EP2344176A1

EP2344176A1 - Use of bradykinin b1 receptor antagonists in intestinal fibrosis treatment

Info

Publication number: EP2344176A1
Application number: EP09778615A
Authority: EP
Inventors: Elsa Locardi; Klaus Dinkel; Marco Schaudt; Dirk Scharn; Ulf Reimer; Uwe Richter; Gerd Hummel; Ulrich Reineke
Original assignee: Jerini AG
Current assignee: Jerini AG
Priority date: 2008-09-18
Filing date: 2009-09-18
Publication date: 2011-07-20
Also published as: TW201024279A; WO2010031577A1

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

USE OF BRADYKININ Bl RECEPTOR ANTAGONISTS IN INTESTINAL FIBROSIS TREATMENT

Crohn's disease (CD) is a multifactorial disorder characterized by chronic inflammation of the intestinal tract resulting from a complex interplay among genetic, immunological and microbial factors. Strictures, both in the small intestine and colon, represent one of the most common complications of CD thus defining a particular form or aspect of CD, namely stricturing Crohn's Disease with a further particular form or aspect of such stricturing Crohn's Disease being intestinal fibrostenosis in CD which is also referred to as fibrostenotic Crohn's Disease (FCD). More than 1/3 of CD patients will develop a distinct fibrostenosing phenotype, often in the absence of luminal inflammatory symptoms, that results in recurrent intestinal stricture formation as end product of chronic transmural inflammation which is characterisitic for fibrostenotic Crohn's Disease.

Stricturing CD can be defined as the occurrence of constant luminal narrowing demonstrated by radiological, endoscopic, or surgical examination, combined with prestenotic dilatation and/or obstructive signs or symptoms (Gasche et al., Infl Bowel Dis. 2000;6:8-15). Strictures are generally silent until the luminal caliber is so reduced that it causes obstruction. Not all obstructive situations in CD are caused by a fibrotic stricture; inflammatory edema may also enhance the degree of stenosis but may be treated by anti-inflammatory agents. Such medical treatment may relieve active inflammation but fibrous strictures will not respond to this. Apart from that, it is currently under debate whether ant-inflammatory treatment may actually promote fibrotic strictures. Those patients which suffer from fibrostenotic Crohn's Disease such that obstructive situations arise, display or suffer from a form of CD which is also referred to as obstructive fibrostenotic CD.

The majority of CD patients and particularly those who suffer from fibrostenotic CD require at least one surgical treatment and more than half of all procedures are carried out to relieve intestinal obstruction as fibrostenotic CD does not respond to medical therapy and requires endoscopic or surgical treatment (Van Assche et al. Inflamm Bowel Dis. 2004; 10 (l):55-60; Froehlich et al. Digestion. 2007; 76 (2): 113-115) . Surgery is rarely curative as appr. 70% of patients will have endoscopic evidence of post-operative recurrence at the anastomotic site; repeated surgical interventions may be necessary. Patients having undergone the first surgical procedure are in desperate need of a treatment to prevent recurrence of strictures to avoid repeated surgery. Repeated resection places these patients at risk of operative morbidity, significant bowel loss and short bowel syndrome (Burke et al., Am J Gastroenterol. 2007; 102:439-448). Those Patients who suffer from fibrostenotic CD, including obstructive fibrostenotic CD, and which have undergone first surgery to relieve intestinal obstruction are also said to suffer from or are at risk of developing recurrent fibrostenotic CD and more specifically recurrent obstructive fibrostenotic CD (RFCD).

Despite advances in CD management the incidence of strictures and the requirement for intestinal resection have not diminished in the last 25 years (Cosnes et al. Gut 2005; 54:237- 241). While an abundance of therapeutic options is available for the treatment of intestinal inflammation in CD, the treatment options for fibrotic strictures are limited to mechanical methods such as endoscopic balloon dilatation, strictureplasty and surgical resection, and universally accompanied by high recurrence rates. Specific medical therapy aimed at preventing or reversing intestinal fibrosis and thus the formation of fibrotic strictures is not available.

In view of these limitations of the means of the prior art for the treatment of stricturing CD, fibrostenotic Crohn's Disease, obstructive fibrostenotic CD and recurrent fibrostenotic CD, the problem underlying the instant application is to provide means and methods for the treatment and/or prevention of said forms of CD. A further problem underlying the instant application is to provide means and methods for the treatment and/or prevention of said diseases, whereby such means and methods are highly efficient. A still further problem underlying the instant application is to provide means and methods for the treatment and/or prevention of said diseases, whereby such means and methods have low side effects.

The problem underlying the present invention is solved by the subject matter of the attached independent claims. Preferred embodiments may be taken from the dependent claims. More specifically, in a first aspect the problem underlying the instant application is solved in a first embodiment by a kinin Bl receptor antagonist for use in the treatment of a patient suffering from stricturing Crohn's Disease.

In a second embodiment of the first aspect, which is preferably an embodiment of the first embodiment of the first aspect, the stricturing Crohn's Disease is fibstrostenotic Crohn's Disease.

In a third embodiment of the first aspect, which is preferably an embodiment of the first and second embodiment of the first aspect, the stricturing Crohn's Disease is obstructive fibstrostenotic Crohn's Disease.

In a fourth embodiment of the first aspect, which is preferably an embodiment of the first, second and third embodiment of the first aspect, the stricturing Crohn's Disease is recurrent obstructive fibstrostenotic Crohn's Disease.

In a fifth embodiment of the first aspect, which is preferably an embodiment of the first, second, third and fourth embodiment of the first aspect, the kinin Bl 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 (R892),

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 (R954),

H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH (B9858),

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-OH (B 10324),

2-[ 1 -(3 ,4-dichloro-benzenesulfonyl)-3 -oxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-2-yl]-N- {2- [4-(4,5 - dihydro- 1 H-imidazol-2-yl)-phenyl] -ethyl} -acetamide,

N-{2-[4-(4,5-dihydro-lH-imidazol-2-yl)-phenyl]-ethyl}-2-[l-(naphthalene-2-sulfonyl)-3- oxo-l,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamide, 3-(3,4-dichloro-phenyl)-N-{l-[4-(4,5-dihydro-lH-imidazol-2-yl)-benzyl]-2-oxo-2-pyπOlidin-

1 -yl-ethyl} -3-(naphthalene-2-sulfonylamino)-propionamide,

4'-(l-{3-[(2,2-difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridin-2-ylamino}-ethyl)-5- methyl-biphenyl-2-carboxylic acid methyl ester,

N-(4-chloro-2-{l-[3^l-fluoro-2^l-(3-methyl-[l,2,4]oxadiazol-5-yl)-biρhenyl-4-yl]-ethylamino}- pyridin-3 -yl)-3 ,3 ,3-trifluoro-propionamide,

4'-{l-[4-chloro-3-(2-cyano-acetylamino)-pyridin-2-ylamino]-ethyl}-3-fluoro-biphenyl-2- carboxylic acid methyl ester,

3 -chloro-4'- { 1 - [4-chloro-3 -(2-cyano-acetylamino)-pyridin-2-ylamino] -ethyl } -biphenyl-2- carboxylic acid methyl ester,

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^l-difluoro-4'- { [5-(4-pyridin-4-yl-piperazine- 1 -carbonyl)-pyridin-2-ylamino]-methyl} - biphenyl-2 -carboxylic acid methyl ester,

3 _s3'-difluoro-4'-( { [ 1 -(3 ,3 ,3-trifluoro-propionylamino)-cyclopropanecarbonyl] -amino} - methyl)-biphenyl-2-carboxylic acid methyl ester,

3 ,3'-difluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino } -ethyl)- biphenyl-2-carboxylic acid methyl ester,

3-chloro-3 '-fluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino} - ethyl)-biphenyl-2-carboxylic acid methyl ester,

2,4-dichloro-6-[5-fluoro-6-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]- amino}-ethyl)-pyridin-3-yl]-benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino}- ethyl)-pyridin-3-yl] -benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino}- ethyl)-pyridin-3-yl] -benzoic acid ethyl ester,

