WO2007000771A2 - Fused quinazolinone derivatives and uses thereof - Google Patents

Abstract

Fused quinazolinone compounds and pharmaceutical compositions comprising fused quinazolinone compounds are provided. The compounds are capable of inhibiting cell-cell interaction mediated by glycosaminoglycans (GAGs), particularly leukocyte adhesion, migration and filtration, and are useful for treating diseases and disorders related to cell adhesion, particularly for the treatment or prevention of inflammatory and autoimmune diseases and disorders and cancer.

Description

FUSED QUINAZOLINONE DERIVATIVES AND USES THEREOF

FIELD OF INVENTION The present invention relates to fused quinazolinone compounds and pharmaceutical compositions comprising them, useful, particularly, for the treatment or prevention of inflammatory and autoimmune diseases and disorders.

BACKGROUND OF THE INVENTION The inflammatory response is mediated primarily by leukocytes, neutrophils and lymphocytes, which circulate in the blood and reversibly interact with the vascular endothelium. In response to inflammatory stimuli, the leukocytes adhere tightly to the vascular endothelium, migrate (extravasate) through the vessel wall, and subsequently move along a chemotactic gradient toward the inflammatory stimulus. The interaction of leukocytes with vascular endothelial cells is thus an essential initial step in the inflammatory response.

Selectins play a key role in inflammation, as they are responsible for the initial attachment of blood borne leukocytes to the vasculature. Preventing selectin- mediated cell adhesion can ameliorate or circumvent the deleterious consequences of inflammation. Therefore, selectins are the prime target for the therapy of cell- adhesion disorders, specifically for treatment of inflammation. The three known selectins are E-selectin (formerly known as ELAM.1), P-selectin (formerly known as PADGEM, GMP- 140, or CD61) and L-selectin (formerly known as mLHR, Leu8, TQ-I, gp90, MEL, Lam-1, or Lecam-1) (Lasky, 1995). Glycosaminoglycans (also referred to herein as "GAG" or "GAGs") are naturally-occurring carbohydrate-based molecules implicated in the regulation of a number of cellular processes, including blood coagulation, angiogenesis, tumor growth, and smooth muscle cell proliferation, most likely by interaction with effector molecules. GAGs are often, but not always, found covalently bound to protein cores in structures called proteoglycans. Proteoglycan structures are abundant on cell surfaces and are associated with the extracellular matrix around cells. GAGs consist of repeating disaccharide units. For example, heparan sulfate glycosaminoglycans (also referred to herein as "HS-GAGs") consist of repeating disaccharide units of D-glucuronic acid and N-acetyl- or N-sulfo-D-glucosamine. The high molecular diversity of HS-GAGs is due to their unique sulfation pattern (Sasisekharan and Venkataraman, 2000). One of the most thoroughly studied HS- GAGs is the widely used anticoagulant heparin. Heparin is a highly sulfated form of heparan sulfate found in mast cells. Many important regulatory proteins including cytokines, growth factors, enzymes, and cell adhesion molecules bind tightly to heparin. Although interactions of proteins with GAGs such as heparin and heparan sulfate are of great biological importance, the structural requirements for protein- GAG binding have not been well characterized. Ionic interactions are important in promoting protein-GAG binding and the spacing of the charged residues may determine protein-GAG affinity and specificity.

The HS-GAG paradigm provides new approaches and strategies for therapeutic intervention at the cell-tissue-organ interface. For example, identification of specific HS-GAG sequences that affect particular biological processes will enable the development of novel molecular therapeutics based on polysaccharide sequence. Synthetic HS-GAGs, or molecular mimics of HS-GAG sequences, may provide new approaches for combating health problems such as bacterial and viral infections, atherosclerosis, cancer, and Alzheimer's disease.

As the interactions between GAGs and selectins play an important role in cell-matrix and cell-cell adhesion and the latter are processes involved in certain diseases and inflammatory disorders, the modulation of these interactions may have therapeutic implications. Xie et al. (Xie et al., 2000) described inhibition of L- and P-selectin mediated cell adhesion by sulfated saccharides, including carboxyl- reduced and sulfated heparin. While these molecules have been useful to show the utility of selectin blockers for treating inflammation, each has significant drawbacks as a therapeutic, including short in vivo half-life, high cost, potential immunogenicity, and other possible side effects. A further limitation of these approaches is lack of efficient means to improve the pharmacological properties of these molecules. The conventional concept is that cytokines in solution act as diffusible factors. However, recent progress in cytokine research suggests that many cytokines and growth factors can function in a non-diffusible fashion when immobilized on either the cell surface or the extracellular matrix (ECM) by binding to heparan sulfate proteoglycan (HS-PG). The number of cytokines that contain heparin- binding domains and can thus potentially be immobilized on HS-PG is large and includes most chemokines such as MIP-I, MCP-3, RANTES and IL-8 as well as IL-6, IL-3, IL-7 and IFN-gamma. The ability of certain cytokines to bind to and be immobilized by HS-PG accentuates their action by: 1) promoting the accumulation of cytokines at high concentrations in the appropriate location to encounter their target cells; 2) activating cytokines by inducing conformational changes in the bound cytokine; 3) promoting conformation-dependent association or polymerization of cytokines and their receptors and facilitating the assembly of the appropriate molecular complex to initiate signal transduction; and 4) protecting cytokines from both chemical and physiologic degradation (Tanaka et al, 1998). Chemokines are small chemoattractant cytokines that control a wide variety of biological and pathological processes, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Genetic and pharmacological studies have shown that chemokines are responsible for the excessive recruitment of leucocytes to inflammatory sites and damaged tissue. Chemokines have an in vivo requirement to bind to GAGs in order to mediate directional cell migration. Prevention of the GAG interaction has been shown to be a viable therapeutic strategy (Johnson et al., 2004). The chemokine system offers many potential entry points for innovative anti-inflammatory therapies for autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and allergic contact dermatitis. There is an unmet need for non-peptidic, small synthetic compounds, which are capable of modulating the functions of GAGs and the interactions between GAGs and GAG effector protein molecules.

Synthesis of certain quinazoline derivatives has been described by Ivatchtchenko et al. (Ivatchtchenko et al., 2003). However, this publication does not describe or suggests that these derivatives of quinazolines have any beneficial pharmaceutical activities. Furthemore, the compounds described in said publication are different from the fused quinazolinones claimed in the present application

SciFinder Scholar database lists 144 derivatives of fused quinazolinones (as of May 16, 2005), but no utility is attributed to any of these compounds and no chemical synthesis data are described.

Chemical Diversity Labs Inc. (San Diego, CA), a supplier of chemical compounds, released a database of about 500,000 compound structures (January 2005), which lists some derivatives of fused quinazolinones, but no utility or chemical synthesis data is described.

Enamine (Kiev, Ukraine), a supplier of chemical compounds, released a database (January 2005; 355,966 compound structures), which lists some derivatives of fused quinazolinones, but no utility or chemical synthesis data is described. As far as known by Applicant, the background art has not taught or suggested that the derivatives of fused quinazolinones described herein in the present application have any biological or pharmaceutical activity.

SUMMARY OF THE INVENTION It is an object of some aspects of the present invention to provide pharmaceutical compositions comprising small organic compounds for medical use, wherein the small organic compounds are inhibitors of leukocyte migration and infiltration to sites of inflammation.

Another object of the present invention is to provide pharmaceutical compositions comprising small organic compounds for medical and diagnostic use, wherein the small organic compounds are inhibitors of the interactions between cell adhesion molecules, chemokines or cytokines with glycosaminoglycans (GAGs)₅ specifically heparan sulfate glycosaminoglycans (HS-GAGs). Accordingly, these compositions are useful as inhibitors of cell-cell interactions mediated by GAGs, particularly leukocyte adhesion, migration and infiltration.

According to one aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and at least one active ingredient selected from the compounds of the general formula I or II:

wherein: n is an integer from 3 to 5;

Ri and R₂ each is selected from:

(i) hydrogen;

(ϋ) C₁-C₆ alkyl or phenyl, optionally substituted by a group containing a basic nitrogen atom or by at least one heterocyclyl group, wherein one of the heterocyclyl groups is a 5-7 membered heterocyclic ring containing one or two heteroatoms, one of them being a basic nitrogen atom, optionally substituted on the additional heteroatom; (iii) a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; or

(iv) Rj and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom;

R₃ and R₄ each is selected from hydrogen, Ci-C₆ alkyl, (Ci-C₆) alkoxy, (C₆- Cio)aryl(C_rC₆) alkoxy or (C₆-Ci₀) aryloxy; and pharmaceutically acceptable salts thereof.

According to one embodiment, the compounds of formula I and II of the pharmaceutical compositions of the present invention inhibit the interactions of GAGs, specifically HS-GAGs.

According to a further embodiment, the compounds of formula I and II of the pharmaceutical compositions of the present invention inhibit leukocyte and neutrophil infiltration in vivo.

According to still another aspect, the present invention provides a method for the treatment or prevention of diseases and disorders related to cell adhesion and cell migration mediated by GAG interaction, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the compounds of the general formula I or II.

The diseases or disorders mediated by GAGs are mainly inflammatory and autoimmune processes or diseases exemplified by, but not restricted to, atherosclerosis, septic shock, post-ischemic leukocyte-mediated tissue damage, frost-bite injury or shock, acute leukocyte-mediated lung injury, acute pancreatitis, nephritis, asthma, traumatic shock, stroke, traumatic brain injury, nephritis, acute and chronic inflammation, including atopic dermatitis, rheumatoid arthritis and multiple sclerosis, psoriasis, uveitis, retinitis, and inflammatory bowel disease. According to another aspect, the present invention relates to the use of a compound of the general formula I and/or II for the preparation of a pharmaceutical composition.

