CZ20002276A3 - Substance antagonizing integrin receptor - Google Patents

Abstract

Integrin receptor antagonists

Description

Technical field

The present invention relates to integrin receptor antagonists.

In particular, the present invention relates to α 1β 3, α 1β 5 and / or α 1β6 receptor antagonists useful for inhibiting bone resorption, treating and preventing osteoporosis to inhibit vascular restenosis, treating diabetic retinopathy, macular degeneration, vascular neoplasms, atherosclerosis, inflammatory conditions, wound healing, viral diseases, tumor growth and metastasis.

BACKGROUND OF THE INVENTION

It is contemplated that a variety of disease states and diseases may be mediated through integrin receptors, so that antagonists of these receptors represent a very useful class of agents for the treatment of such conditions. Integrin receptors are heterodimeric transmembrane receptors through which cells can bind to extracellular matrices and other cells according to S. B. Rodan and B. A. Rodan, Integrin Function In Osteoclasts, Journal of Endocrinology, Vol. 154, pp. 47-56, 1997.

The compounds described below are useful for inhibiting bone resorption. Bone tissue resorption is mediated through cells called osteoclasts.

Osteoclasts are large cells with several nuclei and up to 400 nm in diameter, resorbing mineralized tissue containing calcium carbonate and calcium phosphate in vertebrates. Osteoclasts are actively moving cells on the bone surface, which can bind to bone tissue and secrete the necessary acids and proteases to disrupt mineralized bone tissue. Osteoclasts probably exist

at least two physiological states, namely the secretory state and the movable state. In the secretory state, osteoclasts appear to be flat cells associated with the bone matrix of their attachment region, being highly polarized and secreting lysosomal enzymes and protons. The association of osteoclasts with the bone surface is important in the initial degree of bone resorption. In a migratory or movable state, the osteoclasts move through the bone matrix and do not participate in resorption until they are joined to the bone surface.

Integrins are involved in the association of osteoclasts with bone and their activation and migration. The integrin that is present most in the rat, chicken, mouse and human osteoclasts is the ανβ3 receptor, which is likely to interact with bone proteins containing the RGD sequence in the matrix. Antibodies against ανβ3 block bone resorption in vitro, demonstrating that this integrin plays a key role in resorption. It is believed that ligands capable of binding ανβ3 can certainly be used to inhibit osteoclast-induced bone resorption in mammals in vivo.

Currently, the most common bone disease is osteoporosis, hypercalcaemia in malignancies, osteopenia in bone metastases, periodontal disease, parathyroid disease, joint damage in rheumatoid arthritis, Paget's disease, osteopenia in immobilization and glucocorticide-induced osteoporosis. All of these conditions are characterized by bone loss due to an imbalance between bone resorption and formation. This exchange usually continues throughout life at a rate of 14% per year. However, the rate of bone exchange varies from place to place. It is faster, for example, in the vertebral bone of the vertebrae and jaws than in compact bone in long bones. The potential loss of bone tissue is directly related to the exchange of this tissue and may be up to 5% per year in postmenopausal vertebrae, after which the risk of fractures increases.

• ·

There are currently 20 million people in the United States with demonstrable vertebral fractures due to osteoporosis. In addition, there are approximately 250,000 throat fractures per year as a result of osteoporosis. This clinical situation is associated with a mortality rate of 12% in the first two years, in addition 30% of patients require home fracture treatment.

Obviously, these effects could be mitigated by agents that inhibit bone resorption.

Agents capable of binding to ανβ3 have also been shown to be useful in the treatment and / or inhibition of restenosis, i. atherosclerosis, diabetic rethinopathy, macular degeneration and angiogenesis can be treated with these agents. formation of new blood vessels. In addition, it is believed that tumor growth is dependent on the appropriate blood supply, which is again dependent on the formation of new blood vessels for the tumor, so that inhibition of new blood vessels may lead to tumor regression in animal models, eg, Harris Harris Principles of Internal Medicine, 12 For this reason, agents that antagonize αββ and induce inhibition of angiogenesis may be useful in treating cancer and inhibiting their growth, see Brooks et al., Cell, 79, 1157-1164, 1994.

In addition, the compounds of the invention may also inhibit neovascularization by antagonizing the integrin ανβ5 receptor. The monoclonal antibody to ανβ5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and in the chicken chorionalantoic membrane model of MC Friedlander et al., Science 270, 1500-1502, 1995. This also means that compounds that antagonize ανβ5, are useful in the treatment of and

4 Prevention of macular degeneration, diabetic retinopathy, tumor growth and metastasis.

In addition, the compounds of the invention may inhibit angiogenesis and inflammatory conditions by antagonizing the α 1β6 integrin receptor, expressed at later stages of wound healing, with expression lasting until the wound is closed as described by Christofidou-Solomid et al., Expression and Function of Endothelial Cell αν Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin / SCID Mice Chimeras, American Journal of Pathology, Volume 151, No. 4, pp. 975-983, October 1997. ανβ6 is believed to play an important role in vascular regeneration supply during angiogenesis. In addition, ανβ6 is also involved in inflammation in epithelial cells and arises in response to local injury or inflammation according to Xiao-Zhu Huang et al., Inactivation of the Integrin β6 Subunit Gene Reveals and Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin, Journal of Cell Biology, Vol. 133, No. 4, pp. 921-928, May 1996. Thus, compounds which antagonize ανβ6 are useful for the treatment and prevention of malignant tumors, since they induce inhibition of both tumor growth and metastasis.

In addition, some compounds of the invention may antagonize both ανβ3 and ανβ5 receptors. These substances, known as dual antagonists ανβ3 / ανβ5, can be used to inhibit bone resorption, to treat and prevent osteoporosis and to inhibit vascular restenosis, to treat diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory conditions, cancer growth and metastasis.

In addition, some of the compounds of the invention may antagonize α1β3, ανβ5 and ανβ6 receptors.

• · · ·

SUMMARY OF THE INVENTION It is an object of the present invention to provide a class of substances useful for antagonizing integrin receptors.

SUMMARY OF THE INVENTION It is an object of the present invention to provide α 1β 3 receptor antagonists.

It is also an object of the present invention to provide a family of α 1β 5 receptor antagonists.

It is also an object of the present invention to provide compounds capable of antagonizing α 1β 6 receptors.

It is also an object of the present invention to provide substances having a dual antagonistic effect on α 1β 3 / α 1β 5 receptors.

It is also an object of the present invention to provide a class of substances having an inhibitory effect on the ανβ3, ανβ5 and ανβ6 receptors.

The present invention also provides a pharmaceutical composition comprising integrin receptor antagonists. Also described is a method for making the pharmaceutical composition. It should be possible to use the composition to produce an antagonist effect against integrin receptors in mammals.

A composition of this type should also be useful for inhibiting bone resorption, inhibiting restenosis, atherosclerosis, inflammatory conditions, viral diseases, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth, and metastasis. In particular, the composition should be useful for the treatment of osteoporosis.

• • • •

SUMMARY OF THE INVENTION

The present invention provides an integrin receptor antagonist of formula (I)

X-Y-Z

R ³ R ³

CO ₂ R 'R ^from R ⁸ where

X is selected from groups

- C-NR ¹ R ^{2 —} NR ¹

NR ²

C-NR ¹ R ² or is a 5- or 6-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 N, O and S heteroatoms wherein the ring nitrogen atoms are unsubstituted or substituted by one the substituent R ¹ and the ring carbon atoms are unsubstituted or substituted by one or two substituents R ¹ or

9- to 14-membered polycyclic ring system wherein one or more rings are aromatic, wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the nitrogen atoms in the ring being unsubstituted or are substituted by one • · · · • ·

R ¹ and the ring carbon atoms are unsubstituted or substituted by one or two R ¹ substituents;

Y is selected from groups

- (CH ₂ ) m -

- (CH ₂ ) _m -O- (CH ₂ ) _n -,

- (CH ₂ ) _m -KR ⁴ - (CH ₂ ) _n -,

- (CH ₂ ) _m -S- (CH ₂ ) _n -,

- (CH ₂ ) _m -SO- (CH ₂ ) n -,

- (CH ₂ ) _m -SO ₂ - (CH ₂ ) _n -,

- (CH 2) m -O- (CH 2) n -O- (CH 2) p -,

- (CH 2) m O- (CH 2) n W ⁴ - (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n -NR ⁴ - (CE 2) p -,

- (CH 2) m -O- (CH 2) n -S- (CH 2) p -,

- (CH 2) m -S- (CH 2) n -S- (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n S- (CH 2) p -,

- (CH 2) m -NO ⁴ - (CH 2) n O- (CE 2) p -, - (CH 2) m S- (CH 2) n O- (CH 2) p - and - (CH 2) m S- (CH 2) n - NR ⁴ - (CH 2) p - _; wherein any carbon atom in the methylene group (CH ₂₎ in the meaning of Y,

3, other than R, may be substituted by 1 or 2 R,

Z is selected from the groups II, II

-CNF- -NR ⁴ C- _; -NFRCNRY

-CH ₂ -CH ₂ - and -CH = CH-, wherein any carbon atom may be substituted with 1 or 2 R ³ substituents,

R ¹ and R ² are independently selected from hydrogen, halogen,

C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 3-8 cycloheteroalkyl C 1-6 alkyl, aryl, aryl C 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino, C 1-3 acylaminoC 1-8 alkyl, (C1-6alkyl) _p amino, (C1-6alkyl) _p aminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-3alkoxycarbonyl, C1-3alkoxycarbonylC1-6alkyl, hydroxycarbonylC1-6alkyloxy, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8alkyl-S (O) _p , (C1-8alkyl) _p aminocarbonyl, C1-8alkyloxycarbonylamino, (C1-8alkyl) _p- aminocarbonylamino, (arylC 1-8 alkyl) _p amino, (aryl) _p amino, arylC 1-8 alkylsulfonylamino and C 1-8 alkylsulfonylamino, or form two substituents R ¹ on the same carbon atom together with the carbonyl group,

R ³ is independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH _{2) r} -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - _(CH2) s-, aryl- (CH ₂₎ r -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N ^(R4) - _(CH2) s-, aryl- _{(CH2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy, oxo, trifluoromethyl,

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C? C- (CH _{2) r,}

C 1-6 alkylaryl-C = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH ₂ ) t -,

C1-6alkyl-CH = CH- (CH _{2) r,}

3-7-CH = CH- _{(CH2) t-,} aryl-CH = CH- (CH _{2) t} -,

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _r ,

C1-6alkylaryl-SO ₂ (CH ₂₎ t-

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy,

arylC 1-6 alkylcarbonyloxy, (C 1-6 alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulfonylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C 1-8 alkylcarbonylamino,

C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl.

(aryl) _p aminocarbonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) ) _p aminosulfonylaminoC 1-6 alkyl, (arylC 1-8 alkyl) _p aminosulfonylamino, (arylC 1-8 alkyl) _p aminosulfonylaminoC 1-6 alkyl, C 1-6 alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl, C1-6alkyl; ArylsulfonylC 1-6 alkyl, arylC 1-6 alkylsulfonyl, arylC 1-6 alkylsulfonylC 1-6 alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C1-6alkylthiokarbonylaminoC1-6alkyl, arylthiokarbonylaminoC1-6alkyl, arylC 6alkylthiokarbonylaminoskupina, arylC -6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC 8 alkyl) _p aminocarbonyl, (arylC C8alkyl _p ) aminocarbonylC 1-6 alkyl, or form two R ³ substituents on the same carbon atom together with a carbonyl or cyclopropyl group, wherein any R ³ alkyl group is unsubstituted or substituted by 1 to 3 R ¹ substituents, provided that the substituents R ³ is selected such that in the resulting compound the carbon atom (s) to which R ³ is attached is linked to at most one heteroatom,

R ⁴ is independently selected from hydrogen, aryl, aminocarbonyl,

C3-8cycloalkyl, aminoC1-6alkyl, (aryl) _p aminocarbonyl, (arylC1-5alkyl) _p aminocarbonyl, 9 hydroxycarbonylC1-6alkyl,

C1-8alkyl, arylC1-6alkyl, (C1-6alkyl) _p aminoC2-6alkyl, (arylC1-6alkyl) _p aminoC2-6alkyl,

C 1-8 alkylsulfonyl,

C 1-8 alkoxycarbonyl, aryloxycarbonyl, arylC 1-8 alkoxycarbonyl,

C 1-8 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl, (C 1-8 alkyl) _p aminocarbonyl, aminosulfonyl,

C 1-8 alkylaminosulfonyl, (aryl) _p aminosulfonyl, (arylC 1-8 alkyl) _p aminosulfonyl, arylsulfonyl, arylC 1-6 alkylsulfonyl,

C 1-6 alkylthiocarbonyl, arylthiocarbonyl, arylC 1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R ⁴ is unsubstituted or substituted with 1 to 3 substituents R ¹ , R ⁵ and R ⁶ are independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH ₂₎ r -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH ₂₎ s • 9 ·· · «4 4

Aryl- (CH ₂ ) _r -N (R ⁴ ) -C (O) - (CH 2) 5 -, aryl- (CH ₂ ) _r N (R ⁴ ) - ( ⁹ ) CH 2) _s -, halogen, hydroxy,

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) _t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C = C- _{(CH2) t-,} aryl-C? C- (CH _{2) t} -,

C 1-6 alkylaryl-C 1 -C- (CH ₂ ) _t -,

CH ₂ = CH- (CH _{2) r,}

C 1-6 alkyl-CH = CH- (CH ₂ ) t -,

3-7-CH = CH- _{(CH2) t-,} aryl-CH = CH- (CH _{2) r,}

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _r ,

C 1-6 alkylaryl-SO ₂ (CH ₂ ) _t -,

C1-6alkoxy, arylC1-6alkoxy, 4C4-644, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl , (aryl) _p amino, (aryl) _p aminoC 1-6 alkyl, (arylC 1-6 alkyl) _p amino, (arylC 1-6 alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy, arylC 1-6 alkylcarbonyloxy, (C 1-6 alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C 1-8 alkylcarbonylamino,

C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl.

(aryl) _p aminocarbonylaminoC 1-6 alkyl, (arylC 1-8 alkyl) _p aminocarbonylamino, (arylC 1-8 alkyl) _p aminocarbonylaminoC 1-6 alkyl, aminosulfonylaminoC 1-6 alkyl, (C 1-8 alkyl) _p aminosulfonylamino, (C 1-8 alkyl) _p aminosulfonylaminoC 1-6 alkyl, ( aryl) _p aminosulfonylaminoC1-6alkyl (arylC 1-8alkyl) _p aminosulfonylaminoskupina (arylC -8alkyl) _p aminosulfonylaminoC1-6alkyl,

C1-6alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkyls Ifony I, arylC1-6alkylsulfonylC1-6alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylC1-6alkyl, (aryl) _p aminocarbonylC1-6alkyl, (arylC1-8alkyl) _p aminocarbonyl, (Alkyl) _p- aminocarbonylC ^1-6 alkyl, or form R ⁵ and R ⁶ together with the carbon atom to which they are attached a carbonyl group, wherein any alkyl group R ⁵ or R ⁶ is unsubstituted or substituted by 1 to 3 substituents R ¹ , provided that the meanings of R ⁵ and R ⁶ are such that in the resulting compound the carbon atom to which they are attached is bound to at most one heteroatom,

R ⁷ and R ⁸ are independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH ₂₎ r O- _(CH2) s-, aryl- (CH _{2) r} -S (O) p- _{(CH2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy, trifluoromethyl,

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) _t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C = C- _{(CH2) t-,} aryl-C = C- _(CH2) t-

C 1-6 alkylaryl-C = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH ₂ ) _t -, · ·

C 1-6 alkyl-CH = CH- (CH ₂ ) t -,

3-7-CH = CH- _(CH2) t-, aryl-CH = CH- (CH _{2) r,}

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -,

C1-6alkylaryl-SO ₂ (CH ₂₎ t-

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy, arylC 1-6 alkylcarbonyloxy, (C 1-6 alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino,

arylC 1-6 alkylcarbonylaminoC 1-6 alkyl, aminocarbonylaminoC 1-6 alkyl, arylaminocarbonylamino, (C 1-8 alkyl) _p aminocarbonylamino, (C 1-8 alkyl) _p aminocarbonylaminoC 1-6 alkyl.

(aryl) _p aminocarbonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) ) _p aminosulfonylaminoC1-6alkyl (arylC C8alkyl) _p aminosulfonylaminoskupina (arylC1-8alkyl) _p aminosulfonylaminoC1-6alkyl,

C 1-6 alkylsulfonyl,

C 1-6 alkylsulfonylC 1-6 alkyl, aryl Isons IC 1-6 alkyl, arylC 1-6 alkylsulfonyl, arylC 1-6 alkylsulfonylC 1-6 alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C 1-6 alkylthiocarbonylaminoC 1-6 alkyl, arylthiocarbonylaminoC 1-6 alkyl, arylC 1-6 alkylthiocarbonylamino, arylC 1-6 alkylthiocarbonylaminoC 1-6 alkyl, (C 1-8 alkyl) _p aminocarbonylC 1-6 alkyl, (aryl) _p aminocarbonylC 1-6 alkyl, (arylC 1-8 alkyl) _p • aminocarbonyl

(arylC 1-8 alkyl) _p aminocarbonylC 1-6 alkyl,

C7-20polycyclylC0-8alkylsulfonylamino, wherein any of the alkyl groups R ⁷ and R ⁸ is unsubstituted or substituted by 1 to 3 substituents R ¹ , provided that R ⁷ and R ⁸ are chosen such that the carbon atom in the resulting compound is carbon , to which these symbols are bound, bound by at most one heteroatom,

R ⁹ is selected from hydrogen

C 1-8 alkyl, aryl arylC 1-8 alkyl,

C 1-8 alkylcarbonyloxyC 1-4 alkyl, arylC 1-8 alkylcarbonyloxyC 1-4 alkyl,

C 1-8 alkylaminocarbonylmethylene,

C 1-8 dialkylaminocarbonylmethylene, m independently represents an integer from 0 to 6, n independently represents an integer from 0 to 6, p independently represents an integer from 0 to 2, r independently represents an integer from 1 to 3, s independently represents an integer from 0 to 3, t independently represents an integer from 0 to 3, as well as pharmacologically acceptable salts thereof.

The present invention also provides a pharmaceutical composition comprising, as an active ingredient, the compounds of the invention together with a pharmaceutical carrier.

The invention also provides a process for the manufacture of a pharmaceutical composition according to the invention.

• ·

The pharmaceutical composition can be used to exert an integrin receptor antagonist effect in a mammal to inhibit bone resorption, restenosis, atherosclerosis, inflammatory processes, viral diseases, diabetic retinopathy, macular degeneration, angiogenesis, poor wound healing, tumor growth, and metastasis. The composition may also be used to treat osteoporosis.

The invention therefore relates to integrin receptor antagonists of the formula I

R ² R ⁶

XYZ ^ \ ^ ^{C0 2'S}

R ^? R ^and wherein X is selected from R - C-NFTR ²

-Nr

NR ²

C-NR'R ² or is a 5- or 6-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 N, O and S heteroatoms wherein the ring nitrogen atoms are unsubstituted or substituted by one the substituent R ¹ and the ring carbon atoms are unsubstituted or are substituted by one or two substituents R ¹ or

9- to 14-membered polycyclic ring system wherein one or more rings are aromatic, wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the nitrogen atoms in the ring being unsubstituted or substituted with one R ¹ substituent and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ^1,

Y is selected from groups

- (CH 2) m +>

- (CH 2) m -O- (CH 2) n -,

- (CH 2) m-NK ⁴ - (CH 2) n *,

- (CH 2) m S- (CH 2) n - _?

- (CH 2) m -SO- (CH 2) n _-I

- (CH 2) m -SO 2 - (CH 2) n -,

- (CH 2) m -O- (CH 2) n -O- (CE 2) p -,

- (CH 2) m O- (CH 2) n -NR ⁴ - (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n -NB. ^4- (CH 2) p -,

- (CH 2) m -O- (CH 2) n -S- (CH 2) p -,

- (CH 2) m -S- (CH 2) n -S- (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n S- (CH 2) p -,

- (CH 2) m -NR ⁴ - (CH 2) n -O-fCH 2 -p- ₎

(CH 2) m -S- (CH 2) n -O- (CE 2) p -, a

- (CH 2) m S- (CH 2) n -KK ⁴ - (CH 2) p -, wherein any carbon atom in the methylene group (CH ₂ ) in the meaning of Y, other than R ⁴ , may be substituted by 1 or 2 substituents R ³ ,

Z is selected from groups

O

-CNn ⁴

O θ

H íl

-NR ⁴ C- -NR ⁴ CNR ⁴ '.