S-methoxy-isoxazole-S-carboxylic acid [1 -(I - {5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)- phenyl] -3 -fluoro-pyridin-2-yl } -ethylcarbamoyO-cyclopropyl] -amide,

N-(l-{5-[5-chloro-3-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2- yl} -ethyl)-3 ,3 ,3 -trifluoro-2-hydroxy-2 -methyl -propionamide, l-(l-butyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4- dimethylamino-piperidin- 1 -yl)-phenyl]-urea, l-(l-butyl-2-oxo-5-phenethyl-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4-pyridin-4- yl-piperazin- 1 -yl)-phenyl] -urea,

[4-(2-benzoyl-phenylsulfamoyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester,

{4-[2-(pyridine-2-carbonyl)-phenylsulfamoyl]-phenyl}-carbamic acid tetrahydro-furan-2- ylmethyl ester,

(R)-N-(l-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2- yl)ethyl)-4,4-difluoro- 1 -hydroxycyclohexanecarboxamide,

3-benzo[l,3]dioxol-5-yl-N-[2-[4-(2,6-dimethyl-piperidin-l-ylmethyl)-phenyl]-l-(isopropyl- methyl-carbamoyl)-ethyl]-3-(6-rnethoxy-naphthalene-2-sulfonylarnino)-propionamide

(SSR240612), l-[4-(2,2-diphenyl-ethylamino)-3-(morpholine-4-carbonyl)-benzenesulfonyl]-piperidine-4- carboxylic acid bis-(3-dimethylamino-propyl)-amide,

{ 2-(2,2-diphenyl-ethylamino)-5 - [4-(4-isopropyl-piperazine- 1 -carbonyl)-piperidine- 1 - sulfonyl] -phenyl } -morpholin-4-yl-methanone,

{2-(2,2-diphenyl-ethylamino)-5-[4-(4-methyl-piperazine-l-carbonyl)-piperidine-l-sulfonyl]- phenyl } -morpholin-4-yl-methanone,

3-(naphthalene-2-sulfonylamino)-3-phenyl-N-(7-piperidin-l-ylmethyl-chroman-4-yl)- propionamide,

3 -(4-fluoro-phenyl)-N-(7-piperidin- 1 -ylmethyl-chroman-4-yl)-3 -(3 -trifluoromethyl- benzenesulfonylamino)-propionamide,

N-[6-(tert-butylamino-methyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-2-[l-(3-trifluoromethyl- 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)-butyramide,

2-((R)-3 -oxo- 1 -(phenylsulfonyl)- 1 ,2,3 ^-tetrahydroqumoxalin^-yO-N-^RH-Cpiperidin- 1 - ylmethyl)chroman-4-yl)acetamide,

N-[4-(4,5-dihydro-lH-imidazol-2-yl)-benzyl]-2-{2-[(4-methoxy-2,6-dimethyl- benzenesulfonyl)-methyl-amino] -ethoxy } -N-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 (ELN-441958),

4-bromo-5-(2-chloro-benzoylamino)- 1 -phenyl- 1 H-pyrazole-3 -carboxylic acid [2-(3 ,4,5,6- tetrahydro-2H-[l ,4']bipyridinyl-4-yl)-ethyl]-amide, and 1 -benzyl-N-(2-((4-(6-(4,5-dihydro- 1 H-imidazol-2-yl)pyridin-3-ylamino)benzyl) (methyl)amino)-2-oxoethyl)- 1 H-benzo[d]imidazole-2-carboxamide.

In a second aspect the problem underlying the instant application is solved in a first embodiment by the use of a kinin Bl receptor antagonist for the manufacture of a medicament for the treatment of a patient suffering from stricturing Crohn's Disease.

In a second embodiment of the second aspect, which is preferably an embodiment of the first embodiment of the second aspect, the stricturing Crohn's Disease is fibstrostenotic Crohn's Disease.

In a third embodiment of the second aspect, which is preferably an embodiment of the first and second embodiment of the second aspect, the stricturing Crohn's Disease is obstructive fibstrostenotic Crohn's Disease.

In a fourth embodiment of the second aspect, which is preferably an embodiment of the first, second and third embodiment of the second aspect, the stricturing Crohn's Disease is recurrent obstructive fibstrostenotic Crohn's Disease.

In a fifth embodiment of the second aspect, which is preferably an embodiment of the first, second, third and fourth embodiment of the second aspect, the kinin Bl 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 (R892),

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 (R954),

H-Lys-Lys-Arg-Pro-Hyρ-Gly-Igl-Ser-D-Igl-Oic-OH (B9858),

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-Cρg-OH (B 10324),

2- [ 1 -(3 ,4-dichloro-benzenesulfonyl)-3-oxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-2-yl] -N- { 2- [4-(4,5- dihydro- 1 H-imidazol-2-yl)-phenyl] -ethyl} -acetamide, N-{2-[4-(4,5-dihydro-lH-imidazol-2-yl)-phenyl]-ethyl}-2-[l-(naphthalene-2-sulfonyl)-3- oxo- 1 ,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamide,

3-(3,4-dichloro-phenyl)-N-{l-[4-(4,5-dihydro-lH-imidazol-2-yl)-benzyl]-2-oxό-2-pyrrolidin-

1 -yl-ethyl } -3 -(naphthalene-2-sulfonylamino)-propionamide,

4'-(l-{3-[(2,2-difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridin-2-ylaniino}-ethyl)-5- methyl-biphenyl-2-carboxylic acid methyl ester,

N-(4-chloro-2-{ 1 -[3'-fluoro-2'-(3-methyl-[l ,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethylamino}- pyridin-3 -yl)-3 ,3 ,3 -trifluoro-propionamide,

3-chloro-4'- { 1 - [4-chloro-3 -(2-cyano-acetylamino)-pyridin-2-ylamino] -ethyl } -biphenyl-2- carboxylic acid methyl ester,

N-(4-chloro-2-{l-[3^l-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-piperazine-l -carbonyl)-pyridin-2-ylamino]-methyl} - biphenyl-2 -carboxylic acid methyl ester,

3 ,3 '-difluoro-4'-( { [ 1 -(3 ,3 ,3 -trifluoro-propionylamino)-cyclopropanecarbonyl] -amino } - methyl)-biphenyl-2-carboxylic acid methyl ester,

3 ,3 '-difluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino} -ethyl)- biphenyl-2 -carboxylic acid methyl ester,

3 -chloro-3 '-fluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino } - ethyl)-biphenyl-2-carboxylic acid methyl ester,

2,4-dichloro-6-[5-fluoro-6-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]- amino}-ethyl)-pyridin-3-yl] -benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino } - ethyl)-pyridin-3-yl]-benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino) - ethyl)-pyridin-3-yl]-benzoic acid ethyl ester,

3 -methoxy-isoxazole-S-carboxylic acid [l-(l-{5-[3 ,5-dichloro-2-(2,2-difluoro-ethoxy)- phenyl] -3 -fluoro-pyridin-2-yl } -ethylcarbamoy^-cyclopropyl] -amide,

N-Cl-IS-tS-chloro-S-fluoro^-CS-methyl-tl^^loxadiazol-S-yO-phenyll-S-fluoro-pyridin^- yl } -ethyl)-3 ,3 ,3-trifluoro-2-hydroxy-2-methyl-propionamide, l-(l-butyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4- dimethylamino-piperidin- 1 -yl)-phenyl] -urea, l-(l-butyl-2-oxo-5-phenethyl-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4-pyridin-4- yl-piperazin- 1 -yl)-phenyl] -urea,

{4- [2-(pyridine-2-carbonyl)-phenylsulfamoyl] -phenyl } -carbamic acid tetrahydro-furan-2- ylmethyl ester,

(SSR240612),

1 - [4-(2,2-diphenyl-ethylamino)-3 -(morpholine-4-carbonyl)-benzenesulfonyl] -piperidine-4- carboxylic acid bis-(3-dimethylamino-propyl)-amide,

{2-(2,2-diphenyl-ethylamino)-5-[4-(4-isopropyl-piperazine-l-carbonyl)-piperidine-l- sulfonyl] -phenyl } -morpholin-4-yl-methanone,