According to certain preferred embodiments, the present invention provides compositions comprising one or more of the following compounds of formula I: pyrrolo [2,1 -b]quinazoline- 1,2,3 ,9-tetrahydro-9-oxo-N-methyl-N-(l-methyl- piperidinyl-4)-6-carboxamide (Compound 1); pyrrolo[2, 1 -b]quinazoline- 1 ,2,3,9-tetrahydro-9-oxo-N-(l -phenylmethyl- pyrrolidinyl-3)-6-carboxamide (Compound 2); azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l- methylethyl-piperidinyl-4)-3-carboxamide (Compound 3);

7H-pyrido[2,l-b]quinazoline-6,8,9,l l-tetrahydro-l l-oxo-N-[3-(l-methyl- piperazinyl-4)propyl]-3-carboxamide (Compound 4); azepino[2,l-b]qumazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l-phenyl- methyl-piperidinyl-4)-3-carboxamide (Compound 5); and azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-[3- (dimethylamino)propyl]-3-carboxamide (Compound 6). pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N[(l-phenylmethyl- piperazinyl-4)-phenyl]-6-carboxamide (Compound 23); pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[(3-[(l-methoxy- phenyl)-piperazinyl-4]propyl]-6-carboxamide (Compound 25); pyrrolo[2, 1 -b]quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N-[ 1 -(thienyl-2)- 1 -( 1 - methyl-piperazinyl-4)ethyl]-6-carboxamide (Compound 26); pyrrolo [2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahy dro-9-oxo-N- [ 1 -methylpiperazinyl- 4)phenyl]-6-carboxamide (Compound 27);

According to further certain preferred embodiments, the present invention provides compositions comprising one or more of the following compounds of formula II:

[3-(3-phenylmethyloxy)phenylidene]pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 28); [3 -(3 -phenylmethyloxy-4-methoxy)pheny lidene]pyrrolo [2, 1 -b] quinazoline- l^^^-tetrahydro-θ-oxo-N-fSfCl-methoxyphenyO-piperazinyl-^propyll-β- carboxamide (Compound 29);

[3-(3-phenylmethyloxy-4-methoxy)phenylidene]pyrrolo[2,l-b]quinazoline- l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 30); and 3-(4-cyanophenylidene)pyrrolo[2, l-b]quinazoline- 1 ,2,3 ,9-tetrahydro-9- OXO-N-(I -methyl-piperidinyl-4)-6-carboxamide (Compound 31).

According to yet another aspect, the present invention provides certain novel compounds of the general formula I, namely, the compounds herein above identified as Compound 1, Compound 2, Compound 3, Compound 23, Compound 25, Compound 26 and Compound 27, and certain novel compounds of the general formula II, namely, the compounds herein above identified as Compound 28, Compound 29, Compound 30 and Compound 31.

Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter.

However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 is a graph showing the anti-inflammatory activity of Compound 1 and Compound 3 administered orally at 50 mg/kg in a model of mouse peritonitis (12 mice per group). The y-axis displays counts of neutrophils per volume unit. The inhibition was statistically evaluated for both compounds by Student's t-test.

Fig. 2 is a graph showing the anti-inflammatory activity of Compound 5 administered orally at 50 mg/kg in a model of mouse peritonitis (12 mice per group). The y-axis displays counts of neutrophils per volume unit. The inhibition was statistically evaluated by Student's t-test. Fig. 3 is a graph showing the anti-inflammatory activity of Compound 1 administered intravenously at 5 mg/kg, and Compound 3 administered intramuscularly at 5 mg/kg in paw edema (11-12 mice per group), 2 and 4 hours after induction with carrageenan. The y-axis represents difference in paw thickness in mm. Data were statistically evaluated by Student's t-test.

Fig. 4 is a graph showing the anti-inflammatory activity of Compound 6 administered orally at 50 mg/kg in a model of delayed type hypersensitivity (DTH) (15 mice per group). The y-axis represents difference in ear thickness in mm. The reduction was statistically evaluated by Student's t-test. Fig. 5 is a graph showing the anti-inflammatory activity of Compound 4 administered orally at 50 mg/kg in a model of colitis induced by TNBS. The y-axis represents colonic damage score. The inhibition was statistically evaluated by Student's t-test.

Fig. 6 is a graph showing the anti-inflammatory activity of Compounds 27 and 30 administered orally at 50 mg/kg in a model of DTH (12 mice per group). The y-axis represents difference in ear thickness in mm. Reduction was statistically evaluated by Student's t-test.

Fig. 7 is a graph showing the anti-inflammatory activity of Compounds 23,

25 and 29 administered orally at 50 mg/kg in a model of DTH (12 mice per group). The y-axis represents difference in ear thickness in mm. Ear swelling was measured

24 hours and 48 hours after induction. The reduction in ear swelling was evaluated by Student's t-test.

Fig. 8 is a graph showing the anti-inflammatory activity of Compounds 27,

28, 29, 30 and 31. Compounds were administered intramuscularly at 10 mg/kg (11- 12 mice per group). Paw swelling was measured 24 hours after induction with carageenan. The y-axis represents difference in paw thickness in mm. The data were statistically evaluated by Student's t-test. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical compositions comprising at least one active ingredient selected from the compounds of the general formula I or II:

wherein: n is an integer from 3 to 5;

R₁ and R₂ each is selected from:

(i) hydrogen;

(ii) C₁-C₆ alkyl or phenyl, optionally substituted by a group containing a basic nitrogen atom or by at least one heterocyclyl group, wherein one of the heterocyclyl groups is a 5-7 membered heterocyclic ring containing one or two heteroatoms, one of them being a basic nitrogen atom, optionally substituted on the additional heteroatom;

(iii) a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; or

(iv) R₁ and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; R₃ and R₄ each is selected from hydrogen, C₁-C₆ alkyl, (C₁-C₆) alkoxy, (C₆- Cio)aryl(Ci-C₆) alkoxy or (C₆-C₁₀) aryloxy; and pharmaceutically acceptable salts thereof.

As defined herein, the term "a group containing a basic nitrogen atom" refers to groups including, but not limited to, an amino group -NR₅R₆, an ammonium group -N⁺(R₅R₆R₇), a hydrazine group -NR₅-NR₆R₇, a hydrazonium group -NR₅-

N⁺(R₆R₇R₈), an ammoniumoxy group -0-N⁺(R₅R₆), an imine group -C=NR₅R₆, an iminium group -C=N⁺(R₅R₆R₇), a guanidine group -NR₅-C(=NH)-NR₆R₇, and a guanidinium group -NR₅-C(=NH)-N⁺(R₆R₇R₈), wherein each of R₅, R₆, R₇ and R₈ is H, or optionally substituted C₁-C₁₀ alkyl or C₆-Ci₀ aryl.

The term "5-7 membered heterocyclic ring containing one or two heteroatoms, one of them being a basic nitrogen atom" refers to both saturated, unsaturated and aromatic rings containing one or two nitrogen atoms such as pyrrolidine, pyrroline, pyrrol, imidazolidine, imidazoline, imidazole, piperidine, dihydropyridine, tetrahydropyridine, pyridine, 1,2-pyrazine, tetrahydropyrimidine, dihydro- pyrimidine, pyrimidine, 1,4-pyrazine, 1,4-tetrahydropyrazine, 1,4-dihydropyrazine, piperazine, diazepine, and the like; or containing one nitrogen atom and one oxygen atom such as oxazolidine, oxazoline, oxazole, morpholino, 1,4-dihydrooxazine, 1,4- oxazine, and the like; or containing one nitrogen atom and one sulfur atom such as thiazolidine, thiazoline, thiaazole, thiomorpholino, 1,4-dihydrothiazine, 1,4-thiazine and the like.

When Ri and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom, or when at least one OfR₁ and R₂ is a 5-7 membered saturated heterocyclic ring as herein above defined, the term "5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms" includes, without limitation, the rings pyrrolidine, imidazolidine, piperidine, piperazine, and the like. The substituent at the additional nitrogen atom may be Ci-C₆ alkyl, optionally substituted by halogen, hydroxy, C_r C₆ alkoxy or C₆-Ci₀ aryl, or C₂-C₇ alkoxycarbonyl. The term "halogen" refers to fluoro, chloro, bromo or iodo. As defined herein, the term "C₁-C₆ alkyl" typically refers to a straight or branched alkyl radical having 1-6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 2,2- dimethylpropyl, and n-hexyl, and the term "C₁-Ci₂ alkyl" refers to said alkyl radicals and further to n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

The term "(C₆-C₁₀) aryl" refers to an aromatic carbocyclic group having 6 to 10 carbon atoms such as phenyl and naphthyl.

The term "(Ci-C₆) alkoxy" refers to the group (Ci-C₆)alkyl-O-, wherein (Ci- C₆) alkyl is as defined above. Examples of alkoxy are methoxy, ethoxy, butoxy, hexoxy, and the like.

The term "(C₆-C ₁₀)aryloxy" refers to the group (C_6-Ci₀)aryl-O-, wherein (C₆- Cio)aryl is as defined above. An example of aryloxy is phenoxy.

The term "(C₆-Ci₀)aryl(Ci-C₆)alkoxy" refers to the aralkoxy group (C₆- Cio)aryl-(Ci-C₆)alkyl-O- wherein (C₆-C₁₀)aryl and (Ci-C₆)alkyl are as defined above. Examples of (C₆-Ci₀)aryl(Ci-C₆)alkoxy are phenylmethoxy, naphthylmethoxy, phenylethoxy, phenylbutoxy, and the like.

The term "heterocyclyl" refers to a radical derived from a mono- or poly- cyclic ring containing one to three heteroatoms selected from the group consisting of N, O and S, with or without unsaturation or aromatic character. The term "heteroaryl" refers to such a mono- or poly-cyclic ring having aromatic character. Non-limiting examples of non-aromatic heterocyclyl include dihydrofuryl, tetrahydrofuryl, dihydrothienyl, pyrrolydinyl, pyrrolynyl, dihydropyridyl, piperidinyl, piperazinyl, morpholino,l,3-dioxanyl, and the like. A poly cyclic ring may have the rings fused, as in quinoline or benzofuran, or unfused as in 4- phenylpyridine. Non-limiting examples of heteroaryl include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl thiazolyl, isothiazolyl, pyridyl, 1,3-benzodioxinyl, pyrazinyl, pyrimidinyl, 1,3,4-triazinyl, 1,2,3-triazinyl, 1,3,5- triazinyl, thiazinyl, quinolinyl, isoquinolinyl, benzofuryl, isobenzofuryl, indolyl, imidazo[l,2-a]pyridyl, pyrido[l,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl and the like. It is to be understood that when a polycyclic heteroaromatic ring is substituted, the substitutions may be in any of the carbocyclic and/or heterocyclic rings.