-CH ₂ CH ₂ - and -CH = CH-, wherein any carbon atom is optionally substituted with 1 or 2 R ³ substituents,

R ¹ and R ² are independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 3-8 cycloheteroalkyl C 1-6 alkyl, aryl, aryl C 1-8 alkyl, amino, aminoC1-8alkyl, C1-3acylamino, C1-3acylaminoC1-8alkyl, (C1-6alkyl) _p amino, (C1-6alkyl) _p aminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-3alkoxykarbonyl, C1-3alkoxykarbonylC1-6alkyi, hydroxycarbonylC 6alkyloxyskupina, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1 -8alkyl-S (O) _p, (C1-8 alkyl ) _p aminocarbonyl, C 1-8 alkyloxycarbonylamino, (C 1-8 alkyl) _p aminocarbonyloxy, (arylC 1-8 alkyl) _p amino, (aryl) _p amino, arylC 1-8 alkylsulfonylamino and C 1-8 alkylsulfonylamino, or together form two R ¹ substituents on the same this atom a carbonyl group,

R ³ is independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH _{2) r} -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy, oxo, trifluoromethyl, • ·

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) r,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C 1 -C- (CH ₂ ) t -, aryl-C = C- (CH ₂ ) _t -,

C 1-6 alkylaryl-C = C- (CH ₂ ) _t -,

CH ₂ = CH- (CH ₂ ) _t -,

C 1-6 alkyl-CH = CH- (CH ₂ ) _t -,

C 3-7 cycloalkyl-CH = CH- (CH ₂ ) _t -, aryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -,

C 1-6 alkylaryl-SO ₂ (CH ₂ ) _t -,

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, · (ArylC 1-6 alkyl) _p amino, (arylC 1-6 alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy, arylC 1-6 alkylcarbonyloxy, (C 1-6 alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C 1-8 alkylcarbonylamino,

C1-8alkylkarbonylaminoC1-6alkyl, arylkarbonylaminoC1-6alkyl, arylC 1-6alkylkarbonylaminoskupina, arylC 6alkylkarbonylaminoC1-6alkyl, aminokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminocarbonylamino, (C1-8alky l) _p i am inokarbonylam noC1 -Oalkyl. (aryl) _p aminocarbonylaminoC1-6alkyl, (arylC 1-8alkyl) _p aminocarbonylamino, (arylC 1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p- aminosulfonylaminoC 1-6 alkyl, (arylC 1-8alkyl) _p- aminosulfonylamino,

(arylC1-8alkyl) _p- aminosulfonylaminoC1-6alkyl,

C 1-6 alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkyls Ifonyl, arylC1-6alkylsulfonylC1-6alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C1-6alkylthiokarbonylaminoC1-6alkyl, arylthiokarbonylaminoC1-6alkyl, arylC -6alkylthiokarbonylaminoskupina, arylC -6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC 8 alkyl) _p aminocarbonyl, (arylC C8alkyl _p ) aminocarbonylC 1-6 alkyl, or form two R ³ substituents on the same carbon atom together with a carbonyl or cyclopropyl group, wherein any R ³ alkyl group is unsubstituted or substituted by 1 to 3 R ¹ substituents, provided that the substituents R ³ is selected such that in the resulting compound the carbon atom (s) to which R ³ is attached is linked to at most one heteroatom,

R ⁴ is independently selected from hydrogen, aryl, aminocarbonyl,

C3-8cycloalkyl, ························· · AminoC 1-6 alkyl, (aryl) _p aminocarbonyl, (arylC 1-5 alkyl) _p aminocarbonyl, hydroxycarbonylC 1-6 alkyl,

C1-8alkyl, arylC1-6alkyl, (C1-6alkyl) _p aminoC2-6alkyl, (arylC1-6alkyl) _p aminoC2-6alkyl,

C 1-8 alkylsulfonyl,

C 1-8 alkoxycarbonyl, aryloxycarbonyl, arylC 1-8 alkoxycarbonyl,

C 1-8 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl, (C 1-8 alkyl) _p aminocarbonyl, aminosulfonyl,

C 1-8 alkylaminosulfonyl, (aryl) _p aminosulfonyl, (arylC 1-8 alkyl) _p aminosulfonyl, arylsulfonyl, arylC 1-6 alkylsulfonyl,

C 1-6 alkylthiocarbonyl, arylthiocarbonyl, arylC 1-6 alkylthiocarbonyl, wherein any of the R ⁴ alkyl groups is unsubstituted or substituted with 1 to 3 R ¹ substituents,

R ⁵ and R ⁶ are independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH ₂₎ r -O- (CH _{2) s} -, • • * · · · · · • aryl- _(CH2) rS (O) p- _(CH2) s-, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy,

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) _t -,

C 1-6 alkyl-C = C- (CH ₂ ) _t -,

C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C = C- _(CH2) t-

-6alkylaryl C1-CsC- (CH _{2) t} -,

CH ₂ = CH- (CH ₂ ) t -,

C 1-6 alkyl-CH = CH- (CH ₂ ) _t -,

C 3-7 cycloalkyl-CH = CH- (CH ₂ ) _t -, aryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -, - - - - - - - - - - - - - - - - - - ·· ·· ··

C1-6alkylaryl-SO ₂ (CH ₂₎ t-

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) (C1-6alkyl) _p aminoC1-6alkyl, arylcarbonyloxy, arylC1-6alkylcarbonyloxy, (C1-6alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C 1-8 alkylcarbonylamino,

C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl.

(aryl) _p aminocarbonylaminoC 1-6 alkyl,

(arylC 1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p aminosulfonylaminoC1-6alkyl, ( (arylC 1-8 alkyl) _p aminosulfonylamino, (arylC 1-8 alkyl) _p aminosulfonylaminoC 1-6 alkyl,

C 1-6 alkylsulfonyl,

C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, arylC1-6alkylsulfonylC1-6alkyl,

C 1-6 alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C1-6alkylthiokarbonylaminoC1-6alkyl, arylthiokarbonylaminoC1-6alkyl, arylC 6alkylthiokarbonylaminoskupina, arylC 1-6alkylthiokarbonylaminoC1-6alkyl, (C1-8 alkyl) _p aminokarbonylC1-6alkyl, (aryl) _p aminokarbonylC1-6alkyl (arylC 8 alkyl) _p aminocarbonyl, (aryl 1 -8alkyl) _β aminocarbonylC 1-6 alkyl, or form R ⁵ and R ⁶ together with the carbon atom to which they are attached a carbonyl group, wherein any alkyl group R ⁵ or R ⁶ is unsubstituted or substituted by 1 to 3 substituents R ¹ ,

provided that the meanings of R ⁵ and R ⁶ are such that in the resulting compound the carbon atom to which they are attached is bound to at most one heteroatom,

R ⁷ and R ⁸ are independently selected from hydrogen, aryl,

C1-1 Oalkyl, aryl- (CH _{2) r} -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy,

C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy,

C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl,

C 1-6 alkylcarbonyloxy,

C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC 1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl,

HC = C- (CH ₂ ) _t -,

C 1-6 alkyl-C? C- (CH ₂₎ r,

C 3-7 cycloalkyl-C? C- (CH _{2) t} -, • • · · aryl-C = C- _(CH2) t-

C1-6alkylaryl-C = C- (CH _{2) r,}

CH ₂ = CH- (CH ₂ ) _t -,

C 1-6 alkyl-CH = CH- (CH ₂ ) _t -,

3-7-CH = CH- _{(CH2) t-,} aryl-CH = CH- (CH _{2) t} -,

C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -,

C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -,

C 1-6 alkylaryl-SO ₂ (CH ₂ ) _r ,

C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy, arylC 1-6 alkylcarbonyloxy, (C 1-6 alkyl) _p aminocarbonyloxy,

C 1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl, • · · ♦ · ♦ ·

C1 -8alkylkarbonylaminoC 1 -6alkyl, arylkarbonylaminoC1-6alkyl, arylC -6alkylkarbonylaminoskupina, arylC 6alkylkarbonylaminoC1-6alkyl, aminokarbonylaminoC1-6alkyl, arylaminocarbonylamino, (C1-8 alkyl) _p aminocarbonylamino, (C1-8 alkyl) _p aminokarbonylaminoC1-6alkyl, (aryl) _p aminokarbonylaminoC1 -6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p aminosulfonylaminoC1-6alkyl , (arylC 1-8 alkyl) _p aminosulfonylamino, (arylC 1-8alkyl) _p aminosulfonylaminoC 1-6 alkyl, C 1-6 alkylsulfonyl,

C1-6alkyls IfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, arylC1-6alkylsulfonylC1-6alkyl, C1-6alkylcarbonyl,

C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl,

C 1-6 alkylthiocarbonylamino,

C 1-6 alkylthiocarbonylaminoC 1-6 alkyl, arylthiocarbonylaminoC 1-6 alkyl, arylC 1-6 alkylthiocarbonylamino, arylC 1-6 alkylthiocarbonylaminoC 1-6 alkyl,

(C1 -8alkyl) _p inokarbonylC am I -6alky 1, (aryl) _p aminokarbonylC1-6alkyl (arylC -8alkyl) _p aminocarbonyl, (arylC C8alkyl) _p aminokarbonylC1-6alkyl,

A C 7-20 polycyclylC 0-8 alkylsulfonylamino group wherein any of the alkyl groups R ⁷ and R ⁸ is unsubstituted or substituted with 1 to 3 substituents R ¹ , provided that R ⁷ and R ⁸ are selected such that the resulting compound has a carbon atom, to which these symbols are bound, bound by at most one heteroatom,

R ⁹ is selected from hydrogen

C 1-8 alkyl, aryl, arylC 1-8 alkyl,

C 1-8 alkylcarbonyloxyC 1-4 alkyl, arylC 1-8 alkylcarbonyloxyC 1-4 alkyl,

C 1-8 alkylaminocarbonylmethylene,

C 1-8 dialkylaminocarbonylmethylene, m independently represents an integer from 0 to 6, n independently represents an integer from 0 to 6, p independently represents an integer from 0 to 2, r independently represents an integer from 1 to 3, s independently represents an integer from 0 to 3, t independently represents an integer from 0 to 3, as well as pharmacologically acceptable salts thereof.

In the compounds of the invention, X is preferably a 6-membered monocyclic aromatic ring system containing one or two nitrogen atoms, each carbon atom in the ring being unsubstituted or substituted by one substituent R ¹ or being 9- to 9- to 9-carbon.

A 14-membered polycyclic ring system wherein at least one ring is aromatic, the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the nitrogen atoms in the ring are unsubstituted or substituted with one R substituent ¹ and the ring carbon atoms are unsubstituted or substituted with 1 or 2 substituents R ¹ .

X is preferably selected from groups

Particularly preferred values for X are groups

In the compounds of the invention, Y is preferably selected from the group consisting of:

- (CH 2) m -OCH 2) n ->

- (CH 2) m N ⁴ - ⁽ CH 2) n -.

- (CH2) m ' ^_ (CH2) n.>

- (CH 2) m 'SO (CH 2) n>

- (CH 2) m -SO 2 -CCH 2) n -,

- (CH2) mO- (CH2) nO- (CH2 '; p-, - (CH2) mO- (CH2) nW ^4- (CH2) p-, - (CH2) mM < ^4- (CH2; nN ^ ⁴⁾ - (CH 2) m -NR ⁴ - (CH 2) n -O- (CH 2) p -;

wherein any carbon atom in the methylene group CH 2 of Y, other than R ⁴ , is optionally substituted with 1 or 2 R ³ substituents.

Preferably, Y is selected from (CH ₂ ) _m , (CH ₂ ) _m -S- (CH ₂ ) _n and (CH ₂ ) _m -NR ⁴ - (CH ₂ ) _n , wherein any carbon atom in the methylene group CH in the meaning of Y ₂ is different from R ^4, is optionally substituted with 1 or 2 substituents R ^3rd

In the compounds of the invention, Z is preferably selected from groups

O

-CNR ⁴

-NR ⁴ C- -NR ⁴ CNFT.

-CH ₂ CH ₂ - and -CH = CH-, wherein any carbon atom is optionally substituted with 1 or 2 R ³ substituents.

Particularly preferred values for Z are 0 ° groups

-CNR ⁴ - · ^-NR4 CNR ⁴ - · _a «ί ·· ·» · t> · «· 1 · * •» ·> • · »· · · and · a *» * · and · * And -CH ₂ CH ₂ -, wherein any carbon atom is optionally substituted with 1 or 2 R ³ substituents.

In the compounds of the invention, R ¹ and R ² are preferably selected from hydrogen or halogen, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl and trifluoromethoxy.

Particularly preferred values for R ¹ and R ² are any of hydrogen or halogen, C 1-10 alkyl, C 3-8 cycloalkyl, trifluoromethyl and trifluoromethoxy.

In the compounds of the invention, R ³ is preferably a group selected from hydrogen, fluoro, trifluoromethyl, aryl,

C 1-8 alkyl, arylC 1-6 alkyl, hydroxy, oxo, arylaminocarbonyl, arylC 1-5 alkylaminocarbonyl, aminocarbonyl and aminocarbonylC 1-6 alkyl.

A particularly preferred value for R ³ are groups selected from fluorine, aryl,

C 1-8 alkyl,

99 9 9 9 9 9 9

99

9 9 *

Aryl C1-6alkyl, hydroxy, oxo and arylaminocarbonyl.

In the compounds of the invention, R ⁴ is preferably selected from hydrogen, aryl,

C3-8cycloalkyl,

C 1-8 alkyl,

C 1-8 alkylcarbonyl, arylcarbonyl,

C 1-6 alkylsulfonyl, arylsulfonyl, arylC 1-6 alkylsulfonyl, arylC 1-6 alkylcarbonyl,

C 1-8 alkylaminocarbonyl, arylC 1-5 alkylaminocarbonyl, arylC 1-8 alkoxycarbonyl and

C 1-8 alkoxycarbonyl.

A particularly preferred value for R ⁴ is hydrogen,

C 1-8 alkyl,

C 1-8 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl,

C 1-6 alkylsulfonyl, arylsulfonyl and arylC 1-6 alkylsulfonyl.

• ·

6

In one embodiment of the invention, R and R are independently selected from hydrogen, aryl,

C 1-8 alkyl, aryl-C = C- (CH ₂ ) _t -, arylC 1-6 alkyl,

CH ₂ = CH- (CH _{2) t} -, and

HC = C- (CH ₂ ) _t -.

5

In a subset of this embodiment, R is hydrogen and R is selected from hydrogen, aryl,

C 1-8 alkyl, aryl-C = C- (CH ₂ ) _r , arylC 1-6 alkyl,

CH ₂ = CH- (CH _{2) t} -, and

HC = C- (CH ₂ ) _t -.

In a subgroup of this group, R ⁶ , R ⁷ and R ⁸ are hydrogen and R ⁵ is selected from hydrogen, aryl,

C 1-8 alkyl, aryl-C = C- (CH ₂ ) _r , arylC 1-6 alkyl,

CH ₂ = CH- (CH _{2) t} -, and

HCsC- (CH _{2) t} -.

In another embodiment of the invention, R ⁷ and R ^{8 are} independently selected from hydrogen, aryl,

C 1-8 alkylcarbonylamino, arylcarbonylamino,

C 1-8 alkylsulfonylamino, arylsulfonylamino,

C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl,

C1-8alkoxycarbonylamino,

C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl,

C 1-8 alkylcarbonylaminoC 1-6 alkyl, arylcarbonylaminoC 1-6 alkyl, arylC 1-6 alkylcarbonylamino, arylC 1-6 alkylcarbonylaminoC 1-6 alkyl, aminocarbonylaminoC 1-6 alkyl, (C 1-8 alkyl) _p aminocarbonylamino, (C 1-8 alkyl) _p aminocarbonylaminoC 1-6 alkyl.

(aryl) _p aminokarbonylaminoC1-6alkyl, arylaminocarbonylamino, (arylC -8alkyl) _p aminocarbonylamino, (arylC C8alkyl) _p aminokarbonylaminoC1-6alkyl, aminosulfonylaminoCI 6alkyl, (C1-8 alkyl) _p aminosulfonylaminoskupina, (C1-8 alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p aminosulfonylaminoC 1-6 alkyl, (arylC 1-8 alkyl) _p aminosulfonylamino, (arylC 1-8 alkyl) _p aminosulfonylaminoC 1-6 alkyl, C 1-6 alkylthiocarbonylamino, C 1-6 alkylthiocarbonylaminoC 1-6 alkyl, arylthiocarbonylaminoC 1-6 alkyl, arylC 1-6 alkylthio 6alkylthiocarbonylaminoC 1-6 alkyl, and C 7-20 polycyclylC 0 -C 8 alkylsulfonylamino.

In a class of this embodiment, R ⁸ is hydrogen and R ⁷ is selected from hydrogen, aryl,

C1-8alkylcarbonylamino, arylC1-6alkylcarbonylamino, arylcarbonylamino,

C 1-8 alkylsulfonylamino, arylC 1-6 alkylsulfonylamino, arylsulfonylamino,

C1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylamino, arylaminocarbonylamino, (C1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminosulfonylamino and (arylC1-8alkyl) _p .

In another subset of this embodiment, R ⁵ , R ^6, and R ⁸ are hydrogen, and R ⁷ is selected from hydrogen, aryl, and aryl.

C 1-8 alkylcarbonylamino, arylC 1-6 alkylcarbonylamino, arylcarbonylamino,

C 1-8 alkylsulfonylamino, arylC 1-6 alkylsulfonylamino, arylsulfonylamino,

C1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylamino, arylaminocarbonylamino, (C1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminosulfonylamino and (arylC1-8alkyl) _p .

In the compounds of the invention, R ⁹ is preferably selected from hydrogen, methyl or ethyl, and particularly preferred for R ⁹ is hydrogen.

In the compounds of the invention, m is preferably an integer from 0 to 4 and in particular from 2 to 4.

In the compounds of the invention, n is preferably an integer from 0 to 4, and in particular from 2 to 4.

In the compounds of the invention, r is preferably an integer of 1 to 2.

In the compounds of the invention, preferably is an integer of 0 to 2.

to 2 and in particular 0 to 1.

In the compounds of the invention, t is preferably an integer

Examples of compounds of the invention useful for antagonizing integrin receptors include:

3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3 (S) - (pyridin-3-yl) -3- ( 5- (5,6,7,8-tetrahydro- [1,8-naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3 (S) - (5,6,7,8-tetrahydroquinolin-3-yl) -, trifluoroacetate - 3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 2 (S) -benzenesulfonylamino-3- (5- (5,6,6-trifluoroacetate) -acetate) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (quinolin-3-yl) -3- (5- (5,6,7,8) 3-R - (quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1] -tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3- (quinolin-3-yl) -3- (7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -bistrifluoroacetate) -yl) -pentanoylamino) -propionic acid 3- (quinolin-3-yl) -3- (6- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) - propionic acid, 3 (S) - (3-fluorophenyl) -3- (4- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoyl) bistrifluoroacetate mino) -propionic acid 3 (S) - (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl))

-pentanoylamino) -pent-4-enoic acid 3 (S) - (3-fluorophenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) 2- (3-Fluorophenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid trifluoroacetate, 3 (S) -propionic acid, trifluoroacetate ) - (Benzo [1,3] dioxol-5-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (2-Oxo-2,3-dihydro-benzoxazol-6-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-) -, trifluoroacetate) yl) -pentanoylamino) -propionic acid 3 (S) - (3-fluorophenyl) -3- {3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino] 3 (S) - (3-fluorophenyl) -3- (2- {propyl- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionylamino} -propionic acid trifluoroacetate) (ethyl) -amino} -acetylamino) -propionic acid, 3 (S) - (3-fluorophenyl) -3- (2- {phenethyl- [2- (5,6,7,8-tetrahydro- [1, 5,6,7,8-tetrahydro- 8] Naphthyridine-2 -yl) -ethyl] -amino} -acetylamino) -propionic acid 3 (S) - (3-fluorophenyl) -3- {3 (S) - [(5,6,7,8-tetrahydro [1,8] 3-S (3) - (3-fluorophenyl) -3- {3 (S) - (3-fluorophenyl) -3 - [(] (naphthyridin-2-ylmethyl) amino] pent-4-ynoylamino-propionic acid, bistrifluoroacetate 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino] •

3 (S) - (3-Fluoro-4-phenyl-phenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionylamino) -propionic acid trifluoroacetate 2 (S) - (2-thienylsulfonylamino) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid trifluoroacetate -pentanoylamino) -propionic acid 3 (S) - (3-Fluorophenyl) -3- {3-methyl-3 [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino] -propionylamino} - propionic acid 3 (S) - (3-fluorophenyl) -3- {2- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethylamino] -acetylamino} - Propionic acid 3 (S) - (3-fluorophenyl) -3 {[3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -ureido} -propionic acid 2 (S) - (Methanesulfonylamino) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3 (S) - (2,3) -dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 (R or S), 9-octahydrobenzo [b] [1,8] naphthyridin-8- yl) -propionylamino] -propionic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 (S or