3 -(naphthalene-2-sulfonylamino)-3 -phenyl-N-(7-piperidin- 1 -ylmethyl-chroman-4-yl)- propionamide,

N- [6-(tert-butylamino-methyl)- 1,2,3 ,4-tetrahydro-naphthalen- 1 -yl] -2- [ 1 -(3 -trifluoromethyl- benzenesulfonyl)-piperidin-2-yl]-acetamide,

2-((R)-3 -oxo- 1 -(phenylsulfonyl)- 1 ,2,3 Λ-tetrahydroquinoxalm^-y^-N-CCRH-føiperidin- 1 - ylmethyl)chroman-4-yl)acetamide,

7-chloro-2-[3-(9-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane-3-carbonyl)-phenyl]-2,3-dihydro- isoindol-1-one (ELN-441958), 4-bromo-5-(2-chloro-benzoylamino)- 1 -phenyl- 1 H-pyrazole-3 -carboxylic acid [2-(3 ,4,5 ,6- tetrahydro-2H-[ 1 ,4']bipyridinyl-4-yl)-ethyl]-amide, l-benzyl-N-(2-((4-(6-(4,5-dihydro-lH-imidazol-2-yl)pyridin-3-ylamino)benzyl) (methyl)amino)-2-oxoethyl)- 1 H-benzo[d]imidazole-2-carboxamide.

In a third aspect the problem underlying the instant application is solved in a first embodiment by a method for the treatment of a patient suffering from stricturing Crohn's Disease comprising the administration of a kinin Bl receptor antagonist to the patient in a pharmaceutically effective amount.

In a second embodiment of the third aspect, which is preferably an embodiment of the first embodiment of the third aspect, the stricturing Crohn's Disease is selected from the group comprising fibrostenotic Crohn's Disease, obstructive fibrostenotic Crohn's Disease, recurrent fibrostenotic Crohn's Disease and recurrent obstructive fibrostenotic Crohn's Disease.

The present inventors have surprisingly found that antagonizing the activity of the kinin Bl receptor, also referred to herein as BlR antagonism, provides excellent therapeutic effects in the treatment of specific forms of Crohn's diseases such as stricturing CD, fibrostenotic CD, obstructive fibrostenotic CD and recurrent fibrostenotic CD. These specific forms of CD will also be referred to herein as the "specific forms of CD according to the present invention". In connection therewith it is to be acknowledged that, if not specifically indicated to the contrary, any statement and disclosure, respectively, made herein in relation to the specific forms of CD according to the present invention, is applicable to each and any individual form of these specific forms of CD. Additionally, the present inventors have surprisingly found that such BlR antagonism has excellent anti-inflammatory and anti-fibrotic effects. In the light of this insight and the respective contribution to the art, it will be understood by a person skilled in the art that actually each and any antagonist to the kinin Bl receptor is suitable for the purposes indicated herein and more specifically for use in the treatment and/or prevention of said forms of CD according to the present invention. In a further aspect the present invention is related to the treatment of patients suffering from or being at risk of suffering from or of developing the specific forms of CD according to the present invention and more specifically stricturing CD, fibrostenotic CD, obstructive fibrostenotic CD and recurrent fibrostenotic CD, comprising the administration of a Bl receptor antagonist to a patient in need thereof.

In an embodiment of any aspect of the present application, the use of Bl receptor antagonists for the treatment of inflammatory strictures and/or edema of the intestine, preferably associated with such inflammatory strictures is excluded, whereby the inflammatory strictures are in particular intestinal inflammatory strictures.

It will be understood by a person skilled in the art that the specific forms of CD according to the present invention are further characterized in the introductory part of this application which shall be incorporated herein by reference.

In an embodiment of any aspect of the present application, patients to whom the Bl receptor antagonist is to be administered are different from those patients who have or are at risk of developing inflammatory strictures and/or edema of the intestine, preferably associated with such inflammatory strictures. These patients suffering from entirely inflammatory strictures are preferably identified by achieving a complete response under conventional antiinflammatory therapy such as e.g. steroids or immunomodulators, thus eliminating the need for surgical resection to relieve intestinal obstruction. In connection therewith a complete response is preferably a response such that the patient is essentially free of any symptoms related to or associated with CD and more specifically obstructive forms of CD. It will also be acknowledged by a person skilled in the art that patients suffering from entirely inflammatory strictures are preferably those where the symptoms are relieved or those who no longer suffer from such symptoms upon anti-inflammatory therapy, preferably conventional anti-inflammatory and more specifically steroid and/or immunomodulator based therapy.

In a further embodiment, the patients to be treated are those which suffer or are at risk to suffer from intestinal inflammation and edema, respectively, and from one of the specific forms of CD according to the present invention. It will be acknowledged by a person skilled in the art that a patient who may be treated in accordance with the instant application is one where means for the treatment of inflammatory strictures is not or has proven not to be effective. It will further be acknowledged by a person skilled in the art that a patient who may be treated in accordance with the instant application is one who has received surgery for the removal of intestinal strictures, whereby the patient is preferably one who is suffering from CD and who does not and has not, respectively, been responsive to anti-inflammatory treatment of intestinal strictures.

The kinin Bl receptor is, e.g. described in Leeb-Lundberg et al. Pharmacol Rev. 2005. 57; 27-77; Regoli et al. Pharmacol Rev. 1980; 32(1); 1-46; and Regoli et al. J Cardiovasc Pharmacol 1990; 15: 6: 530-8.

The term "BlR antagonist" is preferably used in its conventional sense to refer to a compound that binds to and antagonizes the kinin Bl receptor. The terms Bl receptor antagonist or kinin Bl receptor antagonist are used herein in a synonymous manner. Unless otherwise indicated, the term "BlR antagonist" is preferably intended to include Bl receptor antagonists as in particular disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof. Furthermore, it is understood that any salts, esters, amides, prodrugs, active metabolites or other derivatives thereof are pharmaceutically acceptable as well as pharmacologically active.

Whether a compound is suitable as a kinin Bl receptor (BlR) antagonist and, if so, its potency and efficacy can be determined by routine experimentation in appropriate assays known to the person skilled in the art. Such assays can, for example, be a cell-based fluorescent calcium-mobilization (CaM) assay (Ransom et al. Eur J Pharmacol. 2004; 499: 77-84; Simpson et al. Eur J Pharmacol. 2000: 392: 1-9) or radioligand binding (RLB) assay (Ransom et al. Eur J Pharmacol. 2004; 499). The CaM assay measures the ability of a test compound, i.e. the kinin Bl receoptor antagonist candidate, to inhibit BlR agonist-induced increase of intracellular free Calcium in different cell lines. Endogenous BlR expression can be induced by IL-I beta pretreatment of human embryonal lung fibroblasts IMR-90 (Phagoo et al. BiochemSocTrans. 1997; 25:43 S). BlR of several non-human species (rat, mouse, rabbit, dog and pig) can be expressed recombinantly after Tetracycline induction in HEK 293 cells bearing the respective transgene coding for BlR. The radioligand binding assay measures the ability of test compounds to displace the 3H-labeled specific Bl ligand desArg- Kallidin. Specific binding to BlR is defined as the difference between total binding and nonspecific binding wells. Specific counts in the presence of compounds are plotted against compound concentration (log M). IC₅₀ values are calculated by fitting a 4-parameter logistic function to the concentration-response data using non-linear regression (Xlfit, IDBS ID Business Solutions Ltd.). In a preferred embodiment an antagonist of the kinin Bl receptor as used in accordance with the present invention is a compound having an IC₅₀ < 5 μM, preferably < 500 nM.

Without going here too much into details, the scientific rational underlying the technical teaching of the instant invention is as follows.