Any alkyl, aryl, heteroaryl or heterocyclyl radical may be substituted by one or more radicals including, but not limited to, halogen, hydroxy, C]-Ci₀ alkyl, C₂-Ci₀ alkenyl, C₂-Ci₀ alkynyl, C₇-C₁₂ aralkyl, C₆-C₁₀ aryl, C₇-Ci₂ alkaryl, Ci-Ci₀ alkoxy, C₆-C₁₀ aryloxy, Ci-Ci₀ alkylthio, C₆-Ci₀ arylthio, C₆-Ci₀ arylamino, C₃-Ci₀ cycloalkyl, C₃-Ci₀ cycloalkenyl, amino, Ci-Ci₀ alkylamino, di(Ci-Ci₀)-alkylamino, C₂-Cj₂ alkoxyalkyl, C₂-C₁₂ alkylthioalkyl, Ci-Ci₀ alkylsulfmyl, Ci-Ci₀ alkylsulfonyl, C₆-C₁₀ arylsulfonyl, hydroxy(C_rCi₀)alkyl, (C₆-Cio)aryloxy(C_rCi₀)alkyl, (C₁- C₁₀)alkoxycarbonyl, (C₆-C₁₀)aryloxycarbonyl, C₂-C₁₁ alkanoyl, (C₇-C₁ Oaroyl, fluoro(Ci-Cio)alkyl, oxo, nitro, nitro(C_rCi₀)alkyl, cyano, cyano(Ci-Ci₀)alkyl, aminocarbonyl, (Ci-C₁₀)alkylaminocarbonyl, di(Ci-Ci₀)-alkylaminocarbonyl, aminocarbonyl(Ci-Ci₀)alkyl, aminocarbonyl(C₆-C₁₀)aryl, aminosulfonyl, (Q- Ci₀)alkylaminosulfonyl, di(Ci-Ci₀)-alkylaminosulfonyl, amidino, carboxy, sulfo, heterocyclyl, and -(CH₂)_O1-Z-(C₁-C₁₀ alkyl), where m is 1 to 8 and Z is oxygen or sulfur.

It is to be understood that the term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

As contemplated herein, the present invention further encompasses isomers, pharmaceutically acceptable salts and hydrates of the compounds defined by the present invention.

The term "isomer" includes, but is not limited to, optical isomers, structural isomers, conformational isomers, and the like. Thus, the present invention encompasses various optical isomers of the compounds of formula I or II. It will be appreciated by those skilled in the art that the compounds of the present invention contain at least one chiral center. Accordingly, these compounds exist in, and are isolated in, optically active or racemic forms. Unless otherwise indicated, all chiral, diastereomeric and racemic forms of the compounds described in the present invention are encompassed by the present invention. The compounds may also have asymmetric centers. Many geometric isomers of olefins, C- and N- double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereroisomeric form, or mixtures thereof. In one embodiment, the compounds are the pure (R)-isomers. In another embodiment, the compounds are the pure (S)- isomers. In another embodiment, the compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the compounds are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. In addition, this invention further includes hydrates of the compounds described herein. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

The compounds of the present invention can also be in the form of prodrugs. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug of formula I or II in vivo, when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I or II are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide the parent compound of formula I or II. Prodrugs include compounds of formula I and/or II wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, are cleaved to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I or II, and the like.

Some of the compounds of the general formula I and II disclosed herein are novel compounds and are claimed in the present application as such. These compounds include: pyrrolo[2, 1 -bjquinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N-methyl-N-( 1 -methyl- piperidinyl-4)-6-carboxamide (also named l,2,3,9-tetrahydro-N-methyl-N-(l- methylpiperidin-4-yl)-9-oxopyrrolo[2,l-b]quinazoline-6-carboxamide) (Compound 1); pyrrolo[2, 1 -bjquinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N-( 1 -phenylmethyl- pyrrolidinyl-3)-6-carboxamide (also named N-(l-benzylpyrrolidin-3-yl)-l,2,3,9- tetrahydro-9-oxopyrrolo[2,l-b]quinazoline-6-carboxamide) (Compound 2); azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l-methyl- ethyl-piperidinyl-4)-3-carboxamide (also named 6,7,8,9, 10, 12-hexahydro-N-(l- isopropylpiperidin-4-yl)-12-oxoazepino[2,l-b]quinazoline-3-carboxamide) (Compound 3); pyrrolo[2, 1 -bjquinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N[( 1 -phenylmethyl- piperazinyl-4)-phenyl]-6-carboxamide (also named N-(4-(4-benzylpiperazin-l- yl)phenyl)-l,2,3,9-tetrahydro-9-oxopyrrolo[2,l-b]quinazoline-6-carboxamide) (Compound 23); pyrrolo[2,l-bjquinazoline-l,2,3,9-tetrahydro-9-oxo-N-[(3-[(l-methoxy- phenyl)-piperazinyl-4]propyl]-6-carboxamide (also named l,2,3,9-tetrahydro~N-(3- (4-(4-methoxyphenyl)piperazin-l-yl)propyl)-9-oxopyrrolo[2₅l-b]quinazoline-6- carboxamide) (Compound 25); pyrrolo [2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahydro-9~oxo-N- [ 1 -(thieny 1-2)- 1 -( 1 - methyl-piperazinyl-4)ethyl]-6-carboxamide (also named l,2,3,9~tetrahydro-N-(2-(4- methylpiperazin- 1 -yl)-2-(thiophen-2-yl)ethyl)--9-oxopyrrolo[2, 1 ~b]quinazoline-6- carboxamide) (Compound 26); pyrrolo [2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N- [ 1 -methylpiperazinyl- 4)phenyl]-6-carboxamide (also named l,2,3,9-tetrahydro-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-9-oxopyrrolo[2, 1 -b]quinazoline-6-carboxamide) (Compound 27); [3-(3-phenylmethyloxy)phenylidene]pyrrolo[2, 1 -b] quinazoline- 1 ,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (also named (E)-3-(3- (benzyloxy)benzylidene)- 1 ,2,3,3 a,4,9-hexahy dro-N-( 1 -methylpiperidin-4-yl)-9- oxopyrrolo[2,l-b]quinazoline-6-carboxamide) (Compound 28);

[3 -(3 -pheny lmethy loxy-4-methoxy)phenylidene]pyrrolo [2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N- [3 [( 1 -methoxyphenyl)-piperazinyl-4]propyl]-6- carboxamide (also named (E)-3-(3-(benzyloxy)-4-methoxybenzylidene)- 1 ,2,3,3 a,4,9-hexahydro-N-(3 -(4-(4-methoxyphenyl)piperazin- 1 -yl)propyl)-9- oxopyrrolo[2,l-b]quinazoline-6-carboxamide) (Compound 29);

[3 -(3 -pheny lmethyloxy-4-methoxy)phenylidene]pyrrolo [2, 1 -b] quinazoline- l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (also named (E)-3-(3-(benzyloxy)-4-methoxybenzylidene)-l,2,3,3a,4,9-hexahydro-N-(l-methyl- piperidin-4-yl)-9-oxopyrrolo[2, l-b]quinazoline-6-carboxamide) (Compound 30); and 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N- (l-methyl-piperidinyl-4)-6-carboxamide (also named (E)-3-(4-cyanobenzylidene) - l,2,3,3a,4,9-hexahydro-N-(l-methylρiρeridin-4-yl)-9-oxopyrrolo[2,l-b] quinazoline-6-carboxamide) (Compound 31).

The synthesis of the eleven novel compounds is described herein below in Examples 2-12.

According to certain preferred embodiments, the present invention provides compositions comprising one or more of the following compounds of formula I: pyπOlo[2,l-b]quinazoline-l,2₅3,9-tetrahydro-9-oxo-N-methyl-N-(l-methyl- piperidinyl-4)-6-carboxamide (Compound 1); pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-( 1 -phenylmethyl-pyrrolidinyl-3)-6-carboxamide (Compound 2); azepino[2, l-b]quinazorine-6,7_s8,9, 1 O₃12-hexahydro- 12-oxo-N-(l-methylethyl- piperidinyl-4)-3-carboxamide (Compound 3); 7H-pyrido[2,l-b]quinazoline- 6,8,9, 11-tetrahydro- 1 l-oxo-N-[3-(l-methyl-piperazinyl-4)propyl]-3-carboxamide (also named 7,8,9,11 -tetrahydro-N-(3 -(4-methylpiρerazin- 1 -yl)propyl)- 11 -oxo-6H- pyrido[2,l-b]quinazoline-3-carboxamide) (Compound 4); azepino[2,l- b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l-phenylmethyl-piperidinyl-4)- 3-carboxamide (also named N-(l-benzylpiperidin-4-yl)-6,7,8,9,10,12-hexahydro- 12-oxoazepino[2,l-b]qumazoline-3-carboxamide) (Compound 5); and azepino[2, 1 -b]quinazoline-6,7,8,9, 10, 12-hexahydro- 12-oxo-N- [3 -(dimethylamino) propyl]-3-carboxamide (also named N-(3 -(dimethylamino) propyl)-6,7,8,9, 10, 12- hexahydro- 12-oxoazepino[2, l-b]quinazoline-3-carboxamide) (Compound 6); pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N[(l-phenylmethyl-piperazinyl- 4)-phenyl]-6-carboxamide] (Compound 23); pyiτolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-[(3-[(l-methoxyphenyl)-piperazinyl-4]proρyl]-6-carboxamide (Compound 25); pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[l-(thienyl- 2)-l-(l-methyl-piperazinyl-4)ethyl]-6-carboxamide (Compound 26); and pyrrolo[2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N-[ 1 -methyl-piperazinyl-4) phenyl] -6-carboxamide (Compound 27);

According to further preferred embodiments, the present invention provides compositions comprising one or more of the following compounds of formula II: [3 -(3 -pheny lmethyloxy)phenylidene]pyrrolo [2, 1 -b] quinazoline- 1,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 28); [3- (3 -pheny lmethyloxy-4-methoxy)phenylidene]pyrrolo [2, 1 -b] quinazoline- 1,2,3,9- tetrahydro-9-oxo-N-[3[(l-methoxyphenyl)-piperazinyl-4]propyl]-6-carboxamide (Compound 29); [3-(3-phenylmethyloxy-4-methoxy)phenylidene]pyrrolo[2, 1- b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 30); and 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 31).