R) 9-octahydrobenzo [b] [1,8] naphthyridin-8-yl) -propionylamino] -propionic acid 3 (S) - (6-methoxy-pyridin-3-yl) -3- [N-methyl 3 - (1,2,3,4,6,7,8,9-octahydrobenzo [b] [1,8] naphthyridin-8-yl-propionyl) -amino] propionic acid, bistrifluoroacetate 3 ( S) - (2,3-Dihydro-benzofuran-6-yl) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethylsulfanyl) -propionylamino] -propionic acid 3- (quinolin-3-yl) -7 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] heptanoic acid, 3- (quinolin-3-yl) - 7- [acetyl- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] -heptanoic acid, 3- (quinolin-3-yl) -7- [methanesulfonyl- (5, 6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] -heptanoic acid 3- [5- (2-amino-pyrimidin-4-yl) -pentanoylamino] -3 (S) - ( quinolin-3-yl) -propionic acid, 2- (benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, bistrifluoroacetate , 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid, 2 (S) - (benzenesulfonylamino) -9- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (R) - (benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) nonanoic acid 2 (S) - (benzenesulfonylamino) -10- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) decanoic acid 2 (S) - (benzenesulfonylamino) -8- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -octanoic acid, 2 (S) - (cyclohexylmethanesulfonylamino) -9- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1 (S) hydrochloride

-ylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (phenylmethanesulfonylamino) -9- (5,6,7,8) -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (cyclohexanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -hydrochloride -nonanoic acid 2 (S) - (butane-1-sulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride 2 (S) - (3-Benzylureido) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (benzyloxycarbonylamino) -9- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (phenylacetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (acetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (benzoylamino) - 9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid; 3- (quinolin-3-yl) -9- (5,6,7, 9,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid; 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl) -nonano 3 (R) - (Quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (quinolin-3) bishydrochloride -yl- -7- (1,2,3,4,6,7,8,9-octahydro-benzo [b] [1,8] naphthyridin-8-yl) -heptanoic acid, 6-oxo- ( quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (N-oxo-quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (phenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl) -nonanoic acid 3 (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 ( R) - (Benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (benzo [ b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (pyridin-3-yl) -9- (5) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate

3 (R) - (Pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (Pyridin-3) -yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (3-fluorophenyl) -9- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (3-fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid 3 (S) - (3-fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid 3- (2,3-dihydro) -benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (2,3-dihydro-benzofuran-6) -yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-benzofuran-6-yl) - 9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (2,3-dihydro-benzofuran-6-yl) -9- (5,6-trifluoroacetate) trifluoroacetate 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid 3- (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9 - (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-furo [3,2-b] pyridine-5- yl) -9- (5,6,7,8-tet rahydro [1,8] naphthyridin-2-yl) -nonano, • ·

3 (S) - (2,3-Dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3- (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (Furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 ( S) - (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (2) 3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate, 3 (S) - (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3- (6-methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) -nonanoic acid - (6-methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (6-methoxy- pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate, trifluoroacetate t 3- (pyrimidin-5-yl) -9- (5,6,7,8) 9 (9,6)

3 (R) - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-) -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid trifluoroacetate 2-yl) -nonanoic acid, 3 (S) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid trifluoroacetate, 3 - (6-Amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (6-amino- pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (benzo [b] thiazol-2-yl) -9- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro) -hydrochloride [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8]) naphthyridin-2-yl) -nonanoic acid, 3- (6-oxo-1,6-dihydro-pyridin-3-yl) -9- (5,6,7,8-tetrahydro [1,8] naphthyridine) bistrifluoroacetate -2-yl) -nonanoic as well as pharmaceutically acceptable salts thereof of these substances.

Further examples of compounds of the invention may be selected from:

Acid 3 (S) - (pyridin-3-yl) -3- (5- (5,6, 5, 5, 5, 5, 5, 6, 7, 8, 9, 8); 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 2 (S) -benzenesulfonylamino-3- (5- (5,6,7,8-tetrahydro- [1,8]) 3 (S) - (quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2)] - (naphthyridin-2-yl) -pentanoylamino) -propionic acid -yl) -pentanoylamino) -propionic acid 3 (R) - (quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - pentanoylamino) -propionic acid, 2 (S) - (2-thienylsulfonylamino) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid trifluoroacetate, 3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 (R or S)), 9-octahydrobenzo [b [1,8] Naphthyridin-8-yl) -propionamino] -propionic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- (1,2,3, 4,6,7,8 (S or R), 9-octahydrobenzo [b] [1,8] naphthyridin-8-yl) -propionamino] -propionic acid 3 (S) - (6-methoxy-pyridin-3) -yl) -3- [N-methyl-3- (1,2,3,4,6) 7,8,9-octahydrobenzo [b] [1,8] naphthyridin-8-yl-propionyl) -amino] -propionic acid 3- [5- (2-amino-pyrimidin-4-yl) -pentanoylamino] -3- (S) - (quinolin-3-yl) -propionic acid, 2- (Benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non- 4-ene, as well as pharmacologically acceptable salts thereof.

Still further examples of compounds of the invention may be the following:

3 (R) - (Quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (quinolin-3) -yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (benzo [b] thiophen-2-yl) -9- (5,6,7,8) -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -nonanoic acid 3 (S) - (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) 1- (3-Fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (3-fluorophenyl) -9- (5) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate,

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (2,3-Dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate, 3 (S) - (2,3-Dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3-R - (furo [2,3b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (Furo [2,3b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate, 3 (S) - (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- acid) yl) -nonanoic acid 3 (R) - (6-methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8} naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-Methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - ( pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S - (pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (6-amino-pyridin-3) -yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (benzo [b] thiazol-2-yl) -9- (5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro) -hydrochloride [1,8] naphthyridin-2-yl) -nonanoic acids and their pharmaceutically acceptable salts.

For use in medicine, salts of the compounds of the invention are termed non-toxic pharmaceutically acceptable salts. However, other salts may be used in the manufacture of the compounds of the invention or their pharmaceutically acceptable salts. As for the pharmaceutically acceptable salts, these are non-toxic salts of the compounds of the invention, which are usually prepared by reacting the free substance with a suitable organic or inorganic acid. Examples of such salts include acetates, benzenesulfonates, benzoates, hydrogen carbonates, hydrogensulfates, hydrogentartrates, borates, bromides, calcium salts, camsylates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, edisylates, estolates, esylates, fumarates, gluconates, glutamates, glycollylarsanilalates, hexylresorcinates, hydrobamine salts, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobiomates, laurates, malate, maleates, mesylates, methylbromides, methyl nitrates, methylsulfates, methylsulfates, methylsulfates N-methylglucamine ammonium salts, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate-hydrogenphosphate mixture, polygalacturonate, salicylate, stearate, sulphate,

subacetates, succinates, tannates, tartrates, theoclates, tosylates, triethiodides and valerates. In addition, when the compounds of the invention carry an acidic group, pharmaceutically acceptable alkali metal salts of the compounds may be formed, e.g., sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, and salts with suitable organic ligands, e.g., quaternary ammonium salts.

The compounds of the invention may contain chiral centers and may therefore exist as racemates, racemic mixtures, diastereomeric mixtures and individual diastereomers or enantiomers, all isomeric forms being within the scope of the invention. That is, in the case of a chiral compound, the invention encompasses the single enantiomers or diastereomers, substantially free of other forms and, in addition, any mixture of the two enantiomers.

Certain compounds of the present invention contain olefinic double bonds and, unless expressly stated otherwise, the invention includes both geometric isomers E and Z.

Some of the compounds described above may exist as tautomers. An example is the ketone and its enol form, usually ketoenol tautomers. The individual tautomers and mixtures thereof are also included within the scope of the invention.

The compounds of the invention may be resolved into diastereoisomeric pairs of enantiomers, e.g., fractional crystallization from a suitable solvent such as methanol or ethyl acetate or a mixture of these solvents. The resulting pair of enantiomers can then be separated into conventional stereoisomers by conventional means, for example using chiral stationary phase HPLC. Alternatively, any enantiomer of the compounds of the invention may be prepared by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

The invention also includes polymorphic forms and hydrates of the compounds of the invention.

The invention also includes prodrugs of the compounds of the invention. The prodrug is usually also a functional derivative of a compound of the invention, readily convertible in vivo to the desired compound. That is, when administering the compounds of the invention in the treatment of various disease states, this also includes the administration of precursors, which change in vivo upon administration to the patient for specific active agents. Conventional procedures for selecting and preparing such precursors are described in Design of Prodrugs, ed. H. Bungaard, Elsevier, 1985. Metabolites of these substances include active substances that are formed upon the introduction of these precursors into the biological environment.

The term "therapeutically effective amount" refers to that amount of the active ingredient or pharmaceutical composition that produces a desired biological or therapeutic response in a tissue, system, animal or human.

The term "integrin receptor antagonists" throughout the application means compounds capable of binding to the ανβ3 receptor, ανβ5 receptor, or ανβ6 receptor with subsequent antagonism of these receptors, or a substance capable of binding to a combination of these receptors, and this can antagonize them, eg it can be a double effect on ανβ3 / ανβ5 receptors.

Bone tissue resorption refers to a process whereby osteoclasts degrade bone tissue.

An alkyl radical is a radical of a straight or branched chain alkane having 1 to 10 carbon atoms in total, e.g. methyl, ethyl,

-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, and the like.

Alkenyl is a straight or branched chain alkene radical containing from 2 to 10 carbon atoms.

Alkynyl means a straight or branched chain alkyne radical having 2 to 10 carbon atoms.

Cycloalkyl means a radical of the cyclic ring of alkanes, having from 3 to 8 carbon atoms in total, and thus is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Cycloheteroalkyl means a 3- to 8-membered, fully saturated heterocyclic ring containing 1 or 2 N, O or S heteroatoms. Examples of such groups include piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and piperazinyl.

Alkoxy means a straight or branched chain alkoxide radical having the specified number of carbon atoms, e.g., 1 to 5 carbon atoms. They are, for example, methoxy or ethoxy.

Aryl means a monocyclic or polycyclic system containing at least one aromatic ring, the monocyclic or polycyclic system containing 0, 1, 2, 3 or 4 heteroatoms from the group N, O or S, the system being unsubstituted or substituted by at least one group which independently selected from the group of hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, aryl C 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino, C 1-3 acylaminoC 1-8 alkyl, C 1-6 alkylamino, C 1-6 alkylaminoC 1 - ·

-8alkyl, C1-6dialkylamino, C1-6-dialkylaminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-5alkoxycarbonyl, C1-3alkoxycarbonylC1-6 alkyl, hydroxycarbonylC1-6alkyloxy, C1-6alkyl, cyano, trifluoromethyl, oxo or C1-5alkylcarbonyloxy. Examples of aryl groups are, for example, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thianyl, furyl, pyrryl, pyrazolyl, dihydrobenzofuryl, benzo (1,3) dioxolane, oxazolyl, isoxazolyl and thiazole these groups are unsubstituted or can be substituted by at least one substituent, the substituents are independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, arylC 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino , C1-3acylaminoC1-8alkyl, C1-6alkylamino, C1-6alkylaminoC1-8alkyl, C1-6dialkylamino, C1-6-dialkylaminoC1-8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-5alkoxycarbonyl, C1-5alkyloxyC1-6alkyl -3alkoxycarbonylC 1-6 alkyl, hydroxycarbonylC 1-6 alkyloxy, hydroxy, hydroxyC 1-6 alkyl, cyano, trifluoromethyl, oxo or C 1-5 alkylcarbonyloxy. The aryl group is preferably substituted with 1 to 4 groups, in particular 1 to 3 groups, most preferably an unsubstituted aryl group or an aryl group which is substituted with 1 or 2 of the above substituents.

When an alkyl or aryl group is present as part of another group, such as arylC0-8alkyl, those groups have the chains mentioned above. The number of carbon atoms, e.g., 1 to 10 carbon atoms, refers independently to a carbon atom in an alkyl or cyclic alkyl group or in the alkyl portion of a larger group.

• ·

Arylalkyl and alkylaryl groups contain an alkyl moiety as defined above and an aryl moiety also as defined above. Examples include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl and thienylpropyl. Examples of alkylaryl groups include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.

In the compounds of the invention, two substituents R ¹ on the same carbon atom with this carbon atom may form a carbonyl group.

In the compounds of the invention, when two R ³ substituents are on the same carbon atom, they can also form a carbonyl group with this atom. In these cases, there is no limitation that in the compounds the carbon atom to which R ³ is attached may not be bound to more than one heteroatom. In addition, two substituents on the same carbon atom may form a cyclopropyl group with that atom.

R ⁵ and R ⁶ can also form a carbonyl group with the carbon atom to which they are attached. Also in this case, there is no limitation that in the resulting compound the carbon atom to which R ⁵ and R ⁶ are bonded may not be bound to more than one heteroatom.

The halogen atom may be an iodine, bromine, chlorine or fluorine atom.

Oxy is oxygen, thio is sulfur. A carbonyl group is a C = O group.

The term "substituted" includes various degrees of substitution. Where a number of substituents are mentioned, it may be

the compound independently substituted with one or more of said groups, singly or multiply. In independent substitution, the substituents may be the same or different.

According to common nomenclature, the end portion of the side chain is described first and then proceeded down the chain to the point of attachment. E.g. C 1-5 alkylcarbonylaminoC 1-6 alkyl is a group

O! L

-C 1-6 alkyl-NH-C 1 -C 6 alkyl.

It will be appreciated that in the compounds of the invention, the individual substituents and their number must be selected in accordance with known principles for the chemical structure of the compounds.

Representative compounds of the invention typically have an affinity for lower order integrin receptors than micromol, especially for ανβ3, ανβ5 and / or ανβ6 receptors. Thus, the compounds of the invention can be used to treat mammals suffering from conditions in which bone resorption is increased. Pharmacologically effective amounts of these compounds or salts thereof are administered to inhibit osteoclast activity.

Thus, the compounds of the invention are administered at doses effective to antagonize α 1β receptors, e.g., in the prevention or treatment of osteoporosis.

In addition to inhibiting bone resorption, antagonizing ανβ3 receptors may also produce other effects such as inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, viral diseases, tumor growth or

metastases. However, inhibition of bone resorption is a very prominent effect in α1β3 receptor antagonism.

In particular, antagonism of α1βδ integrin inhibits restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions and tumor growth including metastasis.

A double antagonist effect at ανβ3 / ανβ5 receptors can be achieved by inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory conditions, viral diseases, tumor growth, or metastasis.

In the case of integrin ανβ6 receptor antagonism, angiogenesis, inflammatory conditions and poor wound healing are inhibited.

The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a compound of the invention together with a pharmaceutically acceptable carrier. The invention also relates to a process for the preparation of a pharmaceutical composition comprising as active ingredient any of the above-mentioned substances. The pharmaceutical compositions can be used for the treatment of the above diseases, in particular for the treatment and prevention of osteoporosis.

In the treatment of bone resorption and in the treatment and / or prevention of osteoporosis in a mammal, an effective amount of a compound of the invention or an effective amount of a pharmaceutical composition thereof is administered to said mammal.

* · ♦ ·

In the treatment of hypercalcemia in cancer, osteopenia due to bone metastasis, bone disease, increased thyroid activity, joint damage in rheumatoid arthritis, Paget's disease, osteopenia after immobilization and glucocorticoid administration conditions in mammals, an effective amount of any compound is administered to these mammals. according to the invention or an effective amount of a pharmaceutical composition comprising such a substance.

The invention also relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment and / or prevention of the aforementioned diseases, in particular for the treatment and / or prevention of bone resorption, tumor growth, especially cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration. inflammatory conditions, viral diseases and / or angiogenesis.

The invention also relates to pharmaceutical compositions which may contain another active ingredient from the following groups:

(a) organic bisphosphonates and their salts or esters;

(b) estrogen receptor modulators;

c) cytotoxic and antiproliferative substances,

d) matrix metalloproteinase inhibitors,

(e) inhibitors of epidermis, fibroblast or platelet-derived growth factors;

(f) VEGF inhibitors;

g) Flk-1 / KDR inhibitor, Flt-1, Tck / Tie-2, or Tie-1;

h) cathepsin K inhibitors; and

i) prenylation inhibitors, e.g., a farnesyltransferase or geranylgeranyltransferase inhibitor or a farnesyl / geranylgeranyltransferase double inhibitor, and mixtures thereof.

These types of compounds have been described in B. Millauer et al., Dominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivo, Cancer Research, 56, 16151620, 1996.

The active ingredient is preferably selected from the group

(a) organic bisphosphonates and their salts or esters;

(b) estrogen receptor modulators; and

c) cathepsin K inhibitors and mixtures thereof.

Examples of bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandronate, as well as pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate and especially alendronate monosodium salt trihydrate.

Examples of estrogen receptor modulators include estrogens, progesterin, estradiol, droloxifene, raloxifene and tamoxifen.

Examples of cytotoxic and antiproliferative agents include taxol, vincristine, vinblastine and doxorubicin.

Cathepsin K, formerly referred to as cathepsin 02, is a cysteine protease and is described in PCT application WO 96/13523, published May 9, 1996, further described in US 5501969 of March 3, 1996, US 5736357 of 7. Cysteine proteases, and in particular cathepsins, are capable of inducing a variety of disease states, such as tumor metastasis, inflammation, arthritis, and bone deformation. At acidic pH values, cathepsins can also degrade collagen type I. Protease inhibitors of cathepsin type can inhibit bone resorption by osteoclasts by inhibiting collagen fiber degradation and are thus useful in the treatment of diseases in which

there is an increased resorption of bone tissue, eg in the treatment of osteoporosis.

Combinations of the compounds of the invention with other active agents also used for the prevention or treatment of osteoporosis can also be used for the purposes of the invention. For example, the compounds of the invention may be administered with good results in combination with effective doses of bisphosphonates, especially organic bisphosphonates, in combination with estrogen receptor modulators or cathepsin K type inhibitors.

Another disease state that can be treated with these agents are those in which tumor growth occurs. In this case, the compound of the invention is administered in combination with other agents known to be cytotoxic or to have an antiproliferative effect. Irradiation in the treatment of tumors and their metastases may also be added to the compounds of the invention.

In addition, α1β3 integrin receptor antagonists may be administered in combination with agents that promote growth hormone secretion in the treatment or prevention of disorders of calcium or phosphate metabolism and related diseases. These are conditions that can be improved by reducing bone resorption. This should reduce bone loss and rebuild the tissue. By reducing bone resorption, the pain associated with bone breakdown can be alleviated and the occurrence of such pain should also be reduced.

Diseases which can be treated in this way include osteoporosis caused by, for example, estrogen deficiency, immobilization, elevated glucocorticoid levels or age, osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic tumors, ostomyostasis. , nephrolithiasis, urolithiasis, atherosclerosis, joint inflammation, bursitis, inflammation of the nerves and tetanus. Increased bone resorption may • • ** ** .......

be accompanied by pathologically elevated blood plasma calcium and phosphate concentrations. Similarly, the compounds of the invention may be used to increase bone mass in patients with growth hormone deficiency. For this reason, the α1β3 integrin receptor antagonist and the growth hormone secretion enhancers are preferably administered simultaneously or alternately. yet with a third component, which may be an organic bisphosphonate, preferably alendronate monosodium salt trihydrate.

The individual components of the combinations may be administered separately at different times during the course of treatment or simultaneously separately or in the form of a combined pharmaceutical composition. The invention encompasses all such processes. It will be appreciated that the combination of the compounds of the invention with other agents for treating conditions mediated by integrins includes substantially any combination, and in particular any pharmaceutical composition that is useful for treating osteoporosis.

As regards the term 'composition', this term means a product made up of specific ingredients in a specific quantity, as well as any product which is the direct or indirect result of a combination of specific ingredients in a specified quantity.

The compounds of the invention may be administered in conventional oral dosage forms, such as tablets, capsules, both in controlled release formulations, pills, powders, granules, elixirs, elixirs, elixirs, suspensions, syrups and emulsions. The compounds may also be administered intravenously by injection or infusion, intraperitoneally, topically, e.g. as eye drops, subcutaneously, intramuscularly or transdermally, e.g., as a patch, all of which are known and commonly known. produced. The active ingredient is used in these compositions in an effective but nontoxic amount.

The dose of the compounds of the invention is determined depending on various factors, e.g., age, weight, sex and disease state of the patient, the severity of the disease being treated, the mode of administration, the level of renal and hepatic function, and also the compound or its salts. The exact dose of the active ingredient for the prevention or treatment of a disease state must always be determined by the attending physician.

For oral administration, the active compounds of the invention will generally be administered in the range of 0.01 mg / kg of body weight per day to 100 mg / kg of body weight per day, preferably 0.01 to 10 and especially 0.01 to 5.0 mg / kg per day. For oral administration, the compounds are preferably formulated into tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 mg so that the appropriate dose can be adjusted to suit the patient. The dosage form typically contains 0.01 to 500 and preferably 1 to 100 mg of active ingredient. For intravenous administration, the preferred dose is in the range of 0.1 to 10 mg / kg / min for a constant rate infusion. The compounds of the invention may be administered once daily or the total daily dose may be divided into 2, 3 or 4 doses administered throughout the day. In addition, preferred compounds of the invention may be administered by the nasal mucosa or transdermally in the form of a patch. Of course, when administered in the form of a transdermal patch, it is rather a continuous administration.

