro-isoindole-1-one (ELN-44 1 958 ), 4-bromo-5-(2-chloro-benzhydrylamino)-1-phenyl-1Η-pyrazole- 3-carboxylic acid [2-(3,4,5,6-tetrahydro-2Η-[1,4,]bipyridyl-4-yl)-ethyl]-nonylamine benzyl-indole- ( 2·((4-(6-(4,5-Dihydro-1Η-imidazol-2-yl)pyridin-3-ylamino)benzyl)(methyl)amino)-2-ketoethyl Base) -1 Η-benzo[d]imidazol-2-carboxyguanamine. 6. Use of a kinin B1 receptor antagonist for the manufacture of a medicament for treating a patient suffering from stenotic Crohn's disease. 7. The use of claim 6 wherein the stenotic Crohn's disease is fibrosonic Crohn's disease. 8. The use of claim 6 wherein the stenotic Crohn's disease is obstructive fibrosis clonality. 9. The use according to any one of claims 6 to 8, wherein the stenotic Crohn's disease is recurrent obstructive fibrostenosis Crohn's disease. 10. The use of any one of claims 6 to 8 wherein the kinin B1 receptor inhibitor is selected from the group consisting of Ac-Lys-Arg-Pro-Pro-Gly-Phe -Ser-D- Nal-Ile-OH ( R715) Ac-Lys-Arg-Pro-Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R892 ), Ac-Lys-Lys-Arg-Pro- Pro-Gly-NMePhe-Ser-D-Nal-Ile-OH ( R9 1 4 ), Ac-Orn-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH ( R9 5 4 ), H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH ( B9 8 5 8 ), H-Lys-Lys-Arg-Pro-Hyp-Gly -Cpg-Ser-D-Tic-Cpg-OH (B9 95 8 ), F5c-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH (B 1 03 24 ), ❹ 2-[l -( 3,4-Dichloro-phenylsulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2- [4-( 4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-acetamide, Ν-{2-[4·( 4,5 -dihydro-1H - Imidazol-2-yl)-phenyl]-ethyl(naphthalene-2-sulfonyl)-3-keto-1,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamidine Amine 3-(3,4-dichloro-phenyl)-indole-{1-[4-(4,5-dihydro-1Η-imidazol-2-yl)-benzyl]-2-indolyl- 2-Batch of each π-1,4--1-ethyl-ethyl}-3-[na-2-ylamino)-propanamine, -55- 201024279 4'-(Bu {3-[ ( 2, 2-Difluoro-cyclopropanecarbonyl)-amino]-4·methyl-pyridine-2-ylamino}•ethyl)-5-methyl-biphenyl-2-carboxylic acid methyl ester, Ν- (4-Chloro-2-{Bu[3'-fluoro-21-(3-methyl-[1,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethyl Amino}-la(1-3-yl)-3,3,3-dichloro-propylamine 4'-{1-[4-chloro-3-(2-cyano-acetyl) Methylamino)-pyridin-2-ylamino]•ethyl}-3-fluoro-biphenyl-2-carboxylic acid methyl ester, 3-chloro-4'-{1-[4-chloro-3- ( Methyl 2-cyano-ethenylamino)-pyridin-2-ylamine®-]ethyl}-biphenyl-2-carboxylate, N-(4-chloro-2-{1-[ 3'-Fluoro-21-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylamino}-pyridin-3-yl)-2-cyano- Acetamide, 3,3, difluoro-4'-{[5-(4-pyridin-4-yl-piped-1-carbonyl)·pyridin-2-ylamino]-methyl}-biphenyl Methyl 2-carboxylate, 3,3'-difluoro-4'-({[1-(3,3,3-trifluoro-propenylamino)-cyclopropanecarbonyl]-amino} -methyl)-biphenyl-2-carboxylic acid methyl ester, 3,3'-difluoro-4'-(1-{[1-(2,2,2-trifluoro-ethylideneamino) -cyclopropane^ carbonyl]-aminoethylethyl)-biphenyl-2-carboxylic acid methyl ester, 3-chloro-3'-fluoro-4|-(1-{[1-(2,2,2-three) Fluoro-acetamidoamino)-cyclopropanecarbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester, 2,4-dichloro-6-[5-fluoro-6-( 1-{[1-(2,2,2-Trifluoro-ethinylamino)-cyclopropanecarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid methyl ester, 2- Chloro-6-[5-fluoro-6-(1-{[1-(2,2,2-trifluoro-ethinylamino)-) Methylcarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid methyl ester, 2-chloro-6-[5-fluoro-6-( 