In accordance with the present invention and as used herein when referring to the biological activity of the compounds of general formula I or II, the following terms are defined with the following meanings, unless explicitly stated otherwise.

The term "GAG" refers to glycosaminoglycans, including heparan sulfate (HS-GAG), heparin, chondroitin sulfate, dermatan sulfate and keratan sulfate. It includes the GAG chains of proteoglycans such as heparan sulfate proteoglycan or chondroitin sulfate proteoglycan. It includes fragments of GAGs produced chemically or enzymatically as well as derivatives of GAG, which may be produced by chemical or enzymatic means as known in the art. The GAG may be free or attached to a linker, support, cell or a protein. GAGs may be crude or purified from organs, tissues or cells.

The term "HS-GAG" refers to heparan sulfate glycosaminoglycan. It includes fragments of heparan sulfate such as those that may be produced chemically, enzymatically or during purification. It includes the HS-GAG chains of proteoglycans such as heparan sulfate proteoglycans. HS-GAG may be free or attached to a linker, support, cell or protein, or otherwise chemically or enzymatically modified. HS-GAGs may be crude or purified from organs, tissues or cells.

"HS-PG" refers to heparan sulfate proteoglycans.

"Heparin" is polysulfated polysaccharide, with no protein associated with it. As used herein, heparin refers to heparin prepared from different organs or species such as from porcine intestinal mucosa. The invention encompasses heparins with various molecular weights including low molecular weight heparins (LMWHs), such as commercially available Fraxiparin, and other heparin derivatives, prepared or modified by chemical or enzymatic reactions as known in the art.

The term "inhibitor compound" refers to a small organic compound that inhibits, modulates or reverses the function of a GAG. For instance, the inhibitor compound may inhibit interaction (binding) between two molecules: (1) a GAG, exemplified by, but not restricted to, heparin or HS-GAG, and (2) L-selectin.

The terms "inflammation", "inflammatory diseases", "inflammatory condition" or "inflammatory process" are meant as physiological or pathological conditions, which are accompanied by an inflammatory response. Such conditions include, but are not limited to, sepsis, ischemia-reperfusion injury, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cardiomyopathic disease, colitis, infectious meningitis, encephalitis, acute respiratory distress syndrome, organ/tissue transplant rejection (such as skin, kidney, heart, lung, liver, bone marrow, cornea, pancreas, small bowel), dermatitis, stroke, traumatic brain injury, psoriasis and lupus.

The term "treatment" or "treating" is intended to include the administration of the compound of the invention to a subject for purposes which may include prophylaxis, amelioration, prevention or cure of disorders mediated by cell adhesion or cell migration events, specifically selectin adhesion events, more specifically L- selectin and P-selectin-mediated adhesion events. Such treatment need not necessarily completely ameliorate the inflammatory response or other responses related to the specific disorder. Further, such treatment may be used as sole treatment or in conjunction with other traditional treatments for reducing the deleterious effects of the disease, disorder or condition as known to those of skill in the art.

The methods of the invention may be provided as a "preventive" treatment before detection of, for example, an inflammatory state, so as to prevent the disorder from developing in patients at high risk for the same, such as, for example, transplant patients. As used through this specification and the appended claims, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes mixtures of such compounds, reference to "a P-selectin", or "an L-selectin" includes reference to respective mixtures of such molecules, reference to "the formulation" or "the method" includes one or more formulations, methods and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.

The present invention relates to pharmaceutical compositions comprising as an active ingredient at least one compound of the general formula I and/or II having anti-inflammatory activity. As described in Example 15 and Example 17, compounds of the general formula I and compounds of the general formula II inhibited leukocyte infiltration in animal models of peritoneal inflammation (Fig. 1 and Fig. 2) and delayed-type hypersensitivity (DTH) (Fig. 4, Fig. 6 and Fig. 7). In the peritonitis model, neutrophils are counted in peritoneum following an inflammatory event (Xie et al., 2000). As shown in Figs. 1 and 2, Compound 1, Compound 3 and Compound 5 significantly inhibited neutrophil infiltration. It is well known that neutrophil migration and infiltration in vivo is a hallmark of many inflammatory disorders. The ability of the inhibitor compounds of the invention to inhibit neutrophil infiltration in vivo indicates, therefore, the potential therapeutic applications of these compounds for treatment of these disorders. The anti- inflammatory activity of Compounds 27, 28, 29, 30 and 31 is described in Example 16 and Fig. 8. Anti-inflammatory activity of Compounds 23, 25, 27, 29 and 30 is also described in Example 17 and Figs. 6 and 7. DTH is associated mostly with T cell infiltration (Lange-Asschenfeldt et al., 2002). An example of inhibition of DTH by a compound of formula I of the invention is described in Example 17 and shown in Fig. 4, and inhibition of DTH by compounds of formula II is described in Example 17 and shown in Figs. 6 and 7. Compounds of general formula I inhibited also carrageenan induced paw edema, a general model of inflammation (Fig. 3), as well as compounds of formula II (Fig. 8). Carrageenan is a family of linear sulphated polysaccharides extracted from red seaweeds).

The present invention relates to pharmaceutical compositions comprising as an active ingredient at least one compound of the general formula I or II capable of inhibiting the interactions of glycosaminoglycans (GAGs) with cell adhesion molecules such as cytokines, chemokines and selectins. As described in Example 13, compounds of the general formula I and II inhibited interactions between HS- GAG and L-selectin and between HS-GAG and MCP-3.

The biological activity of the compounds of the present invention may be assayed in a variety of systems. For example, a compound can be immobilized on a solid surface and adhesion of cells expressing HS-GAGs can be measured. The test compounds can also be tested for the ability to competitively inhibit binding between HS-GAGs and other proteins binding to HS-GAGs such as other cell adhesion molecules or cytokines.

Compounds of the present invention having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties.

For diagnostic purposes, a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal. Thus, the compounds of the present invention may be modified in a variety of ways for a variety of end purposes while still retaining biological activity. In addition, various reactive sites may be introduced in the molecules for linking to particles, solid substrates, macromolecules, or the like.

Labeled compounds can be used in a variety of in vivo or in vitro applications. A wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium- 111), fluorescent agents (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.

Those of ordinary skill in the art will know of other suitable labels for binding to the compounds, or will be able to ascertain such using routine experimentation. The binding of these labels is achieved using standard techniques common to those of ordinary skill in the art.

For in vivo diagnostic imaging to identify, for example, sites of inflammation, radioisotopes are typically used in accordance with well-known techniques. The present invention encompasses also pharmaceutically acceptable salts of the compounds of the present invention. Pharmaceutically acceptable salts can be prepared by reaction with inorganic bases, for example, sodium hydroxide or inorganic/organic acids such as hydrochloric acid, citric acids and the like. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, or zinc salts and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It is to be understood that, as used herein, references to the compounds according to formula I and II of the present invention are meant to also include the pharmaceutically acceptable salts thereof. The pharmaceutical compositions of the present invention can be formulated for administration by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise as an active ingredient at least one compound of formula I and/or II as described herein above, further comprising an excipient or a carrier.

During the preparation of the pharmaceutical compositions according to the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the active ingredient to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active ingredient is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propyl- hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about 500 mg of a compound of formula I or II. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active ingredient is effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings; such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compositions of the present invention may be incorporated, for administration orally or by injection, include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insulation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. No. 5,023,252 incorporated herein by reference in its entirety as if fully set forth herein. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Direct or indirect placement techniques may be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. No. 5,011,472 incorporated herein by reference in its entirety as if fully set forth herein. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra- arterial infusion of hypertonic solutions, which can transiently open the blood-brain barrier. The compounds of general formula I and the compounds of formula II inhibit cell-matrix and cell-cell interaction, thus inhibiting a cascade of events that lead to the development of certain diseases and disorders.

Thus, according to some aspects, the present invention provides a method for the treatment or prevention of diseases and disorders related to cell adhesion and cell migration mediated by HS-GAG interactions, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the general formula I and/or II.

Anti-cell adhesion and anti-cell migration therapy has proven to be highly effective in the treatment of a number of diseases, disorders and conditions including inflammatory processes, autoimmune processes, cancer and tumor metastasis, and platelet-mediated pathologies.

Reperfusion injury is a major problem in clinical cardiology. Therapeutic agents that reduce leukocyte adherence in ischemic myocardium can significantly enhance the therapeutic efficacy of thrombolytic agents. Thrombolytic therapy with agents such as tissue plasminogen activator or streptokinase can relieve coronary artery obstruction in many patients with severe myocardial ischemia prior to irreversible myocardial cell death. However, many such patients still suffer myocardial necrosis despite restoration of blood flow. This "reperfusion injury" is known to be associated with adherence of leukocytes to vascular endothelium in the ischemic zone.

Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sharply delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon. Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.

Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways. The stimuli cause release of various mediators of inflammation that recruit basophils, eosinophils and neutrophils, which cause inflammatory injury.

Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints.

Atherosclerosis is a disease of arteries. The basic lesion, the atheroma, consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap. Atheromas compromise arterial blood flow and weaken affected arteries. Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.

The pharmaceutical compositions of the present invention can be further used in the treatment of organ or graft rejection. Over recent years there has been a considerable improvement in the efficiency of surgical techniques for transplanting tissues and organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the principal outstanding problem is the lack of satisfactory agents for inducing immnunotolerance in the recipient to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into a host, the host immune system is likely to mount an immune response to foreign antigens in the transplant

(host-versus-graft disease) leading to destruction of the transplanted tissue. CD8⁺ cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues.