The compounds according to the invention are used in pharmaceutical formulations as active substances in admixture with other excipients customarily used for this purpose, such as diluents, carriers and excipients suitable for the pharmaceutical form used, e.g. 9 · 9 9 * 9 * 9 9 »v v e 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 administration, capsules, elixirs and syrups, all excipients are commonly used in the pharmaceutical industry.

E.g. for oral administration in the form of a tablet or capsule, the active ingredient may be combined with an orally non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, mannitol, sorbitol and the like. in the case of oral administration of the liquid dosage form, the inert carrier may be ethanol, glycerol, water and the like. In addition, suitable binders, glidants, disintegrants and colorants may be added if desired. Binders include starch, gelatin, natural sugars such as glucose or beta-lactose, maize materials, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. sodium oleate, sodium or magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like can be used. The disintegrating agent can be, for example, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The compounds of the invention may also be administered encapsulated in the form of a liposome, in the form of small vacuoles, whether unilamellar or multilameral. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of the invention can also be delivered to the site using monoclonal antibodies as individual carriers to which the active compounds are bound. The compounds of the invention may also be coupled to soluble polymers as targetable carriers. These polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol copolymer, polyhydroxyethylaspartamide and phenol or polyethylene oxide;

· 4

4 4 e

polylysine, substituted with palmitic acid residues. In addition, the compounds of the present invention can be coupled to biodegradable polymers to control the active ingredient release, for example polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilone caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates crosslinked or amphipathic sequence copolymers or hydrogels.

Various abbreviations of reagents and other materials will be used in the following schemes and examples:

AcOH: acetic acid

BH ₃ * DMS: boramdimethylsulfide

BOC (Boc): t-butyloxycarbonyl

BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

CBZ (Cbz): carbobenzyloxy or benzyloxycarbonyl

CDI: carbonyldiimidazole

CH ₂ Cl ₂ : methylene chloride

CH ₃ CN: acetonitrile

CHCl ₃ : chloroform

DBA: bis (dibenzylidene) acetone

DEAD: diethyl azodicarboxylate

D1 AD: diisopropyl azodicarboxylate

DIBAH or

DIBAL-H: diisobutylaluminum hydride

DIPEA: diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DME: 1,2-dimethoxyethane

DMF: dimethylformamide

DMSO: dimethylsulfoxide

DPPF: 1,1'-bis (diphenylphosphine) ferrocene

DPFN: 3,5-dimethyl-1-pyrazolylformamidine nitrate EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl EtOAc: ethyl acetate EtOH: ethanol HOAc: acetic acid HOAT: 1-Hydroxy-7-azabenzotriazole HOBT: 1-Hydroxybenzotriazole IBCF: isobutylchloroformate LDA: lithium diisopropylamide MeOH: methanol MMNG: 1,1-methyl-3-nitro-1-nitrosoguanidine NEt ₃ : triethylamine NMM: N-methylmorpholine PCA.HCI: pyrazolecarboxamidine hydrochloride Pd / C: palladium on activated carbon Ph: phenyl pTSA: p-toluenesulfonic acid TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography TMEDA: Ν, Ν, Ν, tetramethylethylenediamine TMS: trimethylsilyl.

The novel compounds of the invention can be prepared according to the following schemes and examples using the appropriate starting materials. In the Example section, all temperatures are in ° C unless otherwise indicated.

· __ 70 70 · 70 70 70 70 70 70 70 70 70 70 70 70 70 70

In addition to the procedures in the following Schemes and Examples, the methods of WO 95/32710, published December 7, 1995 and WO 95/17397, published June 29, 1995, were used. according to the invention is Cole, DC, Recent Stereoselective Synthetic Approaches to Beta-Amino Acids, Tetrahedron, 1994, 50, 9517-9582, Juaristi, E. et al., Enantioselective Synthesis of beta-Amino Acids, Aldrichimica Acta, 1994, 27, 3. Synthesis 3-methyl-beta-alanine has been described in Duggan, MF et al., J. Med. Chem., 1995, 38, 3332-3341 and the synthesis of 3-ethynyl-beta-alanine in Zablocki, J. A. et al., J. Med. Chem., 1995, 38, 2378-2394, the synthesis of 3- (pyridin-3-yl) -beta-alanine in Rico, J.G. et al., J. Org. Chem., 1993, 58, 79487951 and the synthesis of 2-amino- and 2-tosylamino-beta-alanine in Xue, C.-B. and other, Biorg. Copper. Chem. Letts., 1996, 6, 339-344.

• ·

SCHEM41

co ₂ ch ₃

CHO nh ₂

proline. EtOH, Δ

10% Pd / C EtOH, H ₂

CO ₂ CH ₂

1-5 • ·

BOP, NMM, CH ₂ CN t

IZ

1-9 ··· · ··· · ··· · ················ 6-Oxo-heptanoic acid methyl ester (1-2) ···········

To a vigorously stirred mixture of 175 mL of diethyl ether and 52 mL of 40% potassium hydroxide at 0 ° C was added 15.4 g (105 mmol) of MNNG. The mixture was stirred for 10 minutes. The ether portion was converted to a solution of 5.0 g (34.68 mmol) of 6-oxo-heptanoic acid (1-1) and methylene chloride at 0 ° C. Argon was bubbled through the solution for 30 minutes and then concentrated.

Flash column chromatography on silica eluting with a gradient of 30% to 50% ethyl acetate in hexanes gave the ester (1-2) as a clear oil.

TLC Rf = 0.88 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 3.67 (s, 3H), 2.46 (m, 2H), 2.33 (m, 2H),

2.14 (s, 3H); 1.62 (m, 4H).

5- [1,8] Naphthyridin-2-yl-pentanoic acid methyl ester (1-4)

A mixture of 1.4 g (9.04 mmol) of compound (1-2), 552 mg (4.52 mmol) of compound (1-3) of 2-amino-3-formyl-pyridine (J. Org. Chem., 1983 , 48, 3401) and 260 mg (2.26 mmol) of proline in 23 mL of absolute ethanol were heated at reflux for 18 h. After removal of the solvent by evaporation, the residue was purified by silica gel column chromatography eluting with 80% ethyl acetate in hexane and then ethyl acetate to give the ester compound (1-4) as a white solid.

TLC Rf = 0.38 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.08 (m, 1H), 8.16 (d, J = 8.0 Hz, 1H),

8.10 (d, J = 8.3Hz, 1H), 7.45 (m, 1H), 7.39 (d, J = 8.3Hz, 1H), 3.66 (s,

3H), 3.08 (t, J = 7.6Hz, 2H), 2.39 (t, J = 7.6Hz, 2H), 1.94 (m, 2H), 1.78 (m, 2H).

5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoic acid methyl ester (1-5)

A mixture of 630 mg (2.58 mmol) of compound (1-4) and 95 mg of a 10% palladium on carbon solution in 25 ml of ethanol was stirred under a hydrogen atmosphere for 72 hours. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexanes to give compound (1-5) as a colorless oil.

TLC Rf = 0.58 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.05 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 4.72 (s, 1H), 3.66 (s, 3H), 3.40 (m, 2H), 2.69 (t, J = 6.3 Hz,

2H), 2.53 (m, 2H), 2.33 (m, 2H), 1.90 (m, 2H), 1.66 (m, 4H).

5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) pentanoic acid hydrochloride (1-6)

A mixture of compound (1-5) (620 mg, 2.50 mmol) and 6N hydrochloric acid (12 mL) was heated at 50 ° C for 18 h. Removal of the solvent by evaporation gave compound (1-6) as a yellow solid.

¹ H NMR (300 MHz, CD ₃ OD): d 7.59 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 3.48 (m 2H, 2.82 (m, 2H), 2.72 (m, 2H), 2.35 (m, 2H), 1.95 (m, 2H), 1.69 (m, 4H).

3 (S) - (Pyridin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) pentanoylamino) propionic acid ethyl ester (1- 8)

A mixture of 50 mg (0.1847 mmol) of compound (1-6), 49 mg (0.1847 mmol) of compound (1-7) (Rico et al., J. Org. Chem, 1993, 58, 7948), 90 mg (0.2032 mmol) BOP and 0.122 mL (1.11 mmol) NMM in 2 mL methyl cyanide were stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and then dried over magnesium sulfate. After removal of the solvent by evaporation, the residue was purified by silica gel column chromatography eluting with 20% methanol in ethyl acetate to give compound (1-8) as a yellow oil.

TLC Rf = 0.23 (20% methanol in ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.54 (s, 1H), 8.43 (d, J = 4.9Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H ), 7.85 (m, 1 H), 7.39 (m, 1 H), 7.15 (d, J = 7.3 Hz, 1 H),

6.34 (d, J = 7.3Hz, 1H), 5.37 (t, J = 7.3Hz, 1H), 4.05 (q, J = 7.1Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H); 2.64 (m, 2H); 2.52 (m, 2H); 2.22 (m, 2H); 1.86 (m, 2H); 64 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H).

3 (S) - (Pyridin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) pentanoylamino) propionic acid (1-9)

To a solution of compound (1-8) (0.1847 mmol) in ethanol (2 mL) was added 1 N sodium hydroxide (0.250 mL, 0.250 mmol). After stirring for 2 hours, the solvent was evaporated and the residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, ethanol, water and ammonium hydroxide (15: 10: 1: 1) to give compound (1-9) as a white solid.

TLC Rf = 0.15 (15: 10: 1: 1 ethyl acetate: ethanol: water: ammonium hydroxide). ¹ H NMR (300 MHz, CD ₃ OD): d 8.55 (s, 1H), 8.42 (d, J = 4.9Hz, 1H),

7.84 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.41 (m, 1H), 6.50 (d, J = 7, 1Hz, 1H), 5.42 (m, 1H), 3.47 (t, J = 5.6 Hz, 2H), 2.55 to 2.81 (m, 6H), 2.41 (m, 1H) 1.32 (m, 1H), 2.93 (m, 2H), 1.71 (m, 4H).

Scheme 2

2-3 «v • ·

N HCl, 50 ° C τ

ethyl 4- (1,8-naphthyridin-2-yl) butanoate (2-3)

A mixture of 2.02 g (16.6 mmol) of aminoaldehyde compound (1-3), (Het. 1993, 36, 2513), 5.3 ml (33.1 mmol) of ketone (2-2) and 0.48 g. Lproline (4.17 mmol) was combined in 75 mL ethanol. The mixture was heated to reflux overnight, and then concentrated. Flash column chromatography on silica eluting with ethyl acetate gave compound (2-3) as an off-white crystalline solid.

TLC Rf 0.23 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.09 (dd, J = 4.2 Hz, 1H), 8.17 (dd, J = 8.2 Hz, 1H), 8.12 (d, J) = 8Hz, 1H), 7.46 (dd, J = 8.4Hz, 1H), 7.42 (d, J = 8Hz).

1H), 4.12 (q, J = 7Hz, 2H), 3.11 (t, J = 8Hz, 2H), 2.44 (t, J = 7Hz, 1H),

2.26 (qn, J = 8 Hz, 2H); 1.25 (t, J = 7 Hz, 3H).

ethyl 4- (1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl) butanoate (2-4)

A solution of 2.3 g (9.4 mmol) of compound (2-3) in 50 mL of ethyl acetate was treated with 230 mg of 10% palladium on charcoal under a hydrogen atmosphere. After 4 days, the reaction mixture was filtered through celite, concentrated and purified by flash column chromatography on silica eluting with 70% ethyl acetate in hexane to give compound (2-4) as a yellow oil.

TLC Rf 0.40 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.05 (d, J = 7 Hz, 1H), 6.35 (d, J = 7 Hz, 1H), 4.73 (br s, 1H), 4, 12 (q, J = 7Hz, 2H), 2.69 (t, J = 6Hz, 2H), 2.57 (t, J = 8Hz, 2H), 2.33 (t, J = 7Hz, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.25 (t, J = 7 Hz, 3H).

4- (1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl) butanoic acid hydrochloride (2-5)

A mixture of 1.8 g (7.25 mmol) of the ester of compound (2-4) in 36 ml of a 6 N hydrochloric acid solution was heated at 50 ° C for 4 hours and then concentrated to give compound (2-5) as yellow solids.

¹ H NMR (300 MHz, CD ₃ OD): d 7.59 (d, J = 7 Hz, 1H), 6.63 (d, J = 7 Hz, 1H), 3.50 (t, J = 5 Hz, 2H) 2.82 (t, J = 6 Hz, 2H), 2.74 (t, J = 8 Hz, 2H), 2.38 (t, J = 7 Hz, 2H), 2.02-1.90 (m) , 4H).

Scheme 3

O

NHSO ₂ Ph • HCI 3J.

EDC, HOBT, DMF

O

O

3-2

NHSO ₂ Ph

JCEt

LiOH, MeOH

H ₂ O

2x5

O

O

NHSO ₂ Ph 'to JCH 2 (S) -Benzenesulfonyl-amino-3- (5 (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoyl) ethyl trifluoroacetate -amino) -propionic (3-2)

A solution of 304 mg (0.85 mmol) of 5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoic acid hydrochloride (1-6) in 5 ml of dimethylformamide is treated successively with 115 mg (0.85 mmol) of HOBT, 263 mg (0.85 mmol) of amine (3-1) (prepared according to the procedure for Intermediate A-4 substituting benzenesulfonyl chloride for 4-iodo-benzenesulfonyl chloride) , 195 mg (1.02 mmol) of EDC and 0.24 ml (1.71 mmol) of triethylamine. The resulting solution was stirred at room temperature for 18 hours, then poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. After washing with a saturated sodium chloride solution, the solvent was evaporated and the residue was purified by silica gel column chromatography eluting with 5% methanol in chloroform to give an oil. Further purification using reverse phase HPLC afforded the title compound as a white solid.

FAB mass spectrum, found (M + H) + = 489.3 2 (S) -Benzenesulfonyl-amino-3- (5- (5,6,7,8-tetrahydro-1,8 [1,8] -) trifluoroacetate) naphthyridin-2-yl) -pentanoyl-amino) -propionic acid (3-3)

To a solution of 180 mg (0.37 mmol) of ester (3-2) in 2 ml of methanol and 2 ml of methanol.

7g of water was added with 0.74 ml (0.74 mmol) of 1N lithium hydroxide solution and stirred for 4 hours. 1 ml of 1N hydrochloric acid solution was added and the solution was purified by reverse phase HPLC to give the title compound as a white solid.

FAB mass spectrum, found (M + H) + = 461.21

Scheme 4

EDC, HOBT, DMF

2. LiOH, MeOH, H ₂ O

2 (S) - (2-Thienylsulfonyl-amino) -3- (5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoyl-amino) trifluoroacetate -propionic acid (4-2) A solution of 5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) pentanoic acid hydrochloride (1-6) in 0.164 mg (0.7 mmol) in 5 ml of dimethylformamide are treated successively with 104 mg (0.77 mmol) of HOBT, 211 mg (0.85 mmol) of amine (4-1) (Egbertson et al., Bioorg. Med. Chem. Letts, 1996, 6, 2519). , 161 mg (0.84 mmol) of EDC and 0.23 mL (2.1 mmol) of N-methyimorpholine. The resulting solution was stirred at room temperature for 18 hours and then poured into saturated sodium bicarbonate solution.

...........

extracted twice with ethyl acetate. After washing with a saturated sodium chloride solution, the solvent is evaporated and the residue is used without further purification in the next synthesis step.

To a solution of 290 mg (0.6 mmol) of this ester in 20 mL of a 1: 1: 1 mixture of tetrahydrofuran, methanol and water was added 100 mg (2.4 mmol) of aqueous lithium hydroxide solution. The mixture was stirred for 20 hours, tetrahydrofuran and methanol were removed in vacuo and the aqueous solution was purified by reverse phase HPLC to give the title compound as a white solid.

1 H NMR (CD ₃ OD): d 7.73-7.78 (1H, dd), 7.54-7.62 (2H, m), 7.08-7.15 (1H, m), 6, 60-6.67 (1H, d), 4.08-4.16 (1H, m), 3.57-3.67 (1H, dd), 3.40-3.50 (2H, t), 3.20-3.30 (1H, m), 2.75-2.85 (2H, t), 2.65-2.75 (2H, t), 2.20-2.30 (2H, t) 1.85-1.97 (2H, m), 1.60-1.80 (4H, m).

EtOH, HCl 25%

3-Amino-3- (quinolin-3-yl) -propionic acid (5-2)

A solution containing 5 g (31.8 mmol) of quinoline-3-carboxaldehyde (5-1),

Malonic acid (3.6 g, 35.0 mmol) and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 ml) were heated at reflux for 12 hours. After cooling to room temperature, the formed white solid was collected by filtration and washed with 150 mL cold ethanol, and then dried in vacuo to give 3.84 g (17.8 mmol, 56%) of compound (5-2) as a white solid. substances.

¹ H NMR (300 MHz, D ₂ O): d 8.91 (d, J = 2 Hz 1H), 8.21 (d, J = 2 Hz, 1H), 8.12 (d, J = 8 Hz) (1H), 7.84 (d, J = 7Hz, 1H), 7.72 (t, J = 7Hz, 1H), 7.54 (t, J = 7Hz, 1H), 4.72 ( m, 1H), 2.73 (m, 2H).

3-Phenyl-acetyl-amino-3- (quinolin-3-yl) -propionic acid (5-3)

Cooled to 0 ° C 3.5 g (16.2 mmol) of compound (5-2) a

Sodium bicarbonate (2.7 g, 32.4 mmol) in 50% aqueous dioxane (100 mL) was treated dropwise with a solution of phenylacetyl chloride (3.00 g, 19.4 mmol) in dioxane (25 mL). The 2.5 and

The mixture was stirred at 0 ° C for 1 h, warmed to room temperature, diluted with 50 mL of water and washed twice with 100 mL of ether. The aqueous portion was brought to pH = 3 by addition of 3N hydrochloric acid solution and then extracted three times with 150 ml of methylene chloride. The organic extracts were dried, filtered and concentrated to give compound (5-3) as an off-white solid. 1 H NMR (300 MHz, CD ₃ OD): d 8.85 (d, J = 2 Hz 1H), 8.20 (d, J = 2 Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 7.86 (d, J = 7Hz, 1H), 7.76 (t, J = 7Hz, 1H), 7.52 (t, J = 7Hz, 1H), 7.28 (m) 6H), 5.53 (t, J = 6.8 Hz, 1H), 3.57 (s, 2H), 2.96 (m, 2H).

3-Amino-3 (S) - (quinolin-3-yl) -propionic acid dihydrochloride (5-6) A suspension of 5.0 g (15 mmol) of acid (5-3) in 3.5 L of water is treated with 15 ml of 1N sodium hydroxide solution to give a clear solution. To the solution was added 10,000 U penicillin amidase (Sigma, EC 3,5,1,11) in 0.1 M phosphate buffer solution. The pH of the mixture was brought to 7.8 by addition of 1N sodium hydroxide solution and the solution was stirred at room temperature for 4 days. The reaction mixture was monitored regularly by HPLC and the reaction was complete as soon as 50% conversion occurred. The reaction solution was cooled to 0 ° C and brought to pH = 3 by addition of 3N hydrochloric acid solution. The resulting oily yellow precipitate was collected by filtration and washed with water to give 1.8 g (5.3 mmol) of crude product (5-5). The filtrate is extracted three times with 500 ml of methylene chloride to give a further portion of the product (5-5) which contains an addition of phenylacetic acid. The two batches were combined and stirred for 12 hours at 50 ° C in 200 ml of 3 N hydrochloric acid. After cooling, the product is washed twice with 100 ml of ether and evaporated to give the product (5-6).

3-Amino-3- (quinolin-3-yl) -propionic acid ethyl ester dihydrochloride (5-7)

The formed acid (5-6) in a methanolic hydrochloric acid solution is heated to reflux to give the product (5-7).

¹ H NMR (300 MHz, CD ₃ OD): d 9.25 (d, J = 2 Hz, 1 H), 8.31 (d, J = 2 Hz, 1 H), 8.15 (d, J = 8) Hz, 1H), 7.84 (d, J = 7Hz, 1H), 7.72 (t, J = 7Hz, 1H), 7.54 (t, J = 7Hz, 1H), 4.72 (m, 1H), 4.15 (q, J = 6Hz, 2H), 2.73 (m, 2H), 1.18 (t, J = 6Hz, 3H).

Diagram 5 (continued)

• · ·

ZI

ethyl 3- (5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoyl-amino) -3 (S) -quinolin-3-yl) -propionate (5 -8)

A mixture of 200 mg (0.74 mmol) of product (1-6), 202 mg (0.74 mmol) of product (5-7), 366 mL (3.33 mmol) of NMM, 130 mg (0.96 mmol) of HOBT and 184 mg (0.96 mmol) of EDC in 2 mL of DMF were stirred overnight. After dilution with 100 ml of ethyl acetate, the mixture was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica column chromatography at

eluting with 10% ethanol in ethyl acetate to give (5-8) as a colorless glassy solid of the title product.