Fibrotic diseases in general and the specific forms of CD according to the present invention are characterized by excessive scarring due to excessive production, deposition and contraction of extracellular matrix. Tissue fibrosis is generally considered to arise from a failure of the normal wound healing response to terminate. Although the mechanisms of fibrogenesis are still not fully understood, a substantial amount of progress has been made over the past few years. This increased knowledge resulted in a growing list of novel mediators and pathways that could be targeted as antifibrotic treatments. These include among many others chemokine and Toll like receptor (TLR) antagonists, angiogenesis inhibitors, inhibition/neutralisation of growth factors and TGF-β signalling modifiers. Table 1 "Antifibrotic strategies" (adapted from Wynn et al. J Clin Invest. 2007; VoI 117 (3): pg527) and table 2 "Compounds in clinical development for pulmonary fibrosis" (Datamonitor report: Idiopoathic pulmonary fibrosis: A new hope. Aug 23, 2005) depicted in Fig. 4, illustrate that a plethora of potential anti-fibrotic strategies are being discussed in the field.

It is noteworthy and immediately evident from these references that the Bl receptor is not mentioned in the very comprehensive and recent list of potential anti-fibrotic strategies (Table 1). Accordingly, the Bl receptor, although its role in inflammation and pain is well known and thoroughly documented by a considerable body of publications (for review see Leeb-Lundberg et al. Pharmacol Rev. 2005; 57:27-77), represents by no means an obvious anti-fibrotic target for a person skilled in the arts.

The pathogenesis of fibrosis in CD is incompletely understood and appears to result from a complex interplay of local inflammatory cells, fibroblasts, smooth muscle cells and cytokines (Rieder et al. 2007. Gut.; 56:130-139). Excess of fibrillar collagens occurs in all bowel wall layers. Quantitative and qualitative variations in collagen phenotype have been documented in CD patients with conflicting results (Graham et al. Gastroenterology. 1988; 94:257-65. Regan MC et al. Ann Surgery. 2000. Stallmach et al. Gastroenterology. 1992; 102: 1920- 1929. McKaig et al. AmJCellPhysiol. 2001).

Fibrosis pathology is more complicated in the intestine than in other organs because the intestine contains a heterogeneous population of mesenchymal cells, some of which synthesize significant amounts of collagen during physiological conditions (Pucilowska et al. Am J Physiol Gastrointest Liver Physiol. 2000; 279:G653-G659). For example the intestine harbours a unique population of specialized mesenchymal cells: Intestinal subepithelial myofibroblasts (ISEMFs) exhibit the ultrastructural features of fibroblasts and smooth muscle cells. These ISEMFs reside subjacent to the basement membrane and are organized in a syncitium that extends throughout the lamina propria of the gut, merging with pericytes surrounding the blood vessels (Powell et al. AmJPhysiolCellPhysiol. 1999; 277:183-201). In contrast to liver fibrosis, recurrent fibrostenotic Crohn's Disease lacks the definition of activated fibrogenic mesenchymal cells by specific markers. Mesenchymal intestinal cells producing collagens include fibroblasts, smooth muscle cells, and myofibroblasts.

Furthermore a microbial component is likely to be of major importance in intestinal fibrosis. Experimental injection of gut bacterial flora into the bowel wall initiates intestinal TGFbI and collagen synthesis (Mourelle et al. Gastroenterology. 1998; 114:519-526). The innate immune system seems to play a distinctive 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, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease and macular degeneration may share some common mechanisms but also have a unique organ- specific fibrogenic pathogenesis (Wynn et al. J Clin Invest. 2007; VoI 117 (3): 524-529).

As a matter of fact, only very view studies addressed the role of the kinin Bl receptor in general fibrosis. To the extent available any information insofar is confined to fibrosis in connection with diseases different from CD and thus limited to tissues and cells, respectively, which are different from those involved in CD and more particularly the specific forms of CD according to the present invention. In the only three available in vitro studies a human embryonal lung cell line (cell line IMR-90) was investigated and the authors found that the kinin Bl receptor was pro-fibrotic, i.e. a stimulation of said receptor went, in vitro, along with an increase in collagen synthesis which may be a starting point for fibrosis. Ricupero et al. JBiolChem. 2000. 275:12475-12480; Romero et al. JBiolChem. 2005. Vol280 (15):14378- 14384; and Goldstein et al. J Biol Chem. 1984. VoI 259 (14): 9263-9268).

The upregulation of BlR has furthermore been described to be associated in vivo with aortic stenotic fibrosis (Helske et al. Eur Heart J. 2007; 28 (15): 1894 - 903) which, again, is a different cell and tissue type than the ones involved in CD and the specific forms of CD according to the present invention.

It is evident that these data obtained from only three in vitro studies using the same cell line and one in vivo study are not sufficient to conclude that the BlR is uniformly pro-fibrotic, let alone is pro-fibrotic in CD in general and the specific forms of CD according to the present invention in particular. Furthermore, there are conflicting in vivo results describing an anti- fibrotic role of BlR in cardiac fibrosis (Moniwa et al. BiolChem. 2006; 387 (2): 203-209) as well as in renal fibrosis (Hagiwara et al. Hypertens Res. 2004. 27(6): 399-408) under high blood pressure conditions rather than a pro-fibrotic activity as one would have expected from the above reported in vitro results.

In addition to the prior art not having recognized the kinin Bl receptor as a potential target for any anti-fibrotic strategy, even if a person skilled in the art would have taken the kinin Bl receptor antagonist as a starting point for fibrosis, (s)he would not have had any reason to assume that an anti-fibrotic strategy in the treatment of CD could be based thereon due to the limited knowledge on the role of BlR and fibrosis suggesting a pro-fibrotic activity in vitro in connection with the only tested cell line and an anti-fibrotic activity in vivo, which is thus clearly conflicting with said in vitro results. In addition and as outlined above, gastrointestinal fibrosis as found in the specific forms of CD according to the present invention and RFCD in particular is much more complicated than fibrotic diseases of other organs not prompting a person skilled in the art to start any experimentation with a reasonable expectation of success to treat CD and the specific forms of CD according to the present invention by addressing the kinin Bl receptor. That the prior art did not conceive the kinin Bl receptor as an entry point in fibrostenotic Crohn's Disease may be taken from Burke et al. (Burke et al. Am J Gastroenterol. 2007; 102; 439-448) who reviewed potential entry points in fibrostenotic Crohn's Disease as summarized in Table 3 of Fig. 4 and not pointing to the kinin Bl receptor.

In view of this it is the merit of the instant inventors that they have recognized that the kinin Bl receptor is not only involved in the pathogenesis of fibrosis in connection with CD and more particularly the specific forms of CD in accordance with the present invention, but that it is even a target or a starting point for an anti-fibrotic strategy in connection with these diseases. From the results available from the prior art, a person skilled in that art could not have been prompted to assume that a BlR antagonist would be a suitable means for the treatment of CD and the specific forms thereof, respectively.

Numerous kinin Bl receptor antagonists are known in the art. Due to their mode of action, i.e. inhibiting the activity of the kinin Bl receptor, and the pathological mechanism underlying the specific forms of CD according to the present invention as outlined above, it is evident that any kinin Bl receptor antagonist may be used for the treatment of any of the specific forms of CD according to the present invention.

More preferred Bl receptor antagonists are the ones disclosed in the following international patent applications the disclosure of which is incorporated herein by reference: WO92017201, WO96016081, WO98007746, WO99051235, WO99051245, WO00075107, WO01005783, WO02017958, WO2002053516, WO02076964, WO02092556, WO02099388, WO2003007958, WO03065789, WO03066577, WO03093245, WO03106428, US20040034064, US20040063761, US20040116353, US20040198666, WO04019868, WO04033436, WO04054584, WO04056319, WO04083173, WO2004087700, WO04092116, WO04092164, WO04098589, WO04098590, WO04099155, US20050020591, WO05004810, US20050084463, US20050085667, US20050124654, WO05016886, US20050215470, US20050234044, US20050261327, US20050288305, WO05037994, WO2005042027, WO2005061467, WO05063690, WO2005085198, US05952346, US20060025400, US20060100213, US20060100216, US20060106011, US20060111347, US20060111392, US20060122236, US20060128765, US20060142612, US06015812, US20060173023, US20060178370, WO06017938, WO06019975, US20060217362, US20060247229, US20060281733, US20060293332, WO2006036664, WO2006041888, WO06044355, WO06044412, WO06048209, WO06071775, WO06113140, WO06132837, US06908921, US06919343, US06919347, US20070032475, US20070093485, US20070123531, US20070161633, US20070189865, US07041785, US07056937, WO07067629, WO07072092, US07074783, US07091380, WO07101007, US07109203, WO07140383, US07157454, US07163951, US07183281, US07211566, US07291642, US07332499, US07393873, US20080064642, WO08011168, WO08024692, WO08033739, WO08046573, WO08050167, WO08050168, WO2008068540.