A related use of the pharmaceutical compositions according to the present invention is in modulating the immune response involved in "graft versus host" disease (GVHD). GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic recipient. In this situation, the donor's immunocompetent cells may attack tissues in the recipient.

A further use of the pharmaceutical compositions according to the present invention is for the treatment of cancer. The term "cancer" as used herein refers to various cancer-associated conditions including both primary tumors and metastasis, tumor growth, and angiogenesis. For certain cancers to spread throughout a patient's body, a process of cell-cell adhesion, or metastasis, must take place. Specifically, cancer cells must migrate from their site of origin, the primary tumor, and gain access to a blood vessel to facilitate colonization at distant sites. A critical aspect of this process is adhesion of cancer cells, a step prior to migrating into surrounding tissue. This process can be interrupted by the administration of compounds of the invention, which generally aid in blocking cell-cell adhesion. The cancer to be treated may be a solid tumor cancer such as, but not limited to, breast, brain, lung, ovary, pancreas, kidney, liver, prostate, and esophagus cancer, or a non-solid cancer such as a leukemia, e.g. acute myeloid leukemia (AML) and adult T-cell leukemia (ATL), which involve extravasation of leukemic cells leading to organ infiltration.

Also embodied in the present invention are methods useful for the treatment and prevention of diseases and disorders associated with angiogenesis. The term "angiogenesis" as used herein includes conditions involving abnormal neovascularization, such as tumor angiogenesis, and in ophthalmologic disorders such as neovascular glaucoma, diabetic retinopathy and macular degeneration, particularly age-related macular degeneration, reperfusion of gastric ulcer, and also for contraception or for inducing abortion at early stages of pregnancy. A further use of the pharmaceutical compositions according to the present invention is in treating multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that is thought to be the result of a specific autoimmune reaction in which certain leukocytes initiate the destruction of myelin, the insulating sheath covering nerve fibers. It is to be understood that while the compounds according to formula I and formula II of the present invention were selected for their capacity to inhibit binding to HS-GAGs and inhibit leukocyte infiltration in vivo, and that this property contributes to their medical activity, it cannot, however, be excluded that the compounds are also exerting their favorable medical effects, either in parallel or in tandem, through additional mechanisms of action. Thus, the skilled practitioner of this art will appreciate that one aspect of the present invention is the description of novel pharmaceutical compositions, and that Applicants intend not to be bound by a particular mechanism of action that may account for their prophylactic or therapeutic effects. The principles of the invention, providing compounds described here for the first time with regard to their pharmaceutical uses and some novel compounds, all these compounds being capable of inhibiting GAG-L-selectin interactions, their pharmaceutical compositions and uses thereof according to the present invention, may be better understood with reference to the following non-limiting examples. EXAMPLES

The structural formulas of the Compounds 1-6, 23, 25-31 are presented in the Appendix just before the claims.

EXAMPLE 1. General procedure for synthesis of Compounds of formula I and formula II

The synthesis of the compounds of formula I and compounds of formula II are schematically presented in Scheme I.

The starting acids of the formula A have been synthesized as described in Hermecz et al. (Hermecz et al., 1987).

To the solution of the acid A (2 mmol) in DMF (5 ml), 2.4 mmole of N, N'- carbonyldiimidazole (CDI) were added dropwise and the mixture was stirred for one hour at 50⁰C. Then, 2.8 mmol of amine were added to the reaction mixture and the resulting solution was treated in ultrasonic bath with heating at 50⁰C and stirring for 3 hours. The reaction mixture was let to cool to room temperature and some water was added. The resulted oil was solidified with isopropyl alcohol and washed with acetonitrile. The yields of the compounds of formula I and II are in the range of 70-90 %.

EXAMPLE 2. Synthesis of pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9- oxo-N-methyl-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 1)

Synthesis of the title compound was performed as follows: to a solution of the acid A (n=3) 0.45g (2 mmol) in DMF (5 ml), 2.4 mmol of CDI were added drop wise and the mixture was stirred for one hour at 5O⁰C. Then, 0.33 g (2.8 mmol) of l-methyl-4-methylamino-piperidine were added to the reaction mixture and the resulting solution was heated on a boiling water-bath for 3 hours. The reaction mixture was let to cool to room temperature, water was added and extracted with CH₂Cl_2. Organic layer was washed with NaHCO₃ solution and then with water. The solvent was evaporated in vacuum and the residue was dried at 70 ⁰C to yield the target compound (65%). ¹H NMR (DMSO-d₆) δ (ppm): 1.60 (m, 3H), 1.80 (m, 2H)₅ 2.00 (m, 2H), 2.20 (m, 3H)₅ 2.70 (m, 3H)₅ 3.10 (m, 2H)₅ 4.05 (m, 2H)₅ 4.25 (m, IH), 7.40 (m, 2H)₅ 8.15 (m, IH). Mass spectra (TOF[time-of-flight]): m/z 341 (M+H)⁺.

EXAMPLE 3. Synthesis of pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo- N-(l-phenyImethyI-pyrroIidinyl-3)-6-carboxamide (Compound 2)

The synthesis of the title compound was performed as follows: to a solution of the acid A (n=3) 0.45 g (2 mmol) in DMF (5 ml), 2.4 mmol of CDI were added dropwise and the mixture was stirred for one hour at 5O⁰C. Then, 0.4 g (2.8 mmol) of l-phenylmethyl-3 -amino-pyrrolidine was added to the reaction mixture and the resulting solution was treated in ultrasonic bath with heating at 5O⁰C and stirring for 3 hours. The reaction mixture was let to cool to room temperature and some water was added. The resulted oil was solidified with isopropyl alcohol and washed with acetonitrile. The title compound was obtained in 82% yield. ¹H NMR (DMSO-d₆) δ (ppm): 1.80 (m, IH), 2.20 (m, 3H), 2.60 (m, IH),

2.80 (m, 2H)₅3.10 (m, 2H), 3.60 (s, 2H), 4.10 (m, 2H)₅ 4.40 (m, IH), 5.80 (s, IH)₅ 7.25 (m, 5H), 7.80 (m, IH), 8.20 (m, IH), 8.80 (d, IH). Mass spectra (TOF): m/z 389 (M+H)⁺.

EXAMPLE 4. Synthesis of azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro- 12-oxo-N-(l-methylethyI-piperidinyI-4)-3-carboxamide (Compound 3)

The synthesis of the title compound was performed as follows: to a solution of the acid A (n=5) 0.5g (2 mmol) in DMF (5 ml), 2.4 mmol of CDI were added dropwise and the mixture was stirred for one hour at 5O⁰C. Then, 0.5 g (2.8 mmol) of l-methylethyl-4-amino-piperidine was added to the reaction mixture and the resulting solution was heated on a boiling water-bath for 3 hours. The reaction mixture was let to cool to room temperature and some water was added. The precipitate formed was washed with NaHCO₃ solution, then with water and with the mixture water: isopropylalcohol 1:1. After drying at 7O⁰C₅ the title compound was obtained in 75% yield. ¹H NMR (DMSO-d₆) δ (ppm): 0.90 (d, 6H), 1.50 (m, 2H), 1.70 (m, 8H), 2.20 (t, 2H), 2.60 (m, IH), 2.70 (m, 2H), 3.10 (m, 2H), 3.70 (m, IH), 4.30 (m, 2H), 7.85 (d, IH), 8.04 (s, IH), 8.15 (d, IH), 8.50 (d, IH). Mass spectra(TOF): m/z 383 (M+H)⁺.

EXAMPLE 5. Synthesis of pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo- N[(l-phenylmethyl-piperazinyl-4)-phenyl]-6-carboxamide (Compound 23)

The synthesis of the title compound was performed as described in Example 2 above, starting from 0.45 g (2 mmol) of pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-6-carboxylic acid and 0.55 g of [1- phenylmethyl-piperazinyl-4)- phenyl] amine in the presence of CDI. Yield 72%

¹H NMR (DMSO-d₆) δ (ppm): 2.15 (m, 2H), 3.05-3.50 (m, 12H), 4.00 (m, 2H), 6.90-8.15 (m, 12H), 10.40 (s,lH).

MS (TOF) m/z (M+H) 480.0.

EXAMPLE 6. Synthesis of pyrroIo[2,l-b]quinazoIine-l,2,3,9-tetrahydro-9-oxo- N-[(3-[(l-methoxyphenyl)-piperazinyl-4]propyl]-6-carboxamide (Compound 25)

The synthesis of the title compound was performed as described in Example 2 above, starting from 0.45 g (2 mmol) of pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-6-carboxylic acid and 0.7 g (2.7 mmol) of 3-[(4- methoxyphenyl)- piperazin-l-yl]propyl] amine in the presence of CDI. Yield 65%

¹H NMR (DMSO-d₆) δ (ppm): 1.70 (m, 2H), 2.15 (m, 2H), 2.25-3.30 (m, 14H), 3.65 (m, 3H), 4.05 (m, 2H), 6.80 (m, 4H), 7.85-8.15 (M,3H), 8.80 (s,lH). MS (TOF) m/z (M+H) 462.4.

EXAMPLE 7. Synthesis of pyrroIo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo- N-[l-(thienyl-2)-l-(l-methyI-piperazinyI-4)ethyl]-6-carboxamide (Compound 26) The synthesis of the title compound was performed as described in Example 2 above, starting from 0.45 g (2 mmol) of pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-6-carboxylic acid and 0.6 g (2.7 mmol) l-(thienyl-2)-l-(l-methyl- piperazinyl-4)ethylamine in the presence of CDI. Yield 60%. ¹H NMR (DMSO-d₆) δ (ppm): 2.00-2.45 (m, 12H), 3.00 (m, 2H), 3.55 (m,

2H), 3.80 (m, IH), 4.05 (m, 2H), 4.20. MS (TOF) m/z (M+H) 438.0.