TLC Rf = 0.6 (10% ethanol in ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.80 (d, J = 2 Hz, 1 H), 8.31 (d, J = 2 Hz, 1 H), 8.15 (d, J = 8 Hz) (1H), 7.84 (d, J = 7Hz, 1H), 7.72 (t, J = 7Hz,

1H), 7.54 (t, J = 7Hz, 1H), 7.00 (d, J = 8.1Hz, 1H), 6.53 (d, J = 7.5Hz, 1H), 5 34 (m, 1H), 4.06 (q, J = 7.5Hz, 2H), 3.48 (t, J = 5.7Hz, 2H), 2.79 (m, 4H), 2 63 (m, 2H), 2.25 (m, 2H), 1.94 (m, 2H), 1.64 (m, 4H), 1.12 (t, J = 7.5 Hz, 3H) .

3 (S) - (Quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) pentanoylamino) -propionic acid (5) -9)

A solution of 145 mg (0.320 mmol) of ester (5-8) in 1 mL of ethanol was treated with 352 mL (0.35 mmol) of 1N lithium hydroxide solution and stirred at room temperature overnight. The reaction solution was neutralized with 352 ml of 1N hydrochloric acid, evaporated and purified by silica gel column chromatography eluting with a gradient of 60% ethanol: ammonium hydroxide / water (20: 1: 1 to 40% ethyl acetate) to give the title product ( 5-9) as white solids.

TLC Rf = 0.5 (60% ammonium ethanol: water 20: 1: 1 40% ethyl acetate).

¹ H NMR (300 MHz, CD ₃ OD): d 8.80 (d, J = 2 Hz, 1 H), 8.31 (d, J = 2 Hz, 1 H), 8.15 (d, J = 8) Hz, 1H), 7.84 (d, J = 7Hz, 1H), 7.72 (t, J = 7Hz, 1H), 7.54 (t, J = 7Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 5.34 (m, 1H), 3.48 (t, J = 5.7 Hz, 2H), 2.79 (m, 2H), 2.63 (m, 2H), 2.25 (m, 2H), 1.94 (m, 2H), 1.64 (m, 4H).

3 (S) - (5,6,7,8) -tetrahydro-quinolin-3-yl) -3- (5- (5,6,7,8) tetrahydro- [1,8] -naphthyridin-2 trifluoroacetate) -yl) -pentanoyl-amino) -propionic acid (5-10)

A mixture of compound (5-8) (0.1 g, 0.3 mmol) and platinum oxide (0.04 g) in trifluoroacetic acid (10 ml) was purged with argon under vacuum three times and then hydrogenated for 18 hours. After filtration through celite, the solution was concentrated, 3 ml of ethanol and 1 ml (1 mmol) of 1 M lithium hydroxide solution were added, and the reaction mixture was stirred for 3 hours. The reaction mixture was then treated with 2 mL of 2N hydrochloric acid solution, concentrated and purified by reverse phase HPLC (C18 column; gradient elution from 95: 5: 0.1 to 5: 95: 0.1 water / methyl cyanide) and trifluoroacetic acid (45 min) to give the desired product (5-10) as trifluoroacetate.

¹ H NMR (300 MHz, CD ₃ OD): d 8.50 (s, 1H), 8.23 (s, 1H), 7.52 (d, 1H), 6.54 (d, 1H), 5 33 (t, 1H), 3.50 (t, 2H), 3.08 (t, 2H), 2.94 (m, 4H), 2.80 (t, 2H), 2.68 (t, 2H), 2.28 (m, 2H), 1.96 (m, 6H), 1.66 (m, 4H).

Scheme 6

OEt

OEt

NaH, DMF CE1

Br

PPA, PhMe τ

Me

Ph

H n BuLi, THF

6-6

1. US, HOAT, EDC, NMM, DMF

2. LiOH, EtOH / H ₂ O

1-Bromo-3- (2,2-diethoxy-ethoxy) -benzene (6-2)

To a suspension of sodium hydride (2.77 g, 115.6 mmol) in DMF (100 mL) at 0 ° C was added 40 mL of a solution of 3-bromophenol (6-1) in DMF at 0 ° C over 40 min. After addition, the solution was stirred for an additional 30 minutes. The solution is then treated with 17.36 g (115.6 mmol) of pure bromoacetaldehyde diethyl acetal. The solution was heated at 100 ° C for 8 hours, cooled to room temperature, and extracted three times with 200 ml diethyl ether. The combined organic extracts were washed with 100 ml of 10% aqueous sodium hydroxide solution and 100 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the product (6-2) as a yellow oil.

TLC Rf = 0.4 (10% ethyl acetate in hexanes).

¹ H NMR (300 MHz, chloroform): d 7.19-7.06 (m, 3H), 6.85 (d, 1H),

4.81 (t, 1H, J = 6.8 Hz), 3.99 (d, 2H, J = 6.8 Hz), 3.71 (m, 4H), 1.22 (t, 6H, J = 7.1Hz) ppm.

6-Bromo-benzofuran (6-3)

To 200 ml of a solution of acetals (6-2) in toluene was added 20 g of polyphosphoric acid. The mixture of the two phases was heated to 100 ° C and stirred at this temperature for 4 hours. The mixture was cooled to room temperature, poured onto ice and extracted twice with 200 ml diethyl ether. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and saturated brine. The solution was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography eluting with 100% hexanes to give the product (6-3) as a yellow oil.

TLC Rf = 0.3 (100% hexanes).

¹ H NMR (300 MHz, chloroform): d 7.68 (s, 1H), 7.60 (d, 1H, J = 2.1 Hz), 7.46 (d, 1H, J = 8.4 Hz) 7.36 (dd, 1H, J = 8.1, 1.5 Hz), 6.75 (dd, 1H, J = 7.1, 0.9 Hz) ppm.

3- (Benzofuran-6-yl) -acrylic acid ethyl ester (6-4)

A mixture of 1.74 g (8.79 mmol) of 6-bromobenzofuran (6-3), 1.09 g (10.98 mmol) of ethyl acrylate, 0.099 g (0.44 mmol) of palladium acetate, 0.268 g (0.880 mmol). of tri-o-tolylphosphine and 3.60 g (43.9 mmol) of sodium acetate in 10 ml of dimethylformamide were heated at 100 ° C in a sealed vessel for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted twice with 40 ml diethyl ether. The combined organic extracts were washed with 30 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purify the residue by flash chromatography eluting with 10% ethyl acetate in hexanes to give the ester (6-4) as an off-white solid.

TLC Rf = 0.3 (10% ethyl acetate in hexanes).

¹ H NMR (300 MHz, chloroform): d 7.78 (d, 1H, J = 15.9 Hz), 7.68 (d, 1H, J = 2.4 Hz), 7.66 (s, 1H 7.59 (d, 1H, J = 8.4 Hz), 7.43 (dd, 1H, J = 9.0,

1.5 Hz), 6.78 (m, 1H), 6.47 (d, 1H, J = 15.9 Hz), 4.27 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz) ppm.

3 (S) - (Benzofuran-6-yl) -3- [benzyl- (1 (R) -phenyl-ethyl) -amino] -propionic acid ethyl ester (6-5)

A solution of 1.32 g (6.30 mmol) of N-benzyl-α- (R) -methyl-benzylamine in 25 mL of tetrahydrofuran at 0 ° C was treated with 2.52 mL of a 2.5 M solution of n-butyllithium in hexanes. The resulting solution was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. A solution of 0.681 g (3.15 mmol) of acrylate (6-4) in 5 mL of tetrahydrofuran was added. After stirring for 15 minutes at -78 ° C, 5 mL of saturated aqueous ammonium chloride solution was added and the cooling bath was removed. The mixture was warmed to room temperature and extracted twice with 40 ml diethyl ether. The combined organic extracts were washed with 30 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified using flash chromatography eluting with 10% ethyl acetate in hexanes to give the b-amino ester (6-5) as a yellow oil.

TLC Rf = 0.8 (10% ethanol in dichloromethane).

¹ H NMR (300 MHz, chloroform): d 7.58 (m, 3H), 7.41 (m, 2H), 7.22 (m, 9H), 7.59 (s, 1H), 4.58 (m, 1H), 4.05 (m, 1H), 3.91 (q, 2H, J = 7.1 Hz), 3.72 (m, 2H), 2.62 (m, 2H), 1, 21 (d, 3H, J = 7.2Hz), 1.03 (t, 3H, J = 7.1Hz) ppm.

3 (S) -Amino-3- (2,3-dihydro-benzofuran-6-yl) -propionic acid ethyl ester (6-6)

A mixture of 1.19 g (2.78 mmol) of dibenzylamine (6-5) in a mixture of 26 ml of ethanol, 3 ml of water and 1.0 ml of acetic acid was degassed with argon and treated with 1.19 g of palladium hydroxide. The mixture is placed under an atmosphere of hydrogen at 10 psi. After stirring for 18 hours, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated and the residue was purified by flash chromatography eluting with 10% ethyl acetate in dichloromethane to give the ester (6-6) as a white solid.

TLC Rf = 0.25 (10% ethanol in dichloromethane).

¹ H NMR (300 MHz, CD ₃ OD) as trifluoroacetate: d 7.25 (d, 1H,

J = 8.1 Hz), 6.88 (m, 1H), 7.66 (s, 1H), 6.82 (s, 1H), 4.58 (m, 3H), 4.12 (m, 2H) ), 3.30 (m, 1H), 3.19 (m, 2H), 2.98 (m, 2H), 1.11 (t, 3H, J = 7.2 Hz) ppm.

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoyl-amino) -propionic acid (6-7)

A solution of 0.162 g (0.596 mmol) of amine (6-6), 0.183 g (0.775 mmol) of acid (1-6), 0.148 g (0.775 mmol) of EDC, 0.156 g (1.55 mmol) of NMM and 0.105 g (0.775 mmol) The HOAT in 6 ml of DMF was stirred at room temperature for 12 hours. The solution was concentrated and the residue was purified by preparative HPLC (gradient of water / methyl cyanide ratios containing 0.1% trifluoroacetic acid solution from 95:05 to 50:50) to give 0.227 g of the ester as a yellow oil.

The ester was dissolved in 6 mL of ethanol in water (9: 1) and treated with 0.065 g (1.55 mmol) of lithium hydroxide. After stirring for 3 hours, the solution is concentrated to a paste which is purified by prepa91

eluting with a gradient of from 95:05 to 50:50 a mixture of water and methyl cyanide containing 0.1% trifluoroacetic acid to give the product (6-7) as a white solid.

TLC Rf = 0.24 (5% methanol in methylene chloride).

¹ H NMR (300 MHz, CD ₃ OD): d 7.57 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.79 (dd) J = 1.5, 7.2 Hz, 1H), 6.70 (s, 1H), 6.58 (d, J = 7.2 Hz, 1H), 5.27 (t, J = 8, 4 Hz, 1H), 4.50 (t, J = 8.7 Hz, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.14 (t, J = 8.7 Hz) 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 2.26 (m, 2H), 1.94 (m, 2H), 1.64 (m, 4H) ppm.

Scheme 7

1. Fe. AcOH

2. CDI.THr

• · t t t t t t t t t t a a a

1-6, HOAT, EDC, NMM, DMF

2. LiOH, EtOH / H _? O

HN '

3- (3-Hydroxy-4-nitro-phenyl) -acrylic acid ethyl ester (7-2)

To a solution of 15.0 g (98.0 mmol) of aldehyde (7-1) in 300 mL of methylene chloride was slowly added 34.1 g (98.0 mmol) of carbo-ethoxy-methylenetrifenylphosphorane. The orange solution was stirred at room temperature for 12 hours. The solution was concentrated and the residue as a paste purified by flash chromatography eluting with 10% ethyl acetate in methylene chloride to give the title product (7-2) as a yellow solid.

TLC Rf = 0.51 (30% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CD ₃ OD): d 8.08 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 16.2 Hz, 1H), 7.35 (d J = 1.5 Hz, 1H), 7.27 (dd, J = 8.4, 1.5 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 4.25 (q, J = 7.2Hz, 2H), 1.32 (t, J = 6.9Hz, 3H) ppm.

3- (2-Oxo-2,3-dihydro-benzo-oxazol-6-yl) -acrylic acid ethyl ester (7-3)

To a solution of 12.0 g (57.4 mmol) of nitrophenol (7-2) in 200 ml of a mixture of acetic acid and water heated to 70 ° C was added 9.61 g (172.2 mmol) of iron powder. The brown heterogeneous mixture was stirred at 70-80 ° C for 30 minutes. The hot mixture was filtered through celite and the celite pad was washed twice with 200 mL ethyl acetate. The filtrate was carefully neutralized by the addition of three times 100 ml of a saturated aqueous solution of sodium hydrogen carbonate. The solution was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to give 9.6 g (81%) of an orange solid.

A portion, 4.5 g (21.7 mmol) of this solid, was dissolved in 150 mL of tetrahydrofuran and treated with 3.87 g (23.8 mmol) of 1,1-carbonyl-diimidazole. The solution was stirred at room temperature for 24 hours, diluted with ethyl acetate (100 ml) and washed with 10% hydrochloric acid (50 ml) and brine (50 ml). The solution was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to give (7-3) as a yellow solid.

TLC Rf = 0.49 (5% methanol in methylene chloride).

¹ H NMR (300 MHz, CD ₃ OD): d 7.77 (d, J = 15.9 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.4 Hz) 1 H, 7.09 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H) 1.31 (t, J = 7.2 Hz, 3H) ppm.

3 (S) -Amino-3- (2-oxo-2,3-dihydro-benzo-oxazol-6-yl) -propionic acid ethyl ester (7-4)

A solution of 4.08 g (19.3 mmol) of N-benzyl-α- (R) -methyl-benzylamine in 120 ml of tetrahydrofuran at 0 ° C is treated with 7.72 ml of a 2.5 M solution of n-butyllithium in a mixture of hexanes . The resulting solution was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. After addition of a solution of 1.5 g (6.43 mmol) of acrylate (7-3) in 20 ml of tetrahydrofuran, the mixture was stirred at -78 ° C for 15 minutes. Subsequently, 25 ml of saturated aqueous ammonium chloride solution were added and the cooling bath was removed. The mixture was warmed to room temperature and extracted twice with 40 ml diethyl ether. The combined organic extracts were washed with 30 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 2.74 g of the title b-aminoester as a yellow oil.

> 0 · 00 · 00 »·« 0 · 0 · »0 ·» · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · '..... ··

The amino ester is dissolved in a mixture of 54 ml of methanol, 4.8 ml of water and 1.2 ml of acetic acid. After degassing with argon, the mixture was treated with 2.74 g of palladium hydroxide. The mixture is placed under an atmosphere of hydrogen at 10 psi. After stirring for 18 hours, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated to give the title product (7-4) as an off-white solid.

TLC Rf = 0.10 (5% methanol in methylene chloride).

¹ H NMR (300 MHz, CD ₃ OD): d 7.34 (s, 1H), 7.26 (dd, J = 1.2, 8.1 Hz,

1H), 7.12 (d, J = 8.1 Hz, 1H), 4.65 (t, J = 7.2 Hz, 1H), 4.13 (q, J = 6.9 Hz,

2H), 2.98 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H) ppm.

3 (S) - (2-Oxo-2,3-dihydro-benzoxazol-6-yl) -3- (5 (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) trifluoroacetate) -pentanoyl-amino) -propionic (7-5)

A solution of 0.196 g (0.784 mmol) of amine (7-4), 0.222 g (0.941 mmol) of acid (1-6), 0.189 g (0.988 mmol) of EDC, 0.190 g (1.88 mmol) of NMM and 0.134 g (0.988 mmol) of acetic acid in 6 ml of DMF was stirred at room temperature for 12 hours. The solution was concentrated and the residue was purified by preparative HPLC eluting with a gradient of from 95:05 to 50:50 a mixture of water and methyl cyanide containing 0.1% trifluoroacetic acid to give 0.144 g of the ester as a yellow oil.

The ester was dissolved in 6 mL of a 9: 1 solution of ethanol in water and treated with 0.065 g (1.55 mmol) of lithium hydroxide. After stirring for 3 hours, the solution was concentrated to give a residue as a paste which was purified by preparative HPLC eluting with a gradient of from 95:05 to 50:50 water / methyl cyanide containing 0.1% trifluoroacetic acid to give 0.068 g (14% in hexane). two steps) of acid (7-5) as a white solid.

TLC Rf = 0.11 (5% methanol in methylene chloride).

¹ H NMR (300 MHz, CD ₃ OD): d 7.54 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H),

7.16 (d, J = 8.4, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H),

5.34 (t, J = 6.9 Hz).

• Φ φ »«

· · * · * · * · * · * · ·

Scheme 8

2-dimethoxymethyl- [1,8] naphthyridine (8-1)

A mixture containing 30 g (0.245 mol) of compound (1-3), 87 g (0.737 mol) of pyruvaldehyde dimethylacetal and 7.0 g (0.062 mol) of L-proline in 300 ml of methanol was refluxed for 16 hours under argon. The cooled solution was filtered, evaporated and the residue was dissolved in 500 ml of methylene chloride. After washing with water and saturated sodium chloride solution, the product is dried and concentrated to a volume of approximately 100 ml. Hexane (300 mL) was added and the mixture was kept at 0 ° C for 3 h and then filtered. The resulting product (8-1) was obtained as an off-white crystalline solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.14 (d, J = 2.2 Hz, 1H); 8.26 (d, J = 8.7Hz, 1H); 8.21 (dd, J = 8.7, 2.2 Hz, 1H); 7.8 (d, J = 8.3Hz, 1H); 7.5 (m, 1 H); 5.48 (s, 1 H); 3.53 (s, 6H).

2-Dimethoxy-methyl-5,6,7,8-tetrahydro- [1,8] -naphthyridine (8-2)

A solution of 10 g (0.049 mol) of product (8-1) in 100 ml of ethanol is treated with 1.5 g of 10% palladium on charcoal and the resulting reaction mixture is stirred for 12.5 hours in atmosphere of hydrogen. The catalyst was removed by filtration through celite and the solution was concentrated to give the title compound (82) as a yellow crystalline solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.18 (d, J = 7.12 Hz, 1H); 6.71 (d, J = 7.12 Hz, 1 H); 5.18 (s, 1 H); 4.96 (br. S, 1H); 3.43 (s, 6H); 3.4 (m. 2H); 2.65 (m, 2 H); 1.91 (m, 2 H).

5,6,7,8-tetrahydro- [1,8] naphthyridine-2-carboxaldehyde (8-3)

10 g (0.048 mol) of product (8-2) are treated with 50 ml of trifluoroacetic acid and the solution is stirred under argon for 12.5 hours. The trifluoroacetic acid was removed under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and methylene chloride. The organic portion was dried, concentrated and passed through a 7.62 cm pad of silica gel eluting with 10% acetone in methylene chloride and concentrated to give the product (8-3) as a yellow crystalline solid. ¹ H NMR (300 MHz, CDCl ₃ ): d 9.80 (s, 1H); 7.31 (d, J = 7.32Hz, 1H); 7.16 (d, J = 7.32Hz, 1H); 5.31 (br. S, 1H); 3.48 (m, 2 H); 2.81 (m, 2 H); 1.94 (m, 2 H).

Scheme 9

DCE, 0 ° C

Q-1

I • · · · · · · · · · · · · ·

ZIZ Z?

9-3

1. 1Ν NaOH

2. 1Ν HCl

EOF, NMM, CH ₃ CN

N NaOH

9-5

3 (S) -Fluorophenyl-b-alanine hydrochloride (9-1) ethyl ester hydrochloride

The resulting compound (9-1) was prepared using 3-fluoro-benzaldehyde according to the procedure for preparing product (7-4) from product (7-1).

¹ H NMR (CD 3 OD): d 1.21 (3H, t), 3.0-3.2 (2H, m), 4.16 (2H, q), 4.76 (1H, t), 7, 2-7.35 (3 H, m), 7.5 (1H, m).

3 (S) - (3-Fluorophenyl) -3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino] -propionic acid ethyl ester (9-2)

To a stirred solution of 300 mg (1.85 mmol) of product (8-3), 458 mg (1.85 mmol) of product (9-1) in 10 mL of dichloroethane was added 570 mg (2.59 mmol) at 0 ° C. ) sodium triacetoxyborohydride. After 1 hour, the reaction mixture was diluted with ethyl acetate, and then washed with 10% potassium carbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography eluting with a mixture of 5% of ethanol: ammonium hydroxide / water (10: 1: 1) and 95% of 70:25 chloroform / ethyl acetate / methanol. : 5 to give the ester (9-2) as a yellow solid.

TLC Rf = 0.50 (silica, 5% [ethanol: ammonium hydroxide: water = 10: 1: 1]: 95% [chloroform: ethyl acetate: methanol = 70: 25: 5]).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.26 (m, 1H), 7.07 (m, 3H), 6.95 (m, 1H), 6.37 (d, J = 7.1 Hz) 1 H, 4.76 (bs, 1 H), 4.10 (m, 3 H), 3.47 (d, J = 7.1 Hz, 2 H), 3.38 (m, 2 H), 2.68 ( m, 4H), 1.90 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).