More preferred Bl receptor antagonists which may be used in accordance with the present invention are the following ones:

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), and

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

Jr. et al. Hypertension 1999, 33, 823-9;

Ac-Orn-Arg-Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH (R954), as described in Gabra, B. H.;

Sirois, P. Peptides 2003, 24, 1131-9;

H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH (B9858) and

H-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH (B9958) as described in Stewart, J.M. et al.; Immunopharmacology 1996, 33, 51-60;

FSc-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg-OH (B 10324) as described in Gera, L. et al.; International Immunopharmacology 2008, 8, 289-92;

2-[l-(3,4-Dichloro-benzenesulfonyl)-3-oxo-l,2,3,4-tetrahydτo-quinoxalin-2-yl]-N-{2-[4-(4,5- dihydro- 1 H-imidazol-2-yl)-phenyl]-ethyl} -acetamide, as described in Su, D.-S. et al; J Am. Chem. Soc. 2003, 125, 7516-7;

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

3 -(3 ,4-Dichloro-phenyl)-N- { 1 - [4-(4, 5 -dihydro- 1 H-imidazol-2-yl)-benzy 1] -2-oxo-2- pyrrolidin- 1 -yl-ethyl} -3-(naphthalene-2-sulfonylamino)-propionamide,

4'-(I - {3-[(2,2-Difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridin-2-ylamino} -ethyl)- 5-methyl-biphenyl-2-carboxylic acid methyl ester,

N-(4-Chloro-2-{l-[3'-fluoro-2'-(3-methyl-[l,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethylamino}- pyridin-3 -yl)-3 ,3 ,3 -trifluoro-propionamide, as described in Hess, J.F. et al.; J. Pharmacol. Exp. Ther. 2004, 310, 488-97;

4'- { 1 - [4-Chloro-3 -(2-cyano-acety lamino)-pyridin-2-ylamino] -ethyl } -3 -fluoro-biphenyl-2- carboxylic acid methyl ester,

3-Chloro-4^l-{l-[4-chloro-3-(2-cyano-acetylamino)-pyridin-2-ylamino]-ethyl}-biphenyl-2- carboxylic acid methyl ester,

N-(4-Chloro-2-{l-[3'-fluoro-2'-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylamino}- pyridin-3 -yl)-2-cyano-acetamide, as described in Kuduk, S.D. et al.; J. Med. Chem. 2004, 47, 6439-42;

3,3'-Difluoro-4'- { [5-(4-pyridin-4-yl-piperazine- 1 -carbonyl)-pyridin-2-ylamino]-methyl} - biphenyl-2-carboxylic acid methyl ester, as described in Kuduk, S.D. et al.; Bioorg. Med. Chem. Lett. 2006, 16, 2791-5;

3,3'-Difluoro-4'-({[l-(3,3,3-trifluoro-propionylamino)-cyclopropanecarbonyl]-amino}- methyl)-biphenyl-2-carboxylic acid methyl ester,

3 ,3 '-Difluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino } -ethyl)- biphenyl-2-carboxylic acid methyl ester,

3-Chloro-3^l-fluoro-4'-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino}- ethyl)-biphenyl-2-carboxylic acid methyl ester, as described in Kuduk, S.D. et al.; J Med. Chem. 2007, 50, 272-82;

2-Chloro-6- [5-fluoro-6-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino } - ethyl)-pyridin-3-yl] -benzoic acid ethyl ester, as described in Kuduk, S.D. et al.; Bioorg. Med. Chem. Lett. 2007, 17, 3608-12;

β-Methoxy-isoxazole-S-carboxylic acid [l-(l-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)- phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-cyclopropyl]-amide, as described in Feng, D.-M. et al.; Bioorg. Med. Chem. Lett. 2008, 18, 682-7;

N-(l-{5-[5-Chloro-3-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2- yl } -ethyl)-3 ,3 ,3 -trifluoro-2-hydroxy-2 -methyl -propionamide, as described in Wood, M.R. et al.; Bioorg. Med. Chem. Lett. 2008,75, 716-20;

1 -(I -Butyl-5-cyclohexyl-2-oxo-2,3-dihydro- 1 H-benzo[e] [ 1 ,4]diazepin-3 -yl)-3 - [4-(4- dimethylamino-piperidin- 1 -yl)-phenyl] -urea,

l-(l-Butyl-2-oxo-5-phenethyl-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4-pyridin-4- yi-piperazin- 1 -yl)-phenyl]-urea, as described in Wood, M.W. et al.; J. Med. Chem. 2003, 46, 1803-6;

{4-[2-(Pyridine-2-carbonyl)-phenylsulfamoyl]-phenyl}-carbamic acid tetrahydro-furan-2- ylmethyl ester, as described in Su, D.-S. et al.; J. Med. Chem. 2008, 51, 3946-52;

(R)-N-(l<5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2- yl)ethyl)-4,4-difluoro- 1 -hydroxycyclohexanecarboxamide, as described by Kuduk, S.D. et al.; Bioorg. Med. Chem. Lett. 2008, in press;

3-Benzo[l,3]dioxol-5-yl-N-[2-[4-(2,6-dimethyl-piperidin-l-ylmethyl)-phenyl]-l-(isopropyl- methyl-carbamoyl)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propionamide

(SSR240612), as described by Gougat, J. et al.; J. Pharmacol. Exp. Ther. 2004, 309, 661-9;

l-[4-(2,2-Diphenyl-ethylamino)-3-(morpholine-4-carbonyl)-benzenesulfonyl]-piperidine-4- carboxylic acid bis-(3-dimethylamino-propyl)-amide,

{2-(2,2-Diphenyl-ethylamino)-5-[4-(4-methyl-piperazine- 1 -carbonyl)-piperidine- 1 -sulfonyl]- phenyl } -morpholin-4-yl-methanone, as described by Ritchie, T.J. et al.; J. Med. Chem. 2004, 47, 4642-4, and by Fox, A. et al.; Br. J. Pharmacol. 2005, 144, 889-99;

3 -(Naphthalene-2-sulfonylamino)-3 -phenyl-N-(7-piperidin- 1 -ylmethyl-chroman-4-yl)- propionamide, as described by D'Amico, D.C. et al.; J. Med. Chem. 2007, 50, 607-10;

3 -(4-Fluoro-phenyl)-N-(7-piperidin- 1 -y lmethyl-chroman-4-yl)-3 -(3 -trifluoromethyl- benzenesulfonylamino)-propionamide, as described by Biswas, K. et al.; J Med. Chem. 2007, 50, 2200-12;

N- [6-(tert-Butylamino-methyl)- 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl] -2- [ 1 -(3 -trifluoromethyl- benzenesulfonyl)-piperidin-2-yl]-acetamide, as described by Fotsch, C. et al.; Bioorg. Med. Chem. Lett. 2006, 16, 2071-5;

2,3-Dihydroxy-N-(6-piperidin- 1 -ylmethyl- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-4-(3- trifluoromethyl-benzenesulfonyl)-butyr amide, as described by Donga, H. et al.; Journal ofNeuroscience Methods 2008, 168, 76—87;

2-((R)-3 -oxo- 1 -(phenylsulfonyl)- 1 ,2,3 ,4-tetrahydroquinoxalin-2-yl)-N-((R)-7-(piperidin- 1 ■ ylmethyl)chroman-4-yl)acetamide, as described by Chen, J. J. 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- benzenesulfonyl)-methyl-amino] -ethoxy } -N-methyl-acetamide (LF22-0542), as described by Porreca, F. et al.; J Pharmacol. Exp. Ther. 2006, 318, 195-205, and by Sevcik, M. A. et al.; J Pain 2005, 6, 771-5;

7-Chloro-2-[3-(9-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane-3-carbonyl)-phenyl]-2,3- dihydro-isoindol- 1 -one (ELN-441958), as described by Hawkinson, J.E. et al.; J Pharmacol. Exp. Ther. 2007, 322, 619-30;

4-Bromo-5-(2-chloro-benzoylamino)-l-phenyl-lH-pyrazole-3-carboxylic acid [2-(3,4,5,6- tetrahydro-2H-[l,4']bipyridinyl-4-yl)-ethyl]-amide, as described by Dressen, D. et al.; J. Med. Chem. 2007, 50, 5161-7;

l-benzyl-N-(2-((4-(6-(4,5-dihydro-lH-imidazol-2-yl)pyridin-3-ylamino)benzyl)

(methyl)amino)-2-oxoethyl)- 1 H-benzo[d]imidazole-2-carboxamide, as described by Guo, Q. et al.; Bioorg. Med. Chem. Lett. 2008, in press.