EXAMPLE 8. Synthesis of pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo- N-[l-methyl-piperazinyl-4)phenyl]-6-carboxamide (Compound 27)

The synthesis of the title compound was performed as described in Example 2 above, starting from 0.45 g (2 mmol) of pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-6-carboxylic acid and 0.3 g (2 mmol) of l-methyl-piperidinyl-4- amine in the presence of CDI. Yield 60%. ¹H NMR (DMSO- d₆) δ (ppm): 2.15-2.45 (m, 9H), 3.05 (m, 6H), 4.02 (m,

2H), 6.9-8.5 (m, 7H), 10.30 (s, IH).

MS (TOF) m/z (M+H) 404.4.

EXAMPLE 9. Synthesis of [3-(3-phenylmethyIoxy)phenylidene]pyrrolo[2,l- b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6- carboxamide (Compound 28)

The synthesis of the title compound was performed as described in Example

2 above, starting from 0.82 g (2 mmol) of [3-(3-phenylmethyloxy) phenylidene]pyrrolo[2,l- b]quinazoline-l,2,3,9-tetrahydro-9-oxo-6-carboxylic acid and 0.3 g (2 mmol) of l-methyl-piperidinyl-4-amine in the presence of CDI. Yield

75%.

¹H NMR (DMSO-d₆) δ (ppm): 1.60 (m, 2H), 1.75 (m, 2H), 1.90 (m, 2H), 2.20 (m, 3H), 2.70-3.20 (m, 5H), 4.20 (m, 2H), 5.20 (m, 2H), 6.80-8.20 (m, 13H), 8.15 (s, IH). MS (TOF) m/z (M+H) 521.5. EXAMPLE 10. Synthesis of [3-(3-phenyImethyIoχy-4-methoxy)phenylidene] pyrroIo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[3-[(l-methoxyphenyI)- piperazinyI-4] propyl] -6-carboxamide (Compound 29)

Synthesis of the title compound was performed as follows: to a solution of [3-(3- phenylmethyloxy-4-methoxy)phenylidene]pyriOlo[2,l-b]quinazoline-l₅2₅3,9-tetra hydro-9-oxo-6-carboxylic acid 0.9 g (2 mmol) in DMF (5 ml), 2.4 mmol of CDI were added and the reaction mixture was stirred for 1 hour at 6O⁰C. Then, 0.7 g (2.8 mmol) of 3-[(4-methoxyphenyl)-piperazin-l-yl]propyl amine were added and the reaction mixture was heated on a boiling water-bath for 3 hours. After cooling, the solution was poured into water and extracted with CH₂Cl₂. Organic layer was washed with NaHCO₃ solution and then with water. The solvent was evaporated in vacuum and the residue was dried at 70⁰C to yield the target compound (65%).

¹H NMR (DMSO-d₆) δ (ppm): 1.75-3.20 (m, 14H), 3.35 (s, 2H), 3.65 (s, 3H), 3.85 (s, 3H), 4.20 (s, 2H), 5.20 (s, 2H), 6.75-8.25 (m, 16H), 8.60 (s, IH). Mass Spectra TOF m/z [M+H)⁺ 686.3.

EXAMPLE 11. Synthesis of [3-(3-phenylmethyIoxy-4-methoxy) phenylidene] pyrrolo[2,l-b]qumazoline-l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)- 6-carboxamide (Compound 30) The synthesis of the title compound was performed as described in Example

10 above, starting from 0.9 g (2 mmol) of [3-(3-phenylmethyloxy-4- methoxy)phenylidene]pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-6- carboxylic and 0.3 g (2 mmol) of l-methyl-piperidinyl-4-amine in the presence of CDI. Yield 68%. ¹H NMR (DMSO-d₆) δ (ppm): 2.20 (m, 2H), 2.50 (m, 2H), 3.20-4.80 (m,

14H), 5.50 (s, 2H), 7.20-8.20 (m, 12H), 8.50 (s, IH). MS (TOF) m/z (M+H) 551.2. EXAMPLE 12. Synthesis of 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoIine- l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 31)

The synthesis of the title compound was performed as described in the Example 10 above, starting from 0.86 g of 3-(4-cyanophenylidene)pyrrolo[2,l- b]quinazoline-l,2,3,9-tetrahydro-9-oxo- 6-carboxylic acid and 0.3 g (2 mmol) of 1- methyl-piperidinyl-4-amine in the presence of CDI. Yield 70%.

¹H NMR (DMSO-d₆) δ (ppm): 1.60-1.80 (m, 4H), 2.15 (m, 3H), 2.70 (m, 2H), 3.00-3.35 (m, 4H), 3.75 (m, IH), 4.20 (m, 2H), 7.70-8.20 (m, 8H), 8.45 (s, IH).

MS (TOF) m/z (M+H) 440.4.

EXAMPLE 13. In vitro assay for determining inhibition of binding to HS- GAGs by compounds of the formula I. An in vitro assay was used to assess the ability of test compounds according to formula I and II to inhibit the interaction of L-selectin with HS-GAGs. The assay was suitable for determining the concentration required for 50% inhibition (IC-50) for each specific compound. In the assay, the HS-GAG used was heparin. Thus, porcine intestinal mucosa heparin conjugated to bovine serum albumin (Heparin- BSA; Sigma Cat. No. H0403) at 5 mg/ml in phosphate-buffered saline (PBS; pH 6.5) was added to a 96-well polystyrene ELISA plate (NUNC Cat. No. 442404; 0.1 ml per well), and incubated over night at 4⁰C. Following the incubation, the plate was washed thoroughly, by immersion, with de-ionized water and PBS (pH 6.5). The ELISA plate was then blocked with BSA (ICN Cat. No.160069, 3%, 200 μl per well) for 1 hour at room temperature. Following blocking, the plate was washed with de-ionized water, and then with PBS (pH 6.5) containing Tween 20 (Sigma Cat. No. P- 1379, 0.05%). The test compound (synthesized or purchased from suppliers of chemical compounds such as ChemDiv Labs., San Diego, CA), was dissolved in DMSO, diluted in PBS and added to the wells at various concentrations in the range of 0.01 to 300 μM. Recombinant Human L-Selectin/IgG (Research and Development Systems Cat. No.728-LS) dissolved in PBS supplemented with BSA (0.1%) and calcium chloride (1 mM) was added to the ELISA plate (100 μl per well) and incubated for 60 minutes at room temperature with shaking. Following incubation, the plate was washed with de-ionized water and three times with PBS (pH 6.5) containing Tween 20. Anti-Human IgG peroxidase conjugate (1 :5000; Sigma Product No. A8667) diluted in PBS supplemented with BSA (0.1%) and calcium chloride (1 mM) was added to the ELISA plate (100 μl per well) and incubated for 30 minutes at room temperature with shaking. The plate was then washed with de-ionized water and three times with PBS (pH 6.5) containing Tween 20. The peroxidase substrate chromogen tetramethyl benzidine (TMB; Dako Cat. No. S1599) was added (100 μl per well) to the ELISA plate and incubated at room temperature. After 15 minutes, ELISA Stop Solution (hydrochloric acid IN, sulfuric acid 3N) was added (200 μl per well) to stop the peroxidase catalyzed colorimetric reaction. The optical density (OD) of the samples was measured at 450 nm using an ELISA plate reader (Dynatech MR5000). Data were analyzed with Graphpad Prism software and IC-50 values were established.

A similar in vitro assay was used to assess the ability of test compounds according to formula I and II to inhibit the interactions of chemokine MCP-3 with HS-GAGs, i.e., heparin. The assay was suitable for determining the concentration required for 50% inhibition (IC-50) for each specific compound. MCP-3 (R&D Systems) was used instead of L-Selectin/IgG reagent, and MCP-3 bound to heparin was detected with a biotinylated polyclonal antibody to MCP-3, followed by detection with streptavidin conjugated horseradish peroxidase, and color development as described above. It was established that compounds of formula I and compounds of formula II had inhibitory activity in the above assays. For example, Compound 6 inhibited 39% of L-selectin binding at 100 μM. In MCP-3 binding assays, Compound 1 inhibited 16% MCP-3 binding at 37.5 μM and Compound 5 inhibited 19% of MCP-3 binding at 37.5 μM. Compound 6 inhibited 39% of MCP-3 binding at 100 μM and 16% at 37.5 μM. Compound 23 inhibited 38% of MCP-3 binding at 30 μM and 45% at 100 μM. Compound 25 inhibited 34% of MCP-3 binding at 30 μM and 37% at 100 μM. Compound 26 inhibited 24% of L-selectin binding at 100 μM. Compound 27 inhibited 44% of L-selectin binding at 100 μM. Compound 27 also inhibited 76% of MCP-3 binding and had an IC-50 of 88 μM. Compound 28 inhibited 40% of MCP-3 binding at 16 μM and 36% at 50 μM. Compound 29 inhibited 26% of L-selectin binding at 30 μM. Compound 30 inhibited 23% of L- selectin binding at 100 μM. Compound 31 inhibited 37% of L-selectin binding at 30 μM and 43% at 100 μM.

EXAMPLE 14. Pharmaceutical compositions

The pharmaceutical compositions of the present invention are illustrated by the following formulation examples:

(i) Formulation 1

Hard gelatin capsules containing the following ingredients are prepared:

The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.

(H) Formulation 2

A tablet formula is prepared using the ingredients below:

The components are blended and compressed to form tablets, each weighing 240 mg. (Hi) Formulation 3

A dry powder inhaler formulation is prepared containing the following components:

The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling-appliance.

(iv) Formulation 4

Tablets, each containing 30 mg of active ingredient, are prepared as follows:

The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 5O⁰C to 6O⁰C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.

(v) Formulation 5

Capsules, each containing 40 mg of the active ingredient, are made as follows:

The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

(vi) Formulation 6

Suppositories, each containing 25 mg of active ingredient, are made as follows:

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

(vii) Formulation 7

Suspensions, each containing 50 mg of an active ingredient per 5.0 ml dose, are made as follows:

The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

(viii) Formulation 8

Capsules, each containing 15 mg of an active ingredient, are made as follows:

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.