3 (S) - (3-Fluorophenyl) -3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] propionic acid (9-3)

To a solution of 450 mg (1.26 mmol) of ester (9-2) in 3 mL of ethanol was added

1.39 ml (1.39 mmol) of 1N sodium hydroxide solution. After stirring for 1 hour, the solvent was evaporated and the residue was dissolved in 1.39 ml (1.39 mmol) of 1N hydrochloric acid. The solution is concentrated, and then azeotroped with methyl cyanide to afford acid (9-3) as a brown solid.

¹ H NMR (300 MHz, CD ₃ OD): d 7.45 (m, 1H), 7.10 to 7.28 (m, 4H),

6.36 (d, J = 7.3 Hz, 1H), 4.41 (m, 1H), 3.80 (s, 2H), 3.31 (m, 2H), 2.62 to 2.85 (m, 4H), 1.90 (m, 2H).

3 (S) - (3-Fluorophenyl) -3- {3 (S) - (3-fluorophenyl) -3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridine-2-) ethyl ester ylmethyl-amino-propionyl-amino} propionic (9-4)

A mixture of 235 mg (0.6056 mmol) of acid (9-3), 150 mg (0.6056 mmol) of amine (9-1), 350 mg (0.7873 mmol) of BOP and 0.333 mL (3.03 mmol) of NMM in 5 ml of methyl cyanide was stirred for 20 hours. The mixture was diluted with ethyl acetate, washed with 10% potassium carbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent by evaporation afforded (9-4) as a brown oil.

TLC Rf = 0.15 (chloroform: ethyl acetate: methanol = 75:10:15).

¹ H NMR (300 MHz, CDCl ₃ ): d 6.85-7.28 (m, 9H), 6.34 (d, J = 7.3 Hz, 1H), 5.40 (m, 1H), 4.92 (s, 1H), 4.10 (m, 3H), 3.52 (d, J = 5.4 Hz, 2H), 3.38 (m, 2H), 2.48-2, 84 (m, 7H), 1.26 (t, J = 7.1 Hz, 3H).

bis (trifluoroacetate) 3 (S) - (3-fluorophenyl) -3- {3 (S) - (3-fluorophenyl) -3 - [(5,6,7,8-tetrahydro [1,8] naphthyridin-2-yl) -methyl-amino-propionyl-amino} propionic acid (9-5)

To a solution (0.6056 mmol) of product (9-4) in 3 mL of ethanol was added 1.21 mL (1.21 mmol) of 1N sodium hydroxide solution. After stirring for 1 hour, the solvent was evaporated and the residue was purified by preparative HPLC (Waters Delta Pak C18, gradient from 100: 0: 0.1 to 5: 95: 0.1 water / methyl cyanide / trifluoroacetic acid) to give (9- 5) as white solids.

¹ H NMR (300 MHz, CD ₃ OD): d 7.45 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 6.1 Hz, 1H), 7.29 (m, 1H), 6.94-7.18 (m, 6H), 6.51 (d, J = 7.6Hz, 1H), 5.43 (m, 1H), 4.26 (m, 1H,) 3.81 (m, 2H); 3.49 (m, 2H);

100 • ·

2.90 (m, 4H); 1.92 (m, 2H).

Scheme 10

BOC K ₃ C _X BOP, NMM

101 • ·

HCl

1) Br

OEt η Pr ₂ NEt 2) BOC ₂ O

OEt

EDC, HOET NMM

101 • · · · «

10-10

1.NaOH

2. TFA

(3-Oxo-butyl) -carbamic acid tert-butyl ester (10-4)

A solution of 20 g (105 mmol) of Boc-beta-alanine, 10.3 g (105 mmol) of product (10-2), 46.5 g (105 mmol) of BOP reagent and 46 ml (420 mmol) of N-methylmorpholine in 500 ml of acetonitrile was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 10% aqueous potassium bicarbonate solution and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to give the crude product (10-3), tert-butyl ester [2- (methoxymethyl) (carbamoyl) ethyl] carbamic acid as a yellow oil.

TLC Rf = 0.42 (silica, 20% ethyl acetate in hexanes).

To a 500 mL solution of this crude amide in tetrahydrofuran at 0 ° C was added 100 mL (300 mmol) of a 3M solution of CH ₃ MgBr in ether over 30 minutes. After 2 hours, a 10% aqueous potassium bicarbonate solution was added, the mixture was warmed to 25 ° C and

103

Dilute with ethyl acetate. The organics were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. Flash column chromatography on silica eluting with 20% ethyl acetate in hexanes gave the title product (10-4) as a yellow oil.

TLC Rf = 0.35 (silica, 20% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 5.02 (br s, 1H), 3.32 (q, 2H, J = 6.8 Hz), 2.66 (q, 2H, J = 6Hz) 2.16 (s, 3H), 1.43 (s, 9H).

(2- [1,8] -naphthyridin-2-yl-ethyl) -carbamic acid tert-butyl ester (10-5) A solution of 10 g (53.4 mmol) of the product (10-4), 7.2 g (64 mmol) of 2-amino-3-formyl-pyridine (1-3), 1 ml of 20% aqueous potassium hydroxide solution and 200 ml of ethanol are heated at reflux temperature for 3 hours. The solvent was removed by evaporation and the residue was purified by flash column chromatography on silica eluting with a mixture of 70 chloroform, 28 ethyl acetate and 2 methanol. Obtained as a solid (10-5). TLC Rf = 0.29 (silica, 70 chloroform: 28 ethyl acetate: 12 methanol).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.11 (m, 1H), 8.16 (m, 2H), 7.45 (m, 2H), 5.27 (s, 1H), 3, 75 (m, 2H); 3.27 (m, 2H); 1.40 (s, 9H).

[2- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -ethyl] -carbamic acid tert-butyl ester (10-6)

A mixture of 5.0 g (20.4 mmol) of product (10-5), 2.5 g of a 10% palladium-on-carbon catalyst solution and 200 ml of ethanol was stirred under a hydrogen atmosphere for 15 hours. The mixture was filtered and the filtrate was concentrated to give the product (10-6) as a yellow oil.

TLC Rf = 0.29 (silica, 70 chloroform: 25 ethyl acetate: 5 methanol).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.16 (d, 1H, J = 6.8 Hz), 6.48 (d, 1H,

J = 4.9 Hz), 5.12 (br s, 2H), 3.45 (m, 4H), 2.72 (m, 4H), 1.88 (m, 2H),

104

1.43 (s, 9H).

2- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -ethylamine dihydrochloride (107)

A solution of 4.0 g (16 mmol) of product (10-6) in 200 ml of ethyl acetate was bubbled through a stream of hydrogen chloride gas at 0 ° C for 10 minutes. After an additional 30 minutes, argon was bubbled through the mixture for 1 hour and then concentrated. The resulting residue was dissolved in acetonitrile and concentrated to give compound (10-7) as a yellow solid.

¹ H NMR (300 MHz, CD ₃ OD): d 7.62 (d, 1H, J = 7Hz), 6.70 (d, 1H, J = 7Hz), 3.53 (t, 2H, J = 6 Hz), 3.34 (m, 2H), 3.11 (m, 2H), 2.84 (m, 2H),

1.96 (m, 2 H).

[tert-Butoxy-carbonyl- [2- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -ethyl] -amino] -acetic acid ethyl ester (10-8)

To a solution of 2.0 g (7.8 mmol) of product (10-7) and 6.8 ml of N, N-diisopropylethylamine in 50 ml of acetonitrile was added 0.975 ml (8.6 mmol) of ethyl at 0 ° C. -bromoacetate. The mixture was stirred at 50 ° C for 15 hours and then cooled to 25 ° C. After addition of 1.7 g (7.8 mmol) of BOCl ₂ , the reaction is continued for an additional 1 hour, and the mixture is then diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Flash column chromatography on silica eluting with 50-60% ethyl acetate in hexanes gave the title product (10-8) as a colorless oil.

TLC Rf = 0.5 (silica, ethyl acetate).

1 H NMR (300 MHz, CDCl ₃ ) mixture of rotamers: d 7.04 (d, 2H, J = 7Hz),

6.35 (dd, 1H, J = 7 Hz), 4.73 (br s, 1H), 4.16 (m, 2H), 3.89 (s, 1H), 3.82 (s, 1H), 3.56 (m, 2H), 3.39 (m, 2H), 2.76 (m, 4H), 1.90 (m, 2H), 1.44 (m, 9H), 1.25 (m , 3H).

3- (2- [tert-butoxycarbonyl- [2- (5,6,7,8-tetrahydro) 105) ethyl ester

[1,8] naphthyridin-2-yl) ethyl] -amino] -acetylamino) -3 (S) - (3-fluoro-phenyl) -propionic acid (10-10)

To a solution of 0.8 g (2.20 mmol) of product (10-8) in 10 mL of ethanol was added 2.4 mL (2.4 mmol) of 1N sodium hydroxide solution and the reaction mixture was stirred for 1 hour. The solvent was removed by evaporation and the residue was dissolved in 1N hydrochloric acid solution. Evaporation followed by evaporation from acetonitrile gave 0.820 g (95%) of crude [tert-butoxycarbonyl- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)] - ethyl] amino] acetic acid (10-9).

To a mixture of the crude product (10-9) in 2 mL acetonitrile was added 0.1 g (0.404 mmol) of 3-amino-3- (S) - [3-fluorophenyl] -propionic acid (9-1) mg (1). , 2 eq) EDC, 55 mg (1 eq) HOBT and 0.222 mL (5 eq) NMM. After stirring for 12 hours, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give the product (10-10) as a yellow oil. TLC Rf = 0.18 (silica, 70 chloroform: 25 ethyl acetate: 5 methanol).

¹ H NMR (300 MHz, CDCl ₃ ) mixture of rotamers: d 9.52 (m, 0.5 H), 9.07 (m, 0.5 H), 7.38-6.91 (m, 6H) 6.36 (m, 1H); 5.48 (m, 1H); 4.67 (m, 1H); 4.10 (m, 3H); 3.82 (m, 1H); 3.66 (m, 1H); m, 1H), 3.44 (m, 1H), 3.21 (m, 1H), 2.82 (m, 1H), 2.63 (m, 1H), 1.78 (m, 4H), 1.51-1.13 (m, 12H).

3 (S) - (3-Fluorophenyl) -3- {2- [2- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -ethylamino] -acetylamino} -propionic acid (10) -11)

To a solution of 0.23 g (0.404 mmol) of product (10-10) in 2 mL of ethanol was added 0.6 mL (0.6 mmol) of 1N sodium hydroxide solution and stirred for 1 hour. The solvent is evaporated, the residue is dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid are added to the solution. After 1 hour, the solution was concentrated by evaporation from toluene. Flash column chromatography on silica eluting with a mixture of ethyl acetate, ethanol, ammonium hydroxide and water in a ratio of 20: 10: 1: 1 to

106

10: 10: 1: 1 gave the product (10-11) as a white solid.

TLC Rf = 0.21 (silica, ethyl acetate: ethanol: ammonium hydroxide: water = 10: 10: 1: 1).

¹ H NMR (300 MHz, CD ₃ OD): d 7.28 (m, 1H), 7.13 (m, 3H), 6.91 (m, 1H), 6.38 (d, 1H, J = 7Hz), 5.37 (m, 1H), 3.36 (m, 4H), 2.82 (m, 2H), 2.68 (m, 4H), 2.61 (m, 2H), 1, 87 (m, 2 H).

Scheme 11

EOC-N

H

11-1

HCl HNCH ₃ (OCH ₃₎

11-2

EDC, HOBT, NMM, CH ₃ CN

BOC-N

H

O

CH ₃ MgBr, THF, 0 ° C

11-3

CHO

BOC-N

H

11-4 'N NH ₂ 1-3

29% KOH, EtOH, Δ

10% Pd / C

• ·

107

HCl

triphosgene, DIPEA, I want /

11-10

108

[3- (N-Methoxy-N-methyl-carbamoyl) -propyl] -carbamic acid tert-butyl ester (11-3)

A mixture of 10 g (49.2 mmol) of product (11-1), 4.8 mg (49.2 mmol) of product (11-2), 9.40 g (49.2 mmol) of EDC, 6.6 g ( HOBT (49.2 mmol) and NMM (2.7 mL, 246 mmol) in methyl cyanide (200 mL) were stirred for 20 h and then concentrated. The resulting residue was dissolved in ethyl acetate, washed with water, 10% potassium bicarbonate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent by evaporation gave the product (11-3) as a colorless oil.

TLC Rf = 0.15 (50% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 4.96 (bs, 1H), 3.55 (s, 3H), 3.46 (m, 5H), 2.48 (t, J = 7.3) Hz, 2H), 1.83 (m, 2H), 1.46 (s, 9H).

(4-Oxo-pentyl) -carbamic acid tert-butyl ester (11-4)

To a stirred solution of 10.0 g (40.5 mmol) of the product (11-3) and 200 mL of tetrahydrofuran at 0 ° C was added dropwise 27.0 mL (91.0 mmol) of a 3M methyl magnesium solution over 20 minutes. -bromide in ether. After 2.0 hours, a 10% potassium bicarbonate solution was added slowly. The mixture was extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent by evaporation gave the product (II-4) as a colorless oil.

TLC R f = 0.53 (silica, 40% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 4.62 (bs, 1H), 3.13 (m, 2H), 2.49 (t, J = 7.1Hz, 2H), 2.16 (s 3H), 1.78 (m, 2H), 1.44 (s, 9H).

(3- [1,8] -naphthyridin-2-yl) -N-Boc-propylamine (11-6)

A mixture of 5.0 g (24.8 mmol) of product (11-4), 3.6 g (29.8 mmol) of compound (1-3), 2-amino-3-formyl-pyridine and 1 ml of 20% hydroxide Potassium ve

109

100 ml of absolute ethanol are heated at reflux temperature for 8 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with 70: 28: 2 chloroform: ethyl acetate: methanol to give the product (11-6) as a yellow oil.

TLC Rf = 0.40 (silica, chloroform: ethyl acetate: methanol = 70:20:10).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.08 (m, 1H), 8.16 (d, J = 8.1Hz, 1H),

8.10 (d, J = 8.1 Hz, 1H), 7.41 (m, 2H), 4.82 (bs, 1H), 3.21 (m, 2H),

3.06 (m, 2H), 2.12 (m, 2H), 1.43 (s, 9H).

3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -N-Boc-propylamine (11-7)

A mixture of 4.0 g (13.9 mmol) of product (11-6) and 10% palladium on charcoal (4.0 g) in ethanol (100 mL) was stirred under a hydrogen atmosphere for 4 h. After filtration and removal of the solvent by evaporation, the residue was purified by silica gel column chromatography eluting with 70: 28: 2 chloroform: ethyl acetate: methanol to give the product (11-7) as a white solid.

TLC Rf = 0.30 (silica, chloroform / ethyl acetate / methanol = 70: 25: 5).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.05 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 5.48 (s, 1H), 4.79 (s, 1H), 3.37 (m, 2H), 3.15 (m, 2H), 2.69 (t, J = 6.3 Hz, 2H), 2.59 (s) t, J = 7.3 Hz, 2H), 1.88 (m, 4H), 1.44 (s, 9H).

3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propylamine dihydrochloride (11-8)

A solution of 2.5 g (8.6 mmol) of product (11-7) in 100 ml of ethyl acetate was bubbled vigorously through hydrogen gas at 0 ° C for 10 minutes. After 30 minutes, argon was bubbled through the solution for 30 minutes.

The solution was concentrated and then azeotroped with methyl cyanide to give the amine (11-8) as a yellow solid.

¹ H NMR (300 MHz, CD ₃ OD): d 7.61 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 3.52 (t, J = 5.6 Hz, 2H), 2.99 (m, 2H), 2.83 (m, 4H), 2.08 (m, 2H) 1.96 (m, 2H).

Ethyl 3 (S) - (3-fluorophenyl) -3- {3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl] ethyl ester 1 ] -u reid o} -p new (11-9)

To a stirred solution of product (9-1) (100 mg, 0.4037 mmol), DIPEA (0.380 mL, 2.42 mmol) and chloroform (5 mL) was added triphosgene (42 mg, 0.1413 mmol). After 30 minutes the product (11-8) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent by evaporation gave the product (11-9) as a yellow solid.

TLC Rf = 0.37 (silica, chloroform: ethyl acetate: methanol 75:10:15).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.22 (m, 2H), 7.11 (m, 2H), 6.99 (m, 1H), 6.36 (d, J = 7.1Hz) 1 H, 6.00 (m, 1 H), 5.78 (m, 1 H), 5.27 (m, 1 H), 4.08 (m, 2 H), 3.66 (m, 1 H), 3 44 (m, 2H); 3.21 (m, 2H); 2.63 to 2.91 (m, 6H); 1.92 (m, 2H); 1.85 (m, 2H); 18 (t, J = 7.1 Hz, 3H).

3 (S) - (3-Fluorophenyl) -3 - {[3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) propyl] -ureido} -propionic acid (11) -10)

To a solution of 0.4037 mmol of product (11-9) in 3 mL of ethanol was added in 0.600 mL (0.600 mmol) of 1 N sodium hydroxide solution. After stirring for 2 hours, the solvents were removed by evaporation and the residue was purified by silica gel column chromatography eluting with 20: 10: 1: 1 to 10: 10: 1: 1 ethyl acetate / ethanol / water / ammonium hydroxide to give the product ( 11-10) as white solids.

TLC Rf = 0.21 (ethyl acetate: ethanol: water: ammonium hydroxide = 10: 10: 1: 1).

¹ H NMR (300 MHz, CD ₃ OD): d 7.41 (d, J = 7.3 Hz, 1H), 7.31 (m, 1H),

111

7.17 (d, O = 7.5 Hz, 1H), 7.09 (d, J = 10.2 Hz, 1H), 6.95 (m, 1H), 6.49 (d, J = 7) 3 Hz, 1H), 5.23 (m, 1H), 3.45 (t, J = 5.6 Hz, 2H), 3.04 (m, 1H), 2.46-2.79 ( m, 7H), 1.76-1.96 (m, 4H).

Scheme 12

2-2

About • · · · · · · · · · · · · · ·

112

3- (5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoylamino) -propionic acid (12-2)

A mixture of 10.8 mg (0.04 mmol) of acid (1-6), 7.7 mg (0.04 mmol) of EDC,

5.4 mg (0.04 mmol) of HOBT and 0.026 ml (0.24 mmol) of NMM in 1 ml of dimethylformamide are shaken to form a clear solution. After 30 minutes, amine (12-1) was added. The solution was shaken for 1 minute and then allowed to stand for 18 hours. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and water. After evaporation of the solvent, the residue is dissolved in 1 ml of a 90:10 mixture of trifluoroacetic acid and water. After 2 hours the solvent was removed by evaporation to give the acid (12-2).

TLC Rf = 0.49 (silica, ethyl acetate: ethanol: ammonium hydroxide: water = 10: 10: 1: 1).

Mass spectrum calculated for C ₁₅ H ₂₃ N ₃ O ₃ = 305, found M + H = 306.

Scheme 13

1%, proline, ethanol, reflux

113

CCH,

13-4, R = CH ₃ -.

^0R) 1N NaOH

R = H X

13-8

O

114

· · · · «· · · · · · · · *

10-Oxo-undecanoic acid methyl ester (13-2)

To a suspension of copper (I) cyanide (5.0 g, 56 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of methyl magnesium bromide (3M, 17M, 17.4 ml) in tetrahydrofuran. After addition was complete, the reaction mixture was warmed to -15 ° C for 5 minutes, re-cooled to -78 ° C, and then treated dropwise with 9.3 mL (42 mmol) of product (13-1). The reaction mixture was heated at -10 ° C for 1.5 hours, then quenched with 300 mL of 90% saturated ammonium chloride solution and 400 mL of ethyl acetate. The organic portion was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to afford (13-2) as a pale yellow oil.

TLC Rf = 0.52 (silica, 30% ethyl acetate in mixture)

115 * Hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 3.65 (s, 3H), 2.43 (t, J = 7Hz, 2H), 2.30 (t, J = 7Hz, 2H), 2 13 (s, 3H), 1.60 (m, 4H), 1.29 (m, 8H).

9 - ([1,8] -naphthyridin-2-yl) -nonanoic acid methyl ester (13-3)

A mixture of 9.2 g (43 mmol) of the product (13-2), 5.3 g (43 mmol) of compound (13), 2.5 g (22 mmol) of proline and 215 ml of ethanol was heated under reflux for 20 hours. The cooled reaction mixture was concentrated and the residue purified by flash column chromatography on silica eluting with ethyl acetate to give the product (13-3) as a yellow oil.

TLC Rf = 0.37 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.08 (m, 1H), 8.16 (m, 1H), 8.10 (d, J = 8 Hz, 1H), 7.44 (m, 1H), 7.40 (d, J = 8Hz, 1H), 3.68 (s, 3H), 3.04 (m,

2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H), 1.50-1.20 (m, 8H).