1-{[1-( 2,2,2 -trifluoro-ethinylamino)-cyclopropane-56-201024279 alkylcarbonyl]-amino}-ethyl)-pyridin-3-yl]-benzoic acid ethyl ester 3-methoxy-isoxanthene -5-carboxylic acid [1-(1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3.fluoro-pyridin-2-yl }-ethylamine-mercapto)-cyclopropyl]-decylamine, 1(1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]) Diazol-3-yl)-phenyl]-3-chloro-indolepyridin-2-yl}-ethyl)-3,3,3-dichloro-2-yl-2-methyl-prop Indoleamine, di(1-butyl-5-cyclohexyl-2-keto-2,3-dihydro-1H-benzo[e][l,4]diazepin-3-yl)-3- [4-( 4 -monomethylamino-indol-1-yl)] (1-butyl-2-keto-5-phenethyl-2,3-dihydro-1H-benzene And [e][l,4]diazepine-3-yl)-3 -[ 4 -( 4 -pyridin-4-yl-piperidin-1 -yl)-phenyl]-urea, [4- ( 2-Benzyl decyl-phenylamine sulfonyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester, {4-[2-(pyridine-2-carbonyl)-phenylamine sulfonate Thio[]phenylphenylamine tetrahydrofuran-2-ylmethyl ester (R)-N-(1-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl))phenyl)-3-fluoropyridine-2 - Ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide, 3-benzo[1,3]dioxo-5-yl-N-[2-[4-( 2 ,6-Dimethyl-piperidinyl-p-methylmethyl)-phenyl]-bu (isopropyl-methyl-amine-mercapto)-ethyl]-3-(6-methoxy-naphthalene- 2-sulfonylamino)-propanamide (SSR2406 1 2 ), 1-[4-( 2,2-diphenyl-ethylamino)-3-(sodium phenyl-4-carbonyl)·benzene Sulfhydryl]-piperidine-4-carboxylic acid bis-(3-dimethylamino-propyl) decylamine, -57- 201024279 {2-(2,2-diphenyl-ethylamino) -5-[4-(4-isopropyl-piperazin-1-carbonyl)-piperidine-1-sulfonyl]-phenyl}-morpholin-4-yl-methanone, {2-( 2,2-Diphenyl-ethylamino)-5-[4-(4-methyl-piperidin-1-carbonyl)-piperidine-1-sulfonyl]-phenyl}-morpholine- 4-yl-ketone, 3-(naphthalene-2-sulfonylamino)-3-phenyl-N-(7-piperidin-1-ylmethyl-D--4-yl)-propanoid Amine, 3-(4-fluoro-phenyl)-N-(7-piperidin-1-ylmethyl-B-gram-4-yl)-3-(3-trifluoromethyl-benzenesulfonylamine -) propylamine, Ο ^[6-(tri-butylamino) -methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[1-(3-trifluoromethyl-phenylsulfonyl)-piperidin-2-yl]_ Acetamide, 2,3-dihydroxy-:^-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)- 4- (3-tri Fluoromethyl-benzenesulfonyl)-butanamine, 2-((R)-3-keto-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoxaline -2-yl)·Ν-((R) -7-(piperidin-1-ylmethyl)(Ig-4-yl)acetamide, N-[4-( 4,5-dihydro- 1H-imidazol-2-yl)-benzyl]-2-{2-[(4-methoxy-2-yl-6,6-dimethyl-benzenesulfonyl)-methyl-amino]-B Oxy}-.methyl-acetamide (LF22-0542), 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane- 3-carbonyl)-phenyl]-2,3-dihydro-isoindol-1-one (£1^-441958), 4-bromo-5-(2-chloro-benzhydrylamino)- 1-phenyl-1H-pyrazole-3-carboxylic acid [2-( 3,4,5,6 -tetras- 2H-[1,4']-batch 0-yl-4-yl)-ethyl ]- awake amine> 1-benzyl-N-(2-((4-(6-(4,5-dihydro-1H-imidazol-2-yl)pyridyl-58- 201024279 pyridine-3-yl) Amino)benzyl)(methyl)amino)-2-ketoethyl)-1H-benzo[d]imidazole-2-carboxamide. 1 1 A pharmaceutical composition for treating a patient suffering from stenotic Crohn's disease, comprising a pharmaceutically effective amount of a kinin B1 receptor antagonist. 12. The pharmaceutical composition according to claim 11, wherein the stenotic Crohn's disease is selected from the group consisting of fibrostenotic Crohn's disease, obstructive fibrostenosis Crohn's disease, recurrent fibrotic clonal Crohn's disease, and Recurrent obstructive fiber stenosis Crohn's disease. -59-