(ix) Formulation 9

An intravenous formulation is prepared as follows:

(x) Formulation 10

A topical formulation is prepared as follows:

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solidified.

EXAMPLE 15. A model of leukocyte and neutrophil infiltration into mouse peritoneum

The compound thioglycollate is known to elicit peritonitis in a mouse model. BALB/c mice (Velaz, Prague; 6-week old, ~ 20 g weight, 12-15 mice/group) received orally a test compound in 0.5% methylcellulose 1 hour before administration of thioglycollate (Sigma). Control groups received vehicle (0.5% methylcellulose in water) and sham controls received no thioglycollate. Mice were injected intraperitoneally with 1 ml of 3% thioglycollate broth (Xie et al., 2000). Mice were sacrificed after 3 hours, and the peritoneal cavities were lavaged with 5 ml of ice-cold saline containing 2 mM EDTA to prevent clotting. After red blood cell lysis, leukocytes were counted in a hemocytometer. Neutrophils were counted after staining with Tϋrck's reagent (Merck, Darmstadt, Germany). Data was expressed as mean ± SEM, and statistical analysis was performed by Student t test. A value of p<0.05 was taken to denote statistical significance. Thioglycollate administration induced approximately 3 -fold increase in neutrophil accumulation in the peritoneal cavity. Fig. 1 shows the anti-inflammatory properties of Compound 1 and Compound 3 administered orally at 50 mg/kg in a model of mouse peritonitis. The inhibition was 38% for Compound 1 and 37% for Compound 3. The inhibition was statistically significant for both compounds, as determined by Student's t-test, with p>0.01. Fig. 2 shows the anti-inflammatory properties of Compound 5 administered orally at 50 mg/kg in the same peritonitis model. The inhibition was 33% and it was statistically significant as determined by Student's t-test with p>0.001. Weak inhibition of about 10% was observed in the peritonitis model with Compound 2 and Compound 6 administered orally at 50 mg/kg. EXAMPLE 16. Carrageenan-induced paw edema

Acute edema was induced in the left hind paw of BALB/c mice (12 mice/group) by injecting 0.02 ml of freshly prepared solution of 2% carrageenan (Sigma) after 60 min of test compound administration (Torres et al., 2000). The right paw received 0.02 ml of saline, which served as a control. Carrageenan was injected under the plantar region of right hind paw and the paw thickness was measured at 2, 4 and 24 hours after carrageenan challenge using a Mitutoyo engineer's micrometer expressed as the difference between right and left pad as mean ± SEM. As shown in Fig. 3, intravenous administration of Compound 1 at 5 mg/kg reduced paw edema by 17% after 2 hours and by 19% after 4 hours and the reduction was statistically significant as determined by Student's t-test with p>0.01 in both cases. Intramuscular administration of Compound 3 at 5 mg/kg reduced paw edema by 19% after 2 hours and by 32.5% after 4 hours and the reduction was statistically significant as determined by Student's t-test with p>0.01 and p>0.001, respectively (Fig. 3). In the same experimental design, Compound 5 administered orally at 100 mg/kg inhibited paw edema by 43% and the reduction was statistically significant as determined by Student's t-test with p>0.001 (results are not shown). Weak inhibition of about 9% was observed in the paw edema model with Compound 2 administered orally at 50 mg/kg.

The anti-inflammatory activity of Compounds 27, 28, 29, 30 and 31 is shown in Fig. 8. Compounds were administered intramuscularly at 10 mg/kg. Paw swelling was measured 24 hours after induction with carageenan and data evaluated by Student's t test. Compound 27 inhibited swelling by 31.1% (ρ>0.001); Compound 28 by 20.2% (p>0.05); Compound 29 by 22.1% (p>0.01); Compound 30 by 30.4% and Compound 31 by 30% (p>0.001).

EXAMPLE 17. Delayed-type hypersensitivity (DTH)

BALB/c mice (Velaz, Prague, Czech Republic; 8 week-old; 15 animals per group) were sensitized by topical application of a 2% oxazolone (4- ethoxymethylene-2-phenyl-2-oxazoline-5-one; Sigma, St Louis, MO) solution in acetone/olive oil (4:1 vol/vol) to shaved abdomen (50 μl) and to each paw (5 μl) (Lange-Asschenfeldt et al, 2002). Topical oxazolone administration induces immunomodulatory activity. Five days after sensitization, right ears were challenged by topical application of 10 μl of a 1% oxazolone solution, whereas left ears were treated with vehicle alone. Compounds were administered 1 hour prior to challenge. The extent of inflammation was measured 24 hours after challenge, using the mouse ear-swelling test. Animals were numbered (tail marking) and weighed and the thickness of both ears was recorded with a constant-loading dial micrometer (Mitutoyo, Tokyo). The unpaired Student t-test was used for statistical analyses.

As shown in Fig. 4, Compound 6 (at a dose of 50 mg/kg, administered orally in 0.5% methylcellulose) inhibited DTH 24 hours after challenge. The inhibition was 22% compared to control and the reduction was statistically significant as determined by Student's ?-test with p>0.05. In another experiment, 24 hours after induction, as shown in Fig. 7,

Compound 23 inhibited swelling by 25.7% (p>0.001); Compound 25 by 15.3% (ρ>0.05) and Compound 29 by 15.9% (p>0.05). After 48 hours, Compound 23 inhibited swelling by 19.7% (ρ>0.05); Compound 25 by 10.9% and Compound 29 by 37.6% (p>0.001). As shown in Fig. 6, Compound 27 inhibited swelling by 28.8% (p>0.01) and Compound 30 by 27.2% (p>0.01).

EXAMPLE 18. Trinitrobenzene Sulfonic Acid (TNBS)-induced colitis model

TNBS is useful in inducing colitis in mouse model of inflammatory bowel disease. Control BALB/c mice (male; aged 6-8 weeks at start of experiment; 12 per group; Harlan, Israel) were given orally a vehicle (0.5% methylcellulose in water), and experimental mice (12 per group) were given orally the test compound TC (50 mg/kg), once per day for 7 successive days. 24 hours after the first administration, colitis was induced in the control, experimental, and in an untreated group by intra- rectal administration of TNBS (150 mg/kg dissolved in NaCl (0.9%): EtOH (50%) (1:1; 80 μl per mouse). All of the mice were killed by cervical dislocation 7 days after TNBS administration. The colons of the mice were examined under a dissecting microscope (X5) to evaluate the macroscopic lesions on a scale of 0 to 10 (colonic damage score). Gross colonic damage is graded according to Reuter et al. (Reuter et al. 1996), using the combined values of the four standard macroscopic parameters: degree of colonic ulcerations (scale from 0 - completely normal, to 10 - most severe); intestinal and peritoneal adhesions (0 to 2); diarrhea (0 to 1); and thickness (0 to 1). The total score is the arithmetic sum of the four scores. The evaluation was performed in a blind procedure. As shown in Fig. 5, Compound 4 improved colonic damage score by 48% and the inhibition was statistically significant as determined by Student's t-test with p>0.05.

A

Scheme 1 REFERENCES

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Ivatchtchenko A. V., Kovalenko S.M. and Drushlyak O.G. 2003. "Synthesis of substituted 4-oxo-2-thioxo-l,2,3,44etrahydroquinazolines and 4-oxo-3,4- dihydroquinazoline-2-thioles". J. Comb. Chem., 5:775-788.

Johnson Z₅ Power C.A., Weiss C₅ Rintelen F., Ji H., Ruckle T., Camps M., Wells T.N., Schwarz M.K., Proudfoot A.E. and Rommel C. 2004. "Chemokine inhibition-why, when, where, which and how?". Biochem Soc Trans., 32(Pt 2):366-

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Lasky, L. 1995. "Selectin-carbohydrate interactions and the initiation of the inflammatory response". Annu. Rev. Biochem., 64:113-139.

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Sasisekharan, R. and Venkataraman, G. 2000. "Heparin and heparan sulphate: biosynthesis, structure and function". Current Opinion in Chem. Biol., 4:626-631. Tanaka Y., Kimata K.₅ Adams D.H., Eto S. 1998. "Modulation of cytokine function by heparan sulfate proteoglycans: sophisticated models for the regulation of cellular responses to cytokines". Proc. Assoc. Am. Physicians 110:118-125.

Torres, S.R., Frode T. S., Nardi G.M., Vita N., Reeb R., Ferrara P., Ribeiro- do-Valle R.M. and Farges R.C. 2000. "Antiinflammatory effects of peripheral benzodiazepine receptor ligands in two mouse models of inflammation". Eur. J. of Pharmacol., 408:199-211.

Xie X., Rivier A.S., Zakrzewicz A., Bernimoulin M., Zeng X., Wessel H.P., Schapira M. and Spertini O. 2000. "Inhibition of Selectin-mediated Cell Adhesion and Prevention of Acute Inflammation by Nonanticoagulant Sulfated Saccharides". J. Biol. Chem., 275:34818-34825.

APPENDIX

Compound 2

10 Compound 3

Compound 4

Compound 5

Compound 6

Compound 23

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

15 Compound 31

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and at least one active ingredient selected from the compounds of the general formula I or II:

wherein: n is an integer from 3 to 5;

R₁ and R₂ each is selected from:

(i) hydrogen;

(ii) C_rC₆ alkyl or phenyl, optionally substituted by a group containing a basic nitrogen atom or by at least one heterocyclyl group, wherein one of the heterocyclyl groups is a 5-7 membered heterocyclic ring containing one or two heteroatoms, one of them being a basic nitrogen atom, optionally substituted on the additional heteroatom;

(iii) a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; or (iv) R₁ and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; R₃ and R₄ each is selected from hydrogen, C₁-C₆ alkyl, (C₁-C₆) alkoxy, (C₆-

C₁₀)aryl(C₁-C₆) alkoxy or (C₆-C₁₀) aryloxy; and pharmaceutically acceptable salts thereof.