9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid methyl ester (13-4)

A mixture of 13-3 (8.5 g, 28 mmol), 10% palladium on charcoal (1.7 g) and ethanol (140 mL) was stirred under a hydrogen atmosphere for 20 h. Filter the reaction mixture through a pad of celite and concentrate to give the product (13-4) as a pale yellow oil.

TLC Rf = 0.45 (silica, ethyl acetate);

¹ H NMR (300 MHz, CDCl ₃ ): d 7.06 (d, J = 8Hz, 1H), 6.33 (d, J = 8Hz, 1H), 3.68 (s, 3H), 3 40 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H) 4H), 1.50-1.20 (m, 8H).

9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid (13-5) A solution of 8.2 g (27 mmol) of compound (13-4), 30 ml of 1N sodium hydroxide solution and 134 ml of methanol are stirred at 0 ° C for 72 hours. After evaporation of the methanol, the resulting residue was dissolved in 30 ml of water and the solution was neutralized by addition of 1N hydrochloric acid solution to give a white precipitate. The solid product was collected by filtration and dried at

116 ·· ·· 0 00 «0 ·· • · · * 00 0 * * * 0

18 9 9 0 * · β · • »8 9 9 0 0

0 00 0 00 00 00 00 00 at 50 ° C to give the product (13-5).

TLC Rf = 0.53 (silica, ethanol: ammonium hydroxide: water 20: 1: 1);

¹ H NMR (300 MHz, CD ₃ OD): d 7.36 (d, J = 8 Hz, 1 H), 6.46 (d, J = 8 Hz, 1 H), 3.44 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.62 (m, 4H), 1.40-1 30 (m, 8H).

9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoyl - [(-) - 4-benzyl-2-oxazolidinone (13-6)

To a suspension of 5.6 g (19 mmol) of compound (13-5), 97 mL of tetrahydrofuran and 3.2 mL (23 mmol) of triethyl nitrile was added dropwise 2.6 mL (21 mmol) at -78 ° C. trimethylacetyl chloride. After the addition was complete, the reaction mixture was warmed to 0 ° C for 2 hours, then re-cooled to -78 ° C and treated with 18 mL (29 mmol) of a 1.6 M solution of (S) (-) - 4- of benzyl-2-oxazolidinone lithium in tetrahydrofuran. The reaction mixture was heated at 0 ° C for 1 h and poured into 300 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Flash chromatography on silica eluting with ethyl acetate gave the product (13-6) as an oil.

TLC Rf = 0.31 (silica, ethyl acetate);

¹ H NMR (300 MHz, CDCl ₃ ): d 7.40-7.15 (m, 5H), 7.03 (d, J = 8 Hz, 1H), 6.33 (d, J = 8 Hz, 1H), 4.67 (m, 1H), 4.13 (m, 2H), 3.40 (m, 2H), 3.29 (1H), 3.00-2.73 (m, 3H), 2.68 (m, 2H), 2.53 (m, 2H), 1.90 (m, 2H), 1.63 (m, 4H), 1.40-1.30 (m, 8H).

2-Azido-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoyl amide (13-7)

To a solution of 19.4 mmol of the product (13-6) and 65 mL of tetrahydrofuran at -78 ° C was added 89 mL (44.6 mmol) of a 0.5 M solution of the compound.

117

KHMDS in tetrahydrofuran. After 30 minutes, 9.0 g (29 mmol) of trisiphyl azide in 50 mL of tetrahydrofuran was added via cannula. After 3 minutes, the reaction is quenched by the dropwise addition of 6.9 ml of acetic acid, followed by removal of the cooling bath. After 20 hours, the reaction mixture was poured into 300 mL of ethyl acetate and 60 mL of saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Flash chromatography on silica eluting with 5-20% isopropanol / ethyl acetate gave the product (13-7) as an oil.

TLC Rf = 0.47 (silica, 5% saturated solution of ammonia in ethanol and ethyl acetate);

¹ H NMR (300 MHz, CDCl ₃ ): d 7.03 (d, J = 8 Hz, 1 H), 6.34 (d, J = 8 Hz, 1 H), 6.30 (bs, 1 H), δ 77 (bs, 1H); 4.82 (bs, 1H); 3.97 (m, 1H); 3.40 (m, 2H); 2.68 (m, 2H); 2.50 (m, 1H); 2H), 2.00-1.20 (m, 14H).

2-Amino-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoyl amide (13-8)

A mixture of 0.4 g (1.2 mmol) of product (13-7), 6 ml of ethanol and 0.4 g of 10% palladium on charcoal was stirred under a hydrogen atmosphere for 30 minutes. The reaction mixture was then filtered through a pad of celite and concentrated to give the product (13-8) as an oil.

TLC Rf = 0.82 (silica, ethanol: ammonium hydroxide: water 10: 1: 1);

¹ H NMR (300 MHz, CDCl ₃ ): d 7.10 (m, 1H), 7.08 (d, J = 8Hz, 1H), 6.35 (d, J = 8Hz, 1H), 6 30 (bs, 1H), 5.48 (bs, 1H), 5.13 (bs, 1H), 3.40 (m, 4H), 2.70 (m, 2H), 2.53 (m, 2H), 2.00-1.20 (m, 14H).

2-Amino-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid (13-9)

A solution of 0.3 g (1.0 mmol) of the product (13-8) and 10 ml of a 6N hydrochloric acid solution was heated at 50 ° C for 20 hours. To the reaction mixture • · · · ·

118

The reaction mixture was then treated with 1 ml of concentrated hydrochloric acid solution and the mixture was heated for 5 hours. The reaction mixture is concentrated, the residue is dissolved in water and neutralized by addition of concentrated ammonium hydroxide solution to form a precipitate. Filtration and drying in vacuo at 40 ° C afforded the product (13-9) as a gray solid.

TLC Rf = 0.90 (silica, ethanol: ammonium hydroxide: water = 10: 1: 1);

¹ H NMR (300 MHz, D ₂ O): d 7.00 (d, J = 8 Hz, 1 H), 6.37 (d, J = 8 Hz, 1 H), 3.10 (m, 2H), 3.00 (m, 1 H), 2.45 (m, 2 H), 2.27 (m, 2 H), 1.63 (m, 2 H),

1.30 (m, 4H); 1.05 (m, 8H).

2 (S) - (Benzenesulfonyl-amino) -9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid (13-10)

A solution of 0.27 g (0.88 mmol) of the product (13-9) in 4.4 mL of water / dioxane (2: 1) was cooled to 0 ° C and then treated dropwise with 1N solution. sodium hydroxide to reach pH 10.5. The reaction mixture was treated with a solution of 0.23 g (1.3 mmol) of PhSO ₂ Cl in 750 mL of dioxane, adjusting the pH to 10.5 by adding 1N sodium hydroxide solution. After 15 minutes, the pH is brought to pH 7 by addition of 1N hydrochloric acid solution.

The white precipitate formed was collected by filtration and triturated with ethyl acetate and then with ether to give the product (13-10) as a colorless solid. ¹ H NMR (300 MHz, D ₂ O): d 7.50 (m, 2H), 7.10 (m, 3H), 6.95 (d, J = 8 Hz, 1H), 6.20 (d J = 8 Hz, 1H), 4.60 (m, 1H), 3.04 (m, 2H), 2.40 (m, 2H), 2.23 (m, 2H), 1.63 (m 2H, 1.20 (m, 4H), 0.08 (m, 8H).

«« • · · ·

119

Scheme 14

NaOH

14-5 R = a 4-6 R = H * 4 · 4 · R

120 3- (6,7,8,9-tetrahydro-benzo [b] - [1,8] naphthyridin-8-yl) -propionic acid ethyl ester (14-2)

To a solution of 0.244 g (2.0 mmol) of 2-amino-pyridine-3-carbaldehyde (1-3) a

0.245 g (2.00 mmol) of 3- (3-oxo-cyclohexyl) -propionic acid ethyl ester (14-1) (J. R. Wiseman et al., J. Am. Chem. Soc., 1970,

92, 956-962) in 10 ml of ethanol is treated with 0.230 g (2.00 mmol) of L-proline and the reaction mixture is heated at reflux for 12 hours. The solution was cooled to room temperature and concentrated. The resulting residue was purified by flash chromatography eluting with 10% acetone in methylene chloride to give the product (14-2).

¹ H NMR (300 MHz, CDCl ₃ ): d 9.02-9.00 (m, 1H), 8.09-8.06 (m, 1H), 7.84-7.37 (m, 1H) 7.27 (s, 1H); 4.15 (q, J = 7.2 Hz, 2H); 3.43-3.35 (m, 1H); 3.31-2.98 (m, 4H) 2.84-2.75 (dd, J = 11.16 Hz, 1H), 2.47 (t,

J = 7.8 Hz, 2H), 2.10-1.77 (m, 3H), 1.57-1.51 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H) ) ppm.

3- (1,2,3,4,6,7,8,9-octahydro-benzo [b] - [1,8] naphthyridin-8-yl) -propionic acid ethyl ester (14-3)

A mixture of 0.298 g (1.05 mmol) of product (14-2) and a solution of 0.060 g of palladium on charcoal in 10 ml of ethanol was placed under an atmosphere of hydrogen at 10 psi and stirred for 12 hours. The solution was concentrated and the residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to give the product (14-3).

¹ H NMR (300 MHz, CDCl ₃ ): d 6.88 (s, 1H), 4.70 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.37 ( m, 2H), 2.80-2.58 (m, 5H), 2.42-2.27 (m, 3H), 1.931.65 (m, 6H), 1.25 (t, J = 7) (2 Hz, 3H) ppm.

3- (1,2,3,4,6,7,8,9-octahydro-benzo [b] - [1,8] naphthyridin-8-yl) -propionic acid (14-4)

A solution of 0.180 g (0.62 mmol) of the product (14-3) and 1.24 ml (1.24 mmol) of 1N sodium hydroxide solution in a mixture of 5 ml of tetrahydrofuran and 5 ml of water was stirred at room temperature for 12 hours. The solution is concentrated and formed

• · · · ·

121

the residue is triturated with diethyl ether to give the product (14-4).

¹ H NMR (300 MHz, CD ₃ OD): d 6.91 (s, 1H), 2.75-2.58 (m, 6H), 2.292.15 (m, 5H), 1.96-1, 62 (m, 5H), 1.34-1.27 (m, 1H) ppm.

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- (3 (1,2,3,4,6,7,8,9-octahydro-benzo [b] - [ 1,8] naphthyridin-8-yl) -propionylamino) -propionic (14-5)

A solution of 0.110 g (0.39 mmol) of the product (14-4), 0.106 g (0.39 mmol) of the baminoester (6-6), 0.075 g (0.39 mmol) of EDC, 0.053 g (0.39 mmol) of HOBT and 0.164 ml (1.17 mmol) of N-methylmorpholine in 5 ml of degassed dimethylformamide were stirred at room temperature for 12 hours.

The solution is concentrated and the residue is purified by flash chromatography to give the product (14-5).

¹ H NMR (300 MHz, CD ₃ OD): d 7.19 (s, 1H), 7.12-7.07 (m, 1H), 6.796.76 (m, 1H), 6.69 (br s (1H), 5.49-5.26 (m, 1H), 4.52-4.45 (m, 2H), 4.05 (q, J = 7.0 Hz, 2H), 3.41- 3.38 (m, 2H), 3.15-3.10 (t, J = 8.5 Hz, 2H), 2.78-2.68 (m, 3H), 3.59 (m, 2H) 2.37-2.21 (m, 5H), 1.61-1.70 (m, 5H), 1.38 (m, 1H), 1.18-1.14 (t, J = 7, 0 Hz, 3H) ppm.

3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- (3- (1,2,3,4,6,7,8,9-octahydrobenzo [b] - [1,8] (naphthyridin-8-yl) -propionyl-amino) -propionic acid (14-6)

A solution of 0.050 g (0.105 mmol) of the product (14-5) and 0.210 ml (0.210 mmol) of 1N aqueous sodium hydroxide solution was stirred at room temperature for 3 hours. The solution is concentrated and the residue is triturated with diethyl ether. Collect a white solid product (14-6).

¹ H NMR (300 MHz, CD ₃ OD): d 7.41 (s, 1H), 7.12-7.10 (d, J = 7.3 Hz, 1H), 6.80-6.78 ( d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 5.38 (m, 1H), 4.43 (m, 2H), 3.43 (m, 4H), 3, 17 (m, 2H), 2.78 (m, 3H), 2.61 (m, 2H), 2.36 (m, 3H), 1.95 (m, 2H), 1.77 (m, 4H) 1.40 (m, 1H) ppm.

• ·

122

Scheme 15

ΞΕΖ

123

IZ

H ₂ , Fc / C, EtOH

2. Chiropsk AD (division)

«· • ·

2-Oxo-6- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -hexyl-phosphonic acid dimethyl ester (15-1)

A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) in anhydrous tetrahydrofuran (165 mL) was cooled to -78 ° C and treated dropwise with n-butyllithium (42.3 mL, 2.5 M). After stirring at -78 ° for 45 min, a solution of compound (1-5) (6.6 g, 26.6 mmol) in tetrahydrofuran (35 ml) was added dropwise and the solution was stirred at -78 ° for 30 min. The reaction was quenched with 100 mL of saturated ammonium chloride solution and then extracted three times with 150 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to a yellow oil. Chromatography on silica gel eluting with 5% methanol in methylene chloride afforded (15-1) as a yellow oil.

Rf (silica, 5% methanol in methylene chloride) = 0.20.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.05 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.32 Hz, 1H), 4.80 (br, s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.4 (m, 2H), 3.08 (d, J = 22.7 Hz), 2.7- 2.5 (m, 6H), 1.91 (m, 2H), 1.68 (m, 4H).

3- (quinolin-3-yl) -7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - (E) -hept-1en-3-one (15- 3)

To a mixture of 2.0 g (5.9 mmol) of ketophosphonate (15-1), 250 mg (5.9 mmol) of anhydrous lithium chloride and 0.77 g (4.9 mmol) of 3-quinoline carboxaldehyde (5-1) ) in 60 ml of anhydrous acetonitrile was treated with 0.73 ml (5.88 mmol) of DBU and the resulting suspension was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between saturated sodium chloride solution and methylene chloride. The organic portion was removed, dried and concentrated to give a yellow solid which was crystallized from a solution of ethyl acetate in hexanes to give the product (15-3) as an off-white solid. Rf (silica, 5% methanol in methylene chloride) = 0.45.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.05 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.8)

125 • ·

Hz, 1H), 8.05 (d, J = 8.5Hz, 1H), 7.87 (d, J = 7.5Hz, 1H), 7.81 (t, J = 7.5

Hz, 1H), 7.68 (d, J = 16Hz, 1H), 7.58 (t, J = 7.5Hz, 1H), 7.05 (d, 3 = 7.3)

Hz, 1H), 6.95 (d, J = 16Hz, 1H), 6.34 (d, J = 7.32Hz, 1H), 4.80 (br, s,

1H), 3.4 (m, 2H), 2.7-2.5 (m, 6H), 1.91 (m, 2H), 1.68 (m, 4H).

3- (quinolin-3-yl) -7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - (E) -hept-1-en-3-ol (15) -4)

A solution of 1.33 g (3.58 mmol) of the product (15-3) in 150 mL of anhydrous tetrahydrofuran was cooled to -78 ° and then treated dropwise with 10.75 mL (10.75 mmol) of isobutyl- aluminum hydride (iBU2AlH). The solution was stirred at -78 ° C for 20 minutes, then quenched with ethyl acetate (20 mL). After warming to room temperature, the mixture was treated with 25 mL of 1 M sodium potassium tartrate solution and stirred for 4 hours. The mixture was extracted twice with 150 mL of ethyl acetate, dried, filtered and evaporated to give the product (15-4) as an off-white solid.

Rf (silica, 10% methanol in methylene chloride) = 0.10.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.05 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 1.8Hz, 1H), 7.87 (d, 3 = 7.5Hz, 1H), 7.81 (t, 3 = 7.5Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 16 Hz, 1H), 6.45 (dd, J = 16.6, 5 Hz, 1H), 6.37 (d, 3 = 7.32 Hz, 1H), 4.80 (br s, 1H), 4.4 (m, 1H), 3.4 (m, 2H), 2.75 (m, 2H), 2.62 (m, 2H), 1.91 (m, 2H), 1.72 (m, 4H), 1.55 (m, 2H).

3- (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - (E) -non-4-enoic acid ethyl ester (15-5) )

A solution of 1.4 g (3.75 mmol) of allylic alcohol (15-4) in 64 ml of triethyl orthoacetate was treated with 0.014 ml (0.19 mmol) of propionic acid and heated under reflux for 1.5 hours. The cooled mixture is treated with 50 ml of saturated sodium chloride solution and 1N hydrochloric acid solution 1: 1 and then extracted three times with 125 ml of methylene chloride. The organic extracts were washed with a saturated solution of hydrogen.

Sodium carbonate, dried, filtered and evaporated. Chromatography on silica gel, eluting with 5% methanol in methylene chloride, afforded the product (15-5) as a yellow glass.

Rf (silica, 5% methanol in methylene chloride) = 0.25.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.08 (brs, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.82 (d, J = 7.5Hz, 1H), 7.71 (t, J = 7.5Hz, 1H) 7.54 (t, J = 7.5Hz, 1H), 7.05 (d, J = 7.3Hz, 1H), 6.25 (d, J = 7.32Hz, 1H), 5 6 (m, 2H); 4.05 (m, 2H); 4.05 (m, 1H); 3.40 (m, 2H); 2.75 (m, 2H); 2.65 (m, 2H); 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 1 .08 (t, J = 7.5Hz, 3H).

ethyl 3 (S or R) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid ethyl ester and ethyl ester 3 (R or R); S) - (Quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic (15-6a and 15-6b)

A solution of 1.0 g (2.25 mmol) of the product (15-5) in ethanol was treated with 200 mg of 10% palladium on charcoal and stirred under a hydrogen atmosphere for 3 hours. The catalyst was removed by filtration through celite and the solvent was evaporated to give a mixture of enantiomers as a colorless glass.

Rf (silica, 5% methanol in methylene chloride) = 0.25.

¹ H NMR (300 MHz, CDCl ₃ ): d 8.81 (d, J = 1.8 Hz, 1H), 8.60 (brs, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.82 (d, J = 7.5Hz, 1H), 7.71 (t, J = 7.5Hz, 1H) 7.54 (t, J = 7.5Hz, 1H), 7.15 (d, J = 7.3Hz, 1H), 6.25 (d, J = 7.32Hz, 1H), 4 050.05 (m, 2H), 3.40 (m, 2H), 3.25 (m, 1H),

2.75 (m, 2H), 2.65 (m, 2H), 2.58 (m, 2H), 1.87 (m, 2H), 1.81 (m, 2H),

1.75 (m, 2H), 1.25 (m, 4H), 1.08 (t, J = 7.5Hz, 3H).

The enantiomers (15-6a) and (15-6b) were separated on a Chiralpak AD (250

X 20 mm, flow rate = 8 ml / min, A: B = 50:50, A = 0.1% diethylamine in hexane, B = 1-propanol).

Retention time: (15-6a) = 18.8 min,

127 (15-6b) = 20.9min.

3- (R or S) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (15-7a)

A solution of 193 mg (0.43 mmol) of the product (15-6a) in 10 mL of a 50% aqueous tetrahydrofuran solution was treated with 27 mg (0.65 mmol) of solid lithium hydroxide. The mixture was stirred at room temperature for 18 hours and then neutralized by addition of 1N hydrochloric acid solution. Silica gel chromatography eluting with a 50:50 mixture of solvent system A and ethyl acetate (A = ethanol: ammonium hydroxide: water = 20: 1: 1) afforded (15-7a) as a colorless glass.

Rf (silica, 50% A: ethyl acetate) = 0.45.

¹ H NMR (300 MHz, CDCl ₃ ): d 10.2 (br, s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.5) Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5Hz, 1H), 7.05 (d, J = 7.3Hz, 1H), 6.25 (d, J = 7.32Hz, 1H) 5.6 (m, 2H), 3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2H), 2.65 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H).

3- (S or R) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (15-7b)

This compound is prepared using compound (15-6b) according to the above procedure for preparing the product (15-7a).

Scheme 16

Br ₂ , KBr, KOH H ₂ O

MeO

Br

16-2

128

Pd (OAc) ₂ , Et ₃ N, tri-o-polyphosphine ethyl acrylate. CH ₃ CN

1st ^of Me

THF

2. nBuLi, THF

3. NH.CI, H ₂ O

Pd (OH) ₂ , H ₂ , EtOH, HOAc. H ₂ O

MeO 16-5

16-5

16-6. R _{1 =} H, R 2 = SO ₇ C _with H ₄ (NO ₂ b 16-7. R _{1 =} Me, R ₉ = SO ₂ C ₆ H ₄ (NO ₂ ) ₂ 16-5. R _{1 =} Me, R ^ = H

129

PyCLU

NaOH (aa)

5-Bromo-2-methoxypyridine (16-2)

To a solution of 4.2 g (0.075 mol) of potassium hydroxide in 750 ml of water is added 16.4 g (0.15 mol) of 2-methoxypyridine (16-1), followed by dropwise addition of 24 g (0.15 mol) of bromine in 750 ml of 1N aqueous potassium bromide solution. The resulting solution was stirred at room temperature for 5 hours. Solid sodium bicarbonate was added to basic pH and the solution was extracted three times with 500 mL of chloroform. The organic portion was washed with 10% sodium bisulfite solution and then with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. The dark brown oil formed contains the desired compound (16-2) and is used in the next synthesis step without further purification.