The present invention will now be further illustrated by the following figures and examples from which further features, embodiments and advantages may be taken, whereby

Fig. 1 shows a diagram demonstrating that the BlR antagonist reference peptide JPE- 1697 (2 mg/kg, i.p. d35-d49) significantly reduced fibrotic collagen deposition, whereby colonic collagen levels were reduced close to baseline levels as seen in Ethanol and TNBS+anti TGF-β groups acting as positive controls determining the maximum possible collagen reduction, whereas JPE-ctrl represents a group treated with a control peptide without any activity on the BlR acting as a negative control;

Fig. 2 shows a diagram demonstrating that the BlR antagonist JPE- 1697 reduced pro- fibrotic IL 13 and TGF-β secretion of lamina propria mononuclear cells from TNBS- treated mice;

Fig. 3 shows a diagramm demonstrating that the BlR antagonist JPE- 1697 reduced pro- inflammatory TNF-α, IFN-γ as well as TH 17 pathway IL23, IL 17 and IL25 secretion of lamina propria mononuclear cells from TNBS-treated mice; and

Fig. 4 depicts tables 1 to 3 showing antifibrotic strategies (Table 1), compounds in clinical development for pulmonary fibrosis (Table 2) and potential therapeutic entry points in fibrostenotic Crohn's Disease (Table 3).

The abbreviations used herein for amino acids correspond to the three letter code customary in peptide chemistry as is described in Eur. J. Biochem 138, 9 (1984). Other abbreviations used are listed below:

TFA 2,2,2-trifluoroacetic acid

Cpg cyclopentylglycyl

NaI 2-naphthylalanyl

Oic cis,endo-octahydroindole-2-carbonyl

Occ octanoic acid

Tic 1 ,2,3 ,4- tetrahydroisoquinoline-3 -ylcarbonyl

F5c 2,3,4,5,6-pentafluorocinnamic acid

Hyp trans-4-hydroxy-L-proline

Ac acetyl

Orn ornithine

IgI alpha-(2-indanyl)glycine

Phe phenylalanine NMePhe N-methyl phenylalanine

GIy glycine

He isoleucine

Lys lysine

Pro proline

GIn glutamine

Arg arginine

Ser serine

VaI valine

Example 1: Effect of BlR antagonist JPE-1697 in a mouse model of colitis and intestinal fibrosis

Objective and Rationale

Jerini aimed to investigate the anti-fibrotic properties of a BlR antagonist in a well referenced mouse model of experimental chronic colitis and intestinal fibrosis. Repeated treatments with progressively increasing doses of TNBS (2,4,6-trinitrobenzene sulfonic acid) over a 7 week period cause increased collagen deposition and high occurrence of fibrosis. As outlined herein Jerini found among others that BlR antagonism significantly reduced fibrotic collagen deposition in this model.

The mouse model used

The objective of this study was to determine the ability of the peptidic BlR antagonist JPE- 1697 which was used as an exemplary kinin Bl receptor antagonist to ameliorate intestinal fibrosis in said mouse model of chronic colitis and associated fibrosis including its effect on colonic collagen deposition, release of pro-fibrotic and pro-inflammatory factors from intestinal immune cells, more specifically from lamina propria mononuclear cells. This widely used model shows TNBS-induced transmural inflammation and fibrosis as seen in fibrostenotic Crohn's disease. (Lawrance et al. Gastroenterology. 2003; 125:1750-1761; Fichtner-Feigl et al. J Clin Invest. 2005; 115:3057-3071; Wu et al. J Immunol. 2007; 179:6988-7000). This recurrent TNBS model represents the only available model including chronic bowel inflammation, subsequent development of fibrosis and a very well characterised pathophysiology including cytokine profile over the entire timecourse of 49 days). Weeks 1-2 are characterized by massive inflammatory infiltration of the mucosal lamina propria, epithelial disruption and secretion of THl cytokines. Weeks 3-5 show subsiding of the acute inflammation, emergence of edma formation, a drop in THl cytokines (except TNF-α, which remains upregulated for the entire 7 weeks) and progression towards a TH 17 cytokine pattern. In weeks 4-6 slowly increasing collagen deposition and upregulation of pro-fibrotic mediators IL 13 and TGF-β are observed. Finally from week 6-7 the animals develop massive collagen deposition in the large intestine (Fichtner-Feigl et al. J Immunol. 2007; 178: 5859-5870).

Materials and Methods

Induction of colitis

Chronic TNBS (2,4,6-trinitrobenzene sulfonic acid) colitis was induced by weekly administration of progressively increasing doses of TNBS (Sigma- Aldrich) (1.5-2.5 mg in 45% ethanol) until d49 (week 7). Mice were lightly anesthesized with isofluorane and then administered TNBS/ethanol per rectum via a 3.5F catheter equipped with a 1 ml syringe; the catheter was advanced into the rectum until the tip was 4 cm proximal to the anal verge, at which time the TNBS was administered in a total volume of 150 μl. Mice were treated with R-954 or JPE-ctrl (i.p. 2 mg/kg/d), anti- TGF-β Ab (i.p. lmg/kg/week) starting on d35 until d49.

Collagen assay

Colons of mice were harvested on d49 of the study and homogenized in 0.5 M acetic acid containing 1 mg of pepsin (at a cone, of 10 mg of tissue/10ml of acetic acid solution). The resulting mixture was then incubated and stirred for 24h at 4°C. Total soluble collagen content of the mixture was then determined with a Sircol Collagen Assay Kit (Biocolor). Acid soluble type I collagen supplied with the kit was used to generate a standard curve (Kitani et al. JExpMed. 2003; 198:1179-1188) Cell isolation and culture

Isolated colonic lamina propria mononuclear cells (LPMC) were isolated from colonic tissue as described (Boirivant et al. JExpMed. 1998; 188:1929-1939) and then cultured for 48h. lxlθ⁶cultured LPMC were stimulated with plate-bound anti-CD3 Ab and soluble anti-CD28 Ab (BD Pharmingen) to determine IFN-γ, IL 13, IL25 and IL 17 protein secretion. To determine IL12p70, TNFa protein secretion LPMC were stimulated with IFN-γ/LPS. To determine IL23 protein secretion LPMC were stimulated with bacterial peptidoglycan (Sigma Aldrich), and to determine TGF-β release LPMC were stimulated with IL13/TNF-α. Cytokine concentrations of LPMC supernatants were measured by ELISA according to manufacturers instructions.

Kinin Bl receptor antagonist

R954 which is also referred to as JPE- 1697, is a highly efficient, well referenced peptidic antagonist of kinin receptors of the Bl subtype having the following structure Ac-Orn-Arg- Oic-Pro-Gly-NMePhe-Ser-D-Nal-Phe-OH 2xHCl. In isolated organ preparations R954 inhibited desArgKallidin-induced contractions with pA2 values of 8.64 on the human umbilical vein and 8.46 on the rabbit aorta (Neugebauer et al., CanJPhysiolPharmacol. 2002 80:287-292). R954 had proven to be effective in various rodent models of pain, extravasation and inflammation (Gabra et al. EurJPharmacol. 2005; 61-67; Gabra et al. Neuropeptides. 2003; 37: 36-44; Eric et al. Br J Pharmacol. 2003; 138: 1589-1597; Simard et al. Can J Physiol Pharmacol. 2002; 80 (12):1203-1207). R954 is also described and claimed in US patent # US7211566B2 (Regoli et al., May 1 2007; claim #5): R954 is a selective peptidic Bl receptor antagonist that is relatively resistant to in vitro and in vivo enzymatic degradation, has good pharmakinetic properties and has shown in vivo efficacy in rodent models of diabetic microvascular leakage, diabetic hyperalgesia and allergic asthma (Regoli et al. US #7211566B2. 2007).