2. The pharmaceutical composition according to claim 1, wherein R₁ and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms selected from pyrrolidine, imidazolidine, piperidine, and piperazine, and the additional nitrogen atom may be substituted by C₁-C₆ alkyl, optionally substituted by halogen, hydroxy, Ci-C₆ alkoxy or C₆-Ci_O ^aryl₅ ^or C₂-C₇ alkoxycarbonyl.

3. The pharmaceutical composition according to claim 1, wherein at least one of R₁ and R₂ is a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms selected from pyrrolidine, imidazolidine, piperidine, and piperazine, and the additional nitrogen atom may be substituted by C₁-C₆ alkyl, optionally substituted by halogen, hydroxy, Ci-C₆ alkoxy or C₆-Ci₀ aryl or C₂-C₇ alkoxycarbonyl.

4. The pharmaceutical composition according to claim 1 wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-methyl-N-(l- methyl-piperidinyl-4)-6-carboxamide (Compound 1).

5. The pharmaceutical composition according to claim 1 wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l- phenylmethyl-pyrrolidinyl-3)-6-carboxamide (Compound 2).

6. The pharmaceutical composition according to claim I₅ wherein the compound of formula I is azepino[2,l-b]quinazoline-6,7,8,9,10₅12-hexahydro-12- OXo-N-(I -methylethyl-piperidinyl-4)-3-carboxamide (Compound 3).

7. The pharmaceutical composition according to claim 1 wherein the compound of formula I is 7H-pyrido[2₅l-b]quinazoline-6,δ,9,l l-tetrahydro-l l-oxo-N-[3-(l- methyl-piperazinyl-4)propyl]-3-carboxamide (Compound 4).

8. The pharmaceutical composition according to claim 1 wherein the compound of formula I is azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l- phenylmethyl-piperidinyl-4)-3-carboxamide (Compound 5).

9. The pharmaceutical composition according to claim 1, wherein the compound of formula I is azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12- oxo-N-[3-(dimethylamino)propyl]-3-carboxamide (Compound 6).

10. The pharmaceutical composition according to claim 1, wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N [( 1 -phenylmethyl-piperazinyl-4)-phenyl]-6-carboxamide (Compound 23).

11. The pharmaceutical composition according to claim 1, wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N- [(3-[(l-methoxyphenyl)-piperazinyl-4]propyl]-6-carboxamide (Compound 25).

12. The pharmaceutical composition according to claim 1, wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[l- (thienyl-2)-l-(l-methyl-piperazinyl-4)ethyl]-6-carboxamide (Compound 26).

13. The pharmaceutical composition according to claim 1, wherein the compound of formula I is pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N- [l-methyl-piperazinyl-4)phenyl]-6-carboxamide (Compound 27).

14. The pharmaceutical composition according to claim 1, wherein the compound of formula II is [3-(3-phenylmethyloxy)phenylidene]pyrrolo[2,l- b]quinazoline-l,2,3,9-tetrahydiO-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 28).

15. The pharmaceutical composition according to claim 1, wherein the compound of formula II is [3-(3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo[2, 1 -bjquinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N- [3 [( 1 -methoxyphenyl)- piperazinyl-4]propyl]-6-carboxamide (Compound 29).

16. The pharmaceutical composition according to claim 1, wherein the compound of formula II is [3-(3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6- carboxamide (Compound 30).

17. The pharmaceutical composition according to claim 1, wherein the compound of formula II is 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoline- l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 31).

18. The pharmaceutical composition according to any one of claims 1 to 17, for the treatment or prevention of inflammatory or autoimmune diseases, disorders or conditions.

19. The pharmaceutical composition according to claim 18, wherein said inflammatory or autoimmune disease, disorder or condition is selected from the group consisting of atherosclerosis, septic shock, post-ischemic leukocyte-mediated tissue damage, frost-bite injury or shock, acute leukocyte-mediated lung injury, acute pancreatitis, asthma, traumatic shock, stroke, traumatic brain injury, nephritis, acute and chronic inflammation, atopic dermatitis, uveitis, colitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and multiple sclerosis.

20. The pharmaceutical composition according to any one of claims 1 to 17, for the treatment of cancer.

21. Use of a compound selected from the compounds of the general formula I or II in claim 1 for the preparation of a pharmaceutical composition.

22. The compound pyrrolo[2,l-b]quinazoline- 1,2,3, 9-tetrahydro-9-oxo-N- methyl-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 1).

23. The compound pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l- phenylmethyl-pyrrolidinyl-3)-6-carboxamide (Compound 2).

24. The compound azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo- N-(l-methylethyl-piperidinyl-4)-3-carboxamide (Compound 3).

25. The compound pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N[(l- phenylmethyl-piperazinyl-4)-phenyl]-6-carboxamide (Compound 23).

26. The compound pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[(3- [(l-methoxyphenyl)-piperazinyl-4]propyl]-6-carboxamide (Compound 25).

27. The compound pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[l- (thienyl-2)-l-(l-methyl-piperazinyl-4)ethyl]-6-carboxamide (Compound 26).

28. The compound pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-[l- methyl-piperazinyl-4)phenyl]-6-carboxamide (Compound 27).

29. The compound [3-(3-phenylmethyloxy)phenylidene]pyrrolo[2,l-b] quinazoline-,2,3 ,9-tetrahy dro-9-oxo-N-( 1 -methy l-piperidinyl-4)-6-carboxamide

(Compound 28).

30. The compound [3-(3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo[2,l- b]quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N- [3 [( 1 -methoxyphenyl)-piperazinyl-4] propyl]-6-carboxamide (Compound 29).

31. The compound [3-(3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo[2,l- b]quinazoline-l,2,3,9-tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 30).

32. The compound 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-( 1 -methyl-piperidinyl-4)-6-carboxamide (Compound 31) .

33. A method for the treatment or prevention of a disease, disorder or condition related to cell adhesion or cell migration, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the compounds of the general formula I or II:

wherein: n is an integer from 3 to 5; R₁ and R₂ each is selected from:

(i) hydrogen;

(ii) C₁-C₆ alkyl or phenyl, optionally substituted by a group containing a basic nitrogen atom or by at least one heterocyclyl group, wherein one of the heterocyclyl groups is a 5-7 membered heterocyclic ring containing one or two heteroatoms, one of them being a basic nitrogen atom, optionally substituted on the additional heteroatom; (iii) a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom; or (iv) R₁ and R₂ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing one or two basic nitrogen atoms, optionally substituted on the additional nitrogen atom;

R₃ and R₄ each is selected from hydrogen, C₁-C₆ alkyl, (C₁-C₆) alkoxy, (C₆- C₁₀)aryl(C₁-C₆) alkoxy or (C₆-C₁₀) aryloxy; and pharmaceutically acceptable salts thereof.

34. The method according to claim 33, wherein the compound of formula I is selected from: pyrroloP_jl-bJquinazoline-l^^^-tetrahydro^-oxo-N-methyl-N-Cl-methyl- piperidinyl-4)-6-carboxamide (Compound 1); pyiτolo[2,l-b]quinazorine-l,2,3,9- tetrahydro-9-oxo-N-( 1 -ρhenylmethyl-pyrrolidinyl-3)-6-carboxamide (Compound 2); azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l-methylethyl- piperidinyl-4)-3-carboxamide (Compound 3); 7H-Pyrido[2,l-b] quinazoline- 6,8,9,1 l-tetrahydiO-l l-oxo-N-[3-(l-methyl-piperazinyl-4)ρiOpyl]-3-carboxamide (Compound 4); azepino[2,l-b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-(l- phenylmethyl-piperidinyl-4)-3-carboxamide (Compound 5); azepino[2,l- b]quinazoline-6,7,8,9,10,12-hexahydro-12-oxo-N-[3-(dimethylamino) propyl]-3- carboxamide (Compound 6); pyrrolo [2,1 -b] quinazoline- 1,2,3, 9-tetrahydro-9-oxo- N[( 1 -phenylmethyl-piperazinyl-4)-phenyl]-6-carboxamide (Compound 23); pyrrolo [2, 1 -b] quinazoline- 1 ,2,3 ,9-tetrahy dro-9-oxo-N- [(3 - [( 1 -methoxyphenyl)- piperazinyl-4]propyl]-6-carboxamide (Compound 25); pyrrolo [2, l-b]quinazoline- 1 ,2,3 ,9-tetrahydro-9-oxo-N-[ 1 -(thienyl-2)- 1 -( 1 -methyl-ρiρerazinyl-4)ethyl]-6- carboxamide (Compound 26); pyrrolo[2,l-b]quinazoline-l,2,3,9-tetrahydro-9-oxo- N-[l-methyl-piperazinyl-4)phenyl]-6-carboxamide (Compound 27); and the compound of formula II is selected from:

[3-(3-phenylmethyloxy)phenylidene]pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 28); [3- (3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo[2, 1 -b] quinazoline- 1 ,2,3,9- tetrahy dro-9-oxo-N- [3 [( 1 -methoxyphenyl)-piperazinyl-4]propyi] -6-carboxamide (Compound 29); [3-(3-phenylmethyloxy-4-methoxy)phenylidene] pyrrolo [2, 1-b] quinazoline- 1 ,2,3 ,9-tetrahy dro-9-oxo-N-( 1 -methyl-piperidinyl-4)-6-carboxamide (Compound 30); 3-(4-cyanophenylidene)pyrrolo[2,l-b]quinazoline-l,2,3,9- tetrahydro-9-oxo-N-(l-methyl-piperidinyl-4)-6-carboxamide (Compound 31).

35. The method according to claim 33 or 34, wherein said disease, disorder or condition is an inflammatory or autoimmune disease, disorder or condition.

36. The method according to claim 35, wherein said inflammatory or autoimmune disease, disorder or condition is selected from the group consisting of atherosclerosis, sepsis, post-ischemic leukocyte-mediated tissue damage, frost-bite injury or shock, acute leukocyte-mediated lung injury, acute pancreatitis, asthma, traumatic shock, stroke, traumatic brain injury, nephritis, acute and chronic inflammation, atopic dermatitis, uveitis, colitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and multiple sclerosis.

37. The method according to claim 33 or 34, wherein said disease is cancer.