R954 was also characterised by the present inventors and showed antagonistic activity on the human BlR (IC50 = 15 nM in Calcium mobilisation assay CaM; IC50 = 3 nM in radioligand binding assay RLB) and mouse BlR (IC50 = 800 nM CaM; IC50= 570 nM RLB). No partial agonism on the human, rat, mouse or rabbit BlR was detected up to 10 μM. No inhibitory activity was detected on the mouse B2R up to 30 μM. Data Analysis

Two-tailed Student's t-test was applied for comparison between test groups and vehicle groups Differences are considered significant at PO.01.

Results and Conclusions

The effect of JPE- 1697 on TNBS-induced intestinal collagen deposition in comparison with ethanol (TNBS vehicle), JPE-ctrl (negative control) and anti- TGF-β treatment (positive control is depicted in Fig.l. Animals treated with ethanol alone without TNBS develop a certain degree of colonic fibrosis which could not be prevented by anti- TGF-β treatment indicating that the ethanol and anti- TGF-β group represent the lowest collagen levels that can be achieved in this model (100% reduction). Since treatment with the BlR antagonist JPE- 1697 was not statistically significantly different from anti- TGF-β or ethanol treatment, BlR antagonism caused a reduction of TNBS-induced fibrosis close to baseline. The control peptide JAL-1364 Occ-Ala-Phe-Arg-Leu-Hyp-Oic- Asp- ATg-IIe-NH₂ IxTFA showed no effect on colonic fibrosis thus demonstrating specificity of the beneficial effects observed with BlR antagonism.

The effect of JPE- 1697 treatment on pro-fibrotic IL 13 and TGF-β secretion of intestinal immune cells LPMC (lamina propria mononuclear cells) from TNBS-treated mice is shown in figure 2. LPMC were harvested, pooled from 10 animals, and cultured on day 49 (d49) after 7 weeks of TNBS or ethanol treatment. Upon stimulation LPMC from ethanol treated animals showed no increase in IL 13 or TGF-β thus confirming that the collagen deposition observed in this group was the result of an atypical fibrotic mechanism. LPMC from TNBS treated mice showed a dramatic increase of IL 13 and TGF-β production in response to stimulation. This response was greatly reduced in animals treated with BlR antagonist JPE- 1697. This showed that BlR antagonism had profoundly changed the LPMC population in TNBS-treated mice after 49 days. The control peptide JPE-ctrl showed no effect on colonic fibrosis thus demonstrating specificity of the beneficial effects observed with BlR antagonism. The effect of JPE-1697 treatment on pro-inflammatory THl (IL12, IFN-γ, TNF-α) and TH17/TH2 (IL23, IL17, IL25) cytokine secretion of intestinal immune cells LPMC (lamina propria mononuclear cells) from TNBS-treated mice is shown in figure 3. LPMC were harvested, pooled from 10 animals, and cultured on d49 after 7 weeks of TNBS or ethanol treatment. Upon stimulation LPMC from TNBS treated mice showed a dramatic increase of THl as well as TH17/TH2 cytokine production. This response was greatly reduced in animals treated with the BlR antagonist JPE-1697. This confirmed that BlR antagonism had profoundly changed the LPMC population in TNBS-treated mice after 49 days. The control peptide JPE-ctrl showed no effect on colonic fibrosis thus demonstrating specificity of the beneficial effects observed with BlR antagonism.

It will be acknowledged by the ones skilled in the art that the results/conclusions obtained with the BlR antagonist R954 (JPE-1697) are applicable to any BlR antagonist characterized as such by appropriate functional and binding assays.

The features of the present invention disclosed in the specification, the claims and/or the drawings may both separately and in any combination thereof be material for realizing the invention in various forms thereof.

Claims

1. A kinin Bl receptor antagonist for use in the treatment of a patient suffering from stricturing Crohn's Disease.

2. The kinin Bl receptor antagonist according to claim 1, wherein the stricturing Crohn's Disease is fibstrostenotic Crohn's Disease.

3. The kinin Bl receptor antagonist according to claim 1 or 2, wherein the stricturing Crohn's Disease is obstructive fibstrostenotic Crohn's Disease.

4. The kinin Bl receptor antagonist according to any one of claims 1 to 3, wherein the stricturing Crohn's Disease is recurrent obstructive fibstrostenotic Crohn's Disease.

5. The kinin Bl receptor antagonist according to any one of claims 1 to 4, wherein the kinin Bl 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 (R892),

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 (R954),

H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH ^δSδ),

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-OH (Bl 0324),

2-[l-(3,4-dichloro-benzenesulfonyl)-3-oxo-l,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[4-(4,5- dihydro- 1 H-imidazol-2-yl)-phenyl] -ethyl} -acetamide,

N-{2-[4-(4,5-dihydro-lH-imidazol-2-yl)-phenyl]-ethyl}-2-[l-(naphthalene-2-sulfonyl)-3- oxo-l,2,3,4-tetrahydro-quinoxalin-2-yl]-acetamide, 3 -(3 ,4-dichloro-phenyl)-N- { 1 - [4-(4,5-dihydro- 1 H-imidazol-2-yl)-benzyl] -2-oxo-2-pyrrolidin-

1 -yl-ethyl} -3-(naphthalene-2-sulfonylamino)-propionamide,

4'-(I- { 3-[(2,2-difluoro-cyclopropanecarbonyl)-amino] -4-methyl-pyridin-2-ylamino } -ethyl)- 5 - methyl-biphenyl-2-carboxylic acid methyl ester,

N-(4-chloro-2-{l-[3'-fluoro-2^l-(3-methyl-[l,2,4]oxadiazol-5-yl)-biphenyl-4-yl]-ethylamino}- pyridin-3 -yl)-3 ,3 ,3-trifluoro-propionamide,

3-chloro-4'-{l-[4-chloro-3-(2-cyano-acetylamino)-pyridin-2-ylamino]-ethyl}-biphenyl-2- carboxylic acid methyl ester,

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^l-{[5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl}- biphenyl-2-carboxylic acid methyl ester,

3 ,3'-difluoro-4'-( { [1 -(3 ,3 ,3 -trifluoro-propionylamino)-cyclopropanecarbonyl] -amino} - methyl)-biphenyl-2 -carboxylic acid methyl ester,

3 ,3 '-difluoro-4'-( l-{[l-(2,2 ,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino } -ethyl)- biphenyl-2 -carboxylic acid methyl ester,

3-chloro-3 '-fluoro-4'-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino } - ethyl)-biphenyl-2-carboxylic acid methyl ester,

2,4-dichloro-6-[5-fluoro-6-(l - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]- amino}-ethyl)-pyridin-3-yl] -benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino} - ethyl)-pyridin-3-yl] -benzoic acid methyl ester,

2-chloro-6- [5-fluoro-6-( 1 -{[ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino }- ethyl)-pyridin-3-yl] -benzoic acid ethyl ester,

S-methoxy-isoxazole-S-carboxylic acid [l-(l-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)- phenyl] -3 -fluoro-pyridin-2-yl } -ethylcarbamoy^-cyclopropyl] -amide,

N-( 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-propionamide,

1 -(I -butyl-5-cyclohexyl-2-oxo-2,3-dihydro- 1 H-benzo[e] [ 1 ,4]diazepin-3-yl)-3-[4-(4- dimethylamino-piperidin- 1 -yl)-phenyl]-urea, 1 -( 1 -butyl-2-oxo-5-phenethyl-2,3 -dihydro- 1 H-benzo[e] [ 1 ,4]diazepin-3 -yl)-3 - [4-(4-pyridin-4- yl-piperazin- 1 -yl)-phenyl] -urea,

3 -benzo [1,3] dioxol-5 -yl-N- [2- [4-(2 ,6-dimethyl-piperidin- 1 -ylmethyl)-phenyl] - 1 -(isopropyl- methyl-carbamoyl)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propionamide

(SSR240612), l-[4-(2,2-diphenyl-ethylamino)-3-(moφholine-4-carbonyl)-benzenesulfonyl]-piperidine-4- carboxylic acid bis-(3-dimethylamino-propyl)-amide,

{2-(2,2-diphenyl-ethylamino)-5-[4-(4-methyl-piperazine-l-carbonyl)-piperidine-l-sulfonyl]- phenyl } -moφholin-4-yl-methanone,

3-(4-fluoro-phenyl)-N-(7-piperidin-l-ylmethyl-chroman-4-yl)-3-(3-trifluoromethyl- benzenesulfonylamino)-propionamide,

N- [6-(tert-butylamino-methyl)- 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl]-2- [ 1 -(3 -trifluoromethyl- benzenesulfonyl)-piperidin-2-yl]-acetamide,

2-((R)-3 -oxo- 1 -(phenylsulfonyl)- 1 ,2,3 ,4-tetrahydroquinoxalin-2-yl)-N-((R)-7-(piperidin- 1 - ylmethyl)chroman-4-yl)acetamide,

N-[4-(4,5-dihydro-lH-imidazol-2-yl)-bεnzyl]-2-{2-[(4-methoxy-2,6-dimethyl- benzenesulfonyl)-methyl-amino] -ethoxy } -N-methyl-acetamide (LF22-0542),

4-bromo-5-(2-chloro-benzoylamino)-l-phenyl-lH-pyrazole-3-carboxylic acid [2-(3,4,5,6- tetrahydro-2H-[l,4^l]bipyridinyl-4-yl)-ethyl]-amide, l-benzyl-N-(2-((4-(6-(4,5-dihydro-lH-imidazol-2-yl)pyridin-3-ylamino)ben2yl) (methyl)amino)-2-oxoethyl)- 1 H-benzo [d] imidazole-2-carboxamide

6. Use of a kinin Bl receptor antagonist for the manufacture of a medicament for the treatment of a patient suffering from stricturing Crohn's Disease.

7. Use according to claim 6, wherein the stricturing Crohn's Disease is fibstrostenotic Crohn's Disease.

8. Use according to claim 6 or 7, wherein the stricturing Crohn's Disease is obstructive fibstrostenotic Crohn's Disease.

9. Use according to any of claims 6 to 8, wherein the stricturing Crohn's Disease is recurrent obstructive fibstrostenotic Crohn's Disease.

10. Use according to any of claims 6 to 9, wherein the kinin Bl receptor antagonist is selected from the group consisting of

Ac-Lys-Arg-Pro-Pro-Gly-Phe-Ser-D- NaI-De-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 (R914),

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 (B9858),

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-OH (B 10324),

2-[l-(3,4-dichloro-benzenesulfonyl)-3-oxo-l,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[4-(4,5- dihydro- 1 H-imidazol-2-yl)-phenyl]-ethyl} -acetamide,

N-{2-[4-(4,5-dihydro-lH-imidazol-2-yl)-phenyl]-ethyl}-2-[l-(naphthalene-2-sulfonyl)-3- oxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-2-yl]-acetamide,

3-(3,4-dichloro-phenyl)-N-{l-[4-(4,5-dihydro-lH-imidazol-2-yl)-benzyl]-2-oxo-2-pyrrolidin-

1 -yl-ethyl} -3-(naphthalene-2-sulfonylamino)-propionamide, 4'-( 1 - { 3 - [(2,2-difluoro-cyclopropanecarbonyl)-amino]-4-methyl-pyridin-2-ylamino } -ethyl)-5- methyl-biphenyl-2-carboxylic acid methyl ester,

N^-chloro^-ll-tS'-fluoro^'^-methyl-tl^^loxadiazol-S-yO-biphenyl^-yη-ethylainino}- pyridin-3 -yl)-3 ,3 ,3 -trifluoro-propionamide,

4'- { 1 -[4-chloro-3-(2-cyano-acetylamino)-pyridin-2-ylamino]-ethyl} -3-fluoro-biphenyl-2- carboxylic acid methyl ester,

N-(4-chloro-2-{l-[3'-fluoro-2'-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylamino}- pyridin-3 -yl)-2-cyano-acetamide,

3,3^l-difluoro-4'-{[5-(4-pyridin-4-yl-piperazine-l-carbonyl)-pyridin-2-ylamino]-methyl}- biphenyl-2-carboxylic acid methyl ester,

3,3'-difluoro-4'-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino}-ethyl)- biphenyl-2 -carboxylic acid methyl ester,

3-chloro-3'-fluoro-4'-(l-{[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino}- ethyl)-biphenyl-2-carboxylic acid methyl ester,

2,4-dichloro-6-[5-fluoro-6-(l - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]- amino}-ethyl)-ρyridin-3-yl] -benzoic acid methyl ester,

2-chloro-6-[5-fluoro-6-(l - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]-amino} - ethyl)-pyridin-3-yl]-benzoic acid methyl ester,

2-chloro-6- [5-fluoro-6-( 1 - { [ 1 -(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl] -amino } - ethyl)-pyridin-3-yl]-benzoic acid ethyl ester,

N-(l-{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-propionamide, l-(l-butyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4- dimethylamino-piperidin- 1 -yl)-phenyl]-urea, l-(l-butyl-2-oxo-5-phenethyl-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-3-[4-(4-pyridin-4- yl-piperazin- 1 -yl)-phenyl]-urea, [4-(2-benzoyl-phenylsulfamoyl)-phenyl]-carbamic acid tetrahydro-furan-2-ylmethyl ester,

3 -benzo [1,3] dioxol-5 -yl-N- [2- [4-(2,6-dimethyl-piperidin- 1 -ylmethyl)-phenyl] - 1 -(isopropyl- methyl-carbamoyl)-ethyl]-3-(6-methoxy-naphthalene-2-sulfonylamino)-propionamide

{2-(2,2-diphenyl-ethylamino)-5-[4-(4-isopropyl-piperazine- 1 -carbonyl)-piperidine- 1 - sulfonyl] -phenyl } -morpholin-4-yl-methanone,

{2-(2,2-diphenyl-ethylamino)-5-[4-(4-methyl-piperazine-l-carbonyl)-piperidine-l-sulfonyl]- phenyl} -morpholin-4-yl-methanone,

N-[6-(tert-butylamino-methyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-2-[l-(3-trifluoromethyl- benzenesulfbnyl)-piperidin-2-yl]-acetamide,

2,3-dihydroxy-N-(6-piperidin-l-ylmethyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-4-(3- trifluoromethyl-benzenesulfonyl)-butyramide,

N-[4-(4,5-dihydro-lH-imidazol-2-yl)-benzyl]-2-{2-[(4-methoxy-2,6-dimethyl- benzenesulfonyl)-methyl-amino]-ethoxy}-N-methyl-acetamide (LF22-0542),

4-bromo-5-(2-chloro-benzoylamino)-l-phenyl-lH-pyrazole-3-carboxylic acid [2-(3,4,5,6- tetrahydro-2H-[l,4']bipyridinyl-4-yl)-ethyl]-amide, l-benzyl-N-(2-((4-(6-(4,5-dihydro-lH-imidazol-2-yl)pyridin-3-ylamino)ben2yl)

(methyl)amino)-2-oxoethyl)- 1 H-benzo[d]imidazole-2-carboxamide.

11. A method for the treatment of a patient suffering from stricturing Crohn's Disease comprising the administration of a kinin Bl receptor antagonist to the patient in a pharmaceutically effective amount.

12. The method according to claim 11, wherein the stricturing Crohn's Disease is selected from the group comprising fibrostenotic Crohn's Disease, obstructive fibrostenotic Crohn's Disease, recurrent fibrostenotic Crohn's Disease and recurrent obstructive fibrostenotic Crohn's Disease.