¹ H NMR (300 MHz, CDCl ₃ ): d 3.91 (3H, s), 6.66 (1H, d), 7.62 (1H, dd),

8.20 (1 H, d).

ethyl 3- (6-methoxy-pyridin-3-yl) acrylate (16-3)

A solution of 74.3 g (0.4 mol) of 5-bromo-2-methoxy-pyridine (16-2), 150 ml (1.4 mol) of ethyl acrylate, 150 ml (1.08 mol) of triethylamine, 10 g (0.045 mol) palladium acetate and 20 g (0.066 mol) tri-o-tolylphosphine in 100 ml acetonitrile were degassed with argon for 10 minutes. The mixture was heated to 90 ° C for hours and then the volatiles were removed in vacuo. Toluene (300 ml) was added and the mixture was concentrated again. After addition of 300 ml of diethyl ether, the mixture is filtered through a pad of silica gel, eluting with 800 ml of diethyl ether. After removal of diethyl ether, the resulting residue was purified by silica gel column chromatography eluting with 1:19 ethyl acetate in hexane followed by 1:14 then 1: 9 to give the product (16-3) as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 1.34 (3H, t), 3.97 (3H, s), 4.26 (2H, q), 6.34 (1H, d), 6, 76 (1H, d), 7.63 (1H, d), 7.77 (1H, dd), 8.27 (1H, d).

N-benzyl- (R) -α-methyl-benzyl-3 (S) - (6-methoxy-pyridin-3-yl) -β-alanine amino ester

To a solution of 97.5 g (462 mmol) of N-benzyl- (R) -α-methyl-benzylamine in 750 mL of tetrahydrofuran at 0 ° C was added 178.5 mL (446 mmol).

A 2.5 M solution of n-butyllithium in a mixture of hexanes. The dark violet solution was stirred at 0 ° C for 20 minutes, cooled to -78 ° C, and 63.7 g (308 mmol) of ester (16-3) in 250 mL of tetrahydrofuran was added over 60 minutes. The resulting solution was stirred at -78 ° C for 1 hour, and was then added via cannula to a saturated ammonium chloride solution and extracted with ethyl acetate. After washing with water and saturated brine, the product is dried and concentrated in vacuo to an oil. Silica gel column chromatography eluting with hexane / ethyl acetate 9: 1 then 4: 1 gave the title product (16-4) as an oil with N-benzyl- (R) -α-methyl-benzylamine. This oil was treated with 5% acetic acid in water and extracted four times with diethyl ether. The organics were dried over magnesium sulfate and the solvent was removed to give the title compound (16-4).

¹ H NMR (300 MHz, CDCl ₃ ): d 1.08 (3H, t), 1.27 (3H, d), 2.52 (1H, dd),

2.62 (1H, dd), 3.66 (1H, d), 3.70 (1H, d), 3.93 (3H, s), 3.95 (2H, m),

4.41 (1H, dd), 6.74 (1H, d), 7.15-7.45 (10H, m), 7.64 (1H, dd), 8.15 (1H, d).

131

3 (S) - (6-Methoxy-pyridin-3-yl) -B-alanine ethyl ester (16-5)

To a argon-degassed solution of 70 g of ester (16-4) in 250 mL of ethanol, 25 mL of acetic acid and 2 mL of water was added 20% palladium hydroxide on charcoal. The mixture was placed under an atmosphere of hydrogen and the reaction mixture was stirred for 24 hours. After filtration through celite and washing with ethyl acetate, the solvent was removed in vacuo to give a waxy solid. The product is dissolved in 200 ml of water and extracted twice with 200 ml of diethyl ether. The aqueous portion was treated with solid potassium carbonate to form a saturated solution, which was extracted four times with 200 mL of ethyl acetate. After drying over magnesium sulfate, the solvent is removed in vacuo to give the title compound (16-5) as an oil which solidifies in the freezer.

¹ H NMR (300 MHz, CDCl ₃ ): d 1.23 (3H, t), 2.61 (1H, dd), 2.68 (1H, dd), 3.92 (3H, s), 4, 15 (2H, q), 4.41 (1H, dd), 6.93 (1H, d), 7.62 (1H, dd), 8.13 (1H, d).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- (4-nitro-benzenesulfonyl-amino) -propionic acid ethyl ester (16-6)

A solution of the aminoester (16-5) (3.0 g, 13.0 mmol) in methylene chloride (20 mL) was treated with aqueous sodium bicarbonate (4.4 g) in water (20 mL). 4.3 g (16 mmol) of 2,4-dinitrobenzenesulfonyl chloride are added and the reaction mixture is stirred for 12 hours. The solution was extracted three times with 40 ml of methylene chloride and the combined organics were washed with 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of saturated sodium chloride solution. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with methylene chloride / methanol (97: 3) to give the desired product (16-6).

TLC Rf = 0.45 (5% methanol in dichloromethane).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- [methyl- (4-nitro-) -, ethyl ester

Benzenesulfonyl) amino] -propionic (16-7)

To a solution of 4.5 g (10 mmol) of sulfonamide (16-6) in 30 mL of tetrahydrofuran was added 3.9 g (15 mmol) of triphenylphosphine. To this solution was added a solution of 2.4 mL (15 mmol) of diethyl azodicarboxylate in a mixture of 10 mL of tetrahydrofuran and 2.02 mL of methanol. A strong exothermic reaction occurs. The mixture was stirred at room temperature overnight. The dark reaction mixture was concentrated and the dark oily residue formed was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to give the desired product (16-7).

TLC Rf = 0.37 (40% ethyl acetate in hexanes).

3 (S) - (6-Methoxy-pyridin-3-yl) -3-methylamino-propionic acid ethyl ester (16-8)

A solution of 4.7 g (10 mmol) of sulfonamide (16-7) in 50 mL of methylene chloride was treated with 2.8 mL (20 mmol) of triethylamine and 1.04 mL (15 mmol) of mercapto-acetic acid. The reaction mixture was stirred at room temperature for 90 minutes. The green solution is diluted with 500 ml of ethyl acetate and washed once with 150 ml of saturated aqueous sodium bicarbonate solution, three times with 100 ml of water and three times with 100 ml of saturated sodium chloride solution. The solution was dried over sodium sulfate, filtered and concentrated to give a black oil. The resulting residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to give the desired product (16-8).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.07 (d, J = 2.4 Hz, 1H), 7.57 (m, 1H),

6.73 (m, 1H); 4.11 (q, J = 7.3 Hz, 2H); 3.93 (s, 3H); 2.72 (m, 2H); 1.21 (t, J) = 7.3 Hz, 3H) ppm 3 (S) - (6-Methoxy-pyridin-3-yl) -3- [N-methyl-3 (1,2,3,4,6,7,8) -ethyl ester 9-octahydrobenzo [b] - [1,8] naphthyridin-8-yl-propionyl) amino-propionic acid (16-9)

The racemic tricyclic ester (14-3) was separated by chiral HPLC (Chiracel

OD column; 25x2 mm; elution with 95: 5 hexanes: isopropanol / 0.1% diethyl • ·

133 ...........

amine; flow rate 8 ml / min; retention time = 6.48 and 7.21 min). The higher polarity enantiomer is hydrolyzed to give the carboxylate (144a). A solution of 0.175 g (0.62 mmol) of the product (14-4a) in a mixture of 10 mL of dimethylformamide and 0.62 mL of a 1N hydrochloric acid solution was treated with 0.540 (3.10 mmol) of disopropylethylamine, a solution of 0.162 g (0.68 mmol). of amino ester (16-8) in 2 mL of DMF followed by 0.224 g (0.62 mmol) of PyCLU. After stirring at room temperature for 12 hours, the solution was concentrated and the residue was partitioned between 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate. The organic solution was washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to give the desired amide (16-9).

TLC Rf = 0.28 (5% methanol in dichloromethane).

3 (S) - (6-Methoxy-pyridin-3-yl) -3- [N-methyl-3- (1,2,3,4,6,7,8,9-octahydrobenzo [b] - [1, 8] -naphthyridin-8-yl-propionyl) -amino] -propionic acid (16-10)

A solution of the ester (16-9) (0.133 g, 0.28 mmol) in a mixture of 1 mL of methanol, mL of tetrahydrofuran and 1 mL of water was treated with 0.56 mL (0.56 mmol) of 1N aqueous sodium hydroxide solution. After stirring at room temperature for 12 hours, the mixture was concentrated and the aqueous residue formed was neutralized by the addition of 0.56 ml of a 1N aqueous hydrochloric acid solution. The resulting residue was purified by flash chromatography eluting with 15% ethanol, 15% ethyl acetate, 1% aqueous ammonium hydroxide and 1% water to give the desired acid (16-10).

¹ H NMR (300 MHz, CDCl ₃ ) mixture of rotamers: d 8.07 (m, 1H), 7.62 (m, 1H), 7.35 (m, 1H), 6.80 (m, 1H), 6.38 (m, 1H), 4.90 (s, 3H), 3.45 (m, 1H), 3.78 (m, 13H), 1.93 (m, 7H), 1.42 (m (1H) ppm.

134

Scheme 17

3-Benzyl-oxycarbonyl-amino-2- (3-fluoro-phenyl) -propionic acid ethyl ester (17-2)

To a stirred solution of 9.43 mL (18.86 mmol) of a 2.0 M solution of LDA in 80 mL of tetrahydrofuran at -78 ° C was added a solution of 3.12 g (17.15 mmol) of ethyl 3-fluoro-phenyl- acetic acid (17-1) in 5 mL of tetrahydrofuran. After 10 minutes, a solution of 4.8 g (17.15 mmol) of aminomethyl-benzotriazole in 5 ml of tetrahydrofuran was added and the solution was slowly warmed to room temperature over 5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted three times with 40 ml of ethyl acetate, and the combined organics were washed with 50 ml of saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated. The rest • »

135 was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give the desired product (17-2).

TLC Rf = 0.19 (20% ethyl acetate in hexanes).

2- (3-Fluoro-phenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentanoylamino) -propionic acid (17-5)

A solution of 0.47 g (1.36 mmol) of ester (17-2) in 15 mL of ethanol was bubbled with argon in the presence of 0.047 g of palladium on charcoal. The heterogeneous mixture was placed under an atmosphere of hydrogen at 50 psi for 12 hours. The mixture was filtered through celite and concentrated to give 0.30 g (100%) of the amine (17-3) as a pale yellow oil. To a stirred solution of 0.09 g (0.33 mmol) of acid (1-6), 0.071 (0.33 mmol) of amine (17-3) and 0.11 mL (0.99 mmol) of N-methylmorpholine in 5 mL methyl cyanide is treated with 0.15 g (0.33 mmol) of BOP. After stirring at room temperature for 12 hours, the mixture is concentrated and the residue is redissolved in 30 ml of methylene chloride. The organic solution was washed with 10 mL of saturated aqueous sodium bicarbonate solution and 10 mL of saturated sodium chloride solution. The solution was dried over sodium sulfate, filtered and concentrated to give 0.140 g of crude adduct (17-4). Dissolve 0.140 g (0.33 mmol) of ester (17-4) in a mixture of 2 mL of methanol and 5 mL of tetrahydrofuran and treat with 1.0 mL of 1N aqueous lithium hydroxide solution. The solution was stirred at room temperature for 12 hours. The desired product was purified by preparative HPLC eluting with a gradient of from 95: 5 to 5:95 water / methyl cyanide to give acid (17-5).

¹ H NMR (300 MHz, CD ₃ OD): d 7.58 (d, J = 7.6 Hz, 1H), 7.33 (m, 1H), 7.13 (m, 3H), 6.59 (d, J = 7.6Hz, 1H), 3.89 (t, J = 7.3Hz, 1H), 3.64 (m, 2H), 3.56 (m, 2H), 2.80 (t, J = 6.1 Hz), 2.65 (m, 2H), 2.19 (m, 2H), 1.96 (m, 2H), 1.58 (m, 4H) ppm.

6-Methoxy-pyridine-3-carboxaldehyde (18-2)

A solution of 3.46 mL of a 1.6 M solution of n-butyllithium in a mixture of hexanes and 18 mL of tetrahydrofuran was cooled to -78 ° C and the cooled solution was treated with a solution of 1.04 g (5.53 mmol) of 5-bromo-2. -methoxypyridine (18-1) (CR Johnson; NS Sirisoma Tetrahedron Lett., 1998, 39, 2059) in 2 ml tetrahydrofuran. The heterogeneous mixture was stirred for 40 minutes and added

1.5 ml of pure dimethylformamide. The solution was stirred at -78 ° C for 90 minutes and quenched with 2 mL of saturated aqueous ammonium chloride solution. Remove the cooling bath and warm to room temperature. After extraction twice with 30 ml of ethyl acetate and the combined organics were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired aldehyde (18-2).

TLC Rf = 0.45 (10% ethyl acetate in hexanes).

137 • · · · ·

3- (6-Methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,1'-naphthyridin-4-yl) -nonanoic acid (18-3)

6-Methoxy-pyridine-carboxaldehyde (18-2) is converted to the acid (18-3) according to Scheme 15.

¹ H NMR (300 MHz, CD ₃ OD): d 8.31 (m, 1H), 8.19 (s, 1H), 7.59 (m,

1H), 7.45 (m, 1H), 6.60 (m, 1H), 4.16 (s, 3H), 3.51 (m, 2H), 3.20 (m, 1H), 2, 79 (m, 6H), 1.95 (m, 2H), 1.71 (m, 4H), 1.37 (m, 3H) ppm.

Scheme 19

CHO

19-1

19-3b. R = H

3 (R or S) - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid; and

3- (S or R) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (19-3a) and (19- 3b)

5-Pyrimidine-carboxaldehyde (19-1) (T. Rho; Y. F. Abuh, Synthetic Comm., 1994, 24, 253) is converted to acid (19-2) according to Scheme 15. The enantiomers of the racemic ethyl ester (19-2) were separated by HPLC (Chiralcel OD, 25x2 mm column, eluting from 90:10 to 40:60 hexanes: isopropanol: 0.1% diethylamine mixture over 60 minutes; flow rate 7.0 ml) / min) to give two enantiomers (retention time = 7.79 and 8.72 minutes). Hydrolysis of the optically active esters formed according to Scheme 15 yields acids (19-3a) and (19-3b).

»· ·

138 ¹ H NMR (300 MHz, CD ₃ OD): d 9.01 (s, 1H), 8.71 (s, 2H), 7.57 (d,

J = 7.4 Hz), 6.59 (d, J = 7.4 Hz, 1H), 3.49 (m, 2H), 3.12 (m, 1H), 2.72 (m, 6H) ), 1.96 (m, 2H), 1.72 (m, 4H), 1.30 (m, 6H) ppm ·

Scheme 20

TBS-CI, Et ₃ N

2. NaBH 4 then HCl (aq)

PhNTi ₂ , Et ₃ N

Pd (OAc) ₂ , dppp, CO (g) Q

20-2. R = OH 20-3, R = OH 20-4, R = CHO

ΌΗ

139

Benzofuran-6-ol (20-2)

To a solution of 7.84 g (62.2 mmol) of 6-hydroxy- [2H] -benzofuran-3-one (201) in 100 ml of DMF at room temperature was added 8.17 g (80.9 mmol) of triethylamine and 10 ml of dimethylformamide. , 32 g (68.4 mmol) of tert-butyl-dimethylsulfonyl chloride. After stirring for 2 hours, the solution was diluted with 300 mL of diethyl ether and washed with 150 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution. The solution was dried over magnesium sulfate, filtered and concentrated to give benzofuranone as a yellow oil which solidified on standing and was not further purified. A solution of 44.2 g (167 mmol) of ketone in 400 mL of methanol at room temperature was treated with 9.5 g (251 mmol, 1.5 eq) of sodium borohydride in four equivalent portions. Material consumption (after about 1 hour) was verified by TLC and quenched with 10 mL acetone. The mixture was treated at room temperature with 200 mL of 3 N aqueous hydrochloric acid and the completion of the reaction was verified by TLC (approximately 24 hours). The solution was concentrated in vacuo to a volume of 150 mL and the residue was extracted twice with 250 mL of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give phenol (20-2) (99%). TLC Rf = 0.35 (30% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.53 (d, J = 1.5 Hz, 1H); 7.41 (d, J = 6.3Hz, 1H); 7.1 (brs, 1H), 6.81-6.78 (dd, J = 1.5, 6.3 Hz, 1H), 6.69 (d,

J = 1.5 Hz, 1H) ppm.

trifluoromethanesulfonic acid benzofuran-6-yl ester (20-3)

The solution cooled to 0 DEG C., 4.00 g (29.85 mmol) of benzofuran-6-ol (20-2) and 10.66 g (29.85 mmol) of N-phenyl-triplimide in 150 ml of methylene chloride is treated with 5. 37 mL (3.92 g, 38.81 mmol) of triethylamine. The reaction mixture was warmed to room temperature over 90 minutes and diluted with 200 mL diethyl ether. The organic solution was washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated solution

140

sodium chloride. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to give trifluoroacetate (20-3) as a colorless oil which solidified on standing.

TLC Rf = 0.39 (10% ethyl acetate in hexanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.72 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.48 (br s 1H, 7.20 (dd, J = 8.4, 1.0 Hz, 1H), 6.82 (br s, 1H) PPm.

Benzofuran-6-carbaldehyde (20-4)

A solution of 0.798 g (3.0 mmol) of trifluoroacetate (20-3), 13.5 mg (0.060 mmol) of palladium acetate and 24 mg (0.060 mmol) of diphenylphosphinepropane in 15 ml of dimethylformamide was allowed to warm slightly at 70 ° C. to pass through carbon dioxide gas. 1.66 ml (12 mmol) of triethylamine is added, followed by 2.70 ml (6.0 mmol) of trioctyl-silane. The solution was kept at 70 ° C for 2 hours and cooled to room temperature. After dilution with 10 ml of water, the mixture is extracted twice with 30 ml of diethyl ether. The combined organic extracts were washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% acetone in hexanes to give the desired aldehyde (20-4). TLC Rf = 0.39 (10% ethyl acetate in hexanes).

3- (2,3-Dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid (20-5)

The aldehyde (20-4) is converted to the acid (20-5) according to Scheme 15.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.3 (m, 1H); 7.11 (m, IH); 6.8 (m. 1H);

6.62 (s, 1H), 6.35 (m, 1H), 4.5 (m, 2H), 3.51 (m, 2H), 3.15 (m, 3H), 2.61 (m 5H), 1.91 (m, 3H), 1.72 (m, 4H), 1.4 (m, 6H) ppm.

• · • ·

141

EDC, NMM

HCl’HN (Me) OMe

Scheme 21

OH

CH, i

.0

N CH ₃

• ·

[4- (Methoxy-methyl-carbamoyl) -butyl] -carbamic acid tert-butyl ester (21-2)

92 mmol of N-Boc-amino-valeric acid (21-1) are dissolved in 300 ml of methyl cyanide and the solution is then treated with 10.8 g (110 mmol).

HCl-NH (Me) OMe, 17.6 g (92 mmol) EDC, 12.4 g (92 mmol) HOBT and 61 mL (552 mmol) NMM. The mixture was stirred for 18 hours and then concentrated. The resulting residue was dissolved in ethyl acetate, washed with water, 10% potassium bicarbonate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give amide (21-2) as a brown oil.

TLC Rf = 0.67 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 4.66 (s, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 3.13 (t, 2H, 6Hz), 2.45 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.44 (s, 9H).

(5-Oxo-5-quinolin-3-yl-pentyl) -carbamic acid tert-butyl ester (213)

To a stirred solution of 25 g (120 mmol) of 3-bromoquinoline in diethyl ether.

143 ...............

at 78 ° C, 48 ml (120 mmol) is added dropwise over 30 minutes

Of a 2.5 M solution of n-butyllithium in tetrahydrofuran. After 30 minutes, 3.9 g (15 mmol) of the product (21-2) in 50 mL of ether was added dropwise over 10 minutes. After 30 minutes the cooling bath was removed and after 1.0 hour the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography eluting with 20-50% ethyl acetate in hexanes to give the title compound (21-3) as a yellow solid.

TLC R f = 0.33 (silica, 50% ethyl acetate in hexanes).

7-tert-Butoxy-carbonyl-amino-3-quinolin-3-yl-heptanoic acid methyl ester (21-5)

To a stirred solution of 6.7 g (36.5 mmol) of trimethyl phosphone acetate and tetrahydrofuran was added dropwise over 30 minutes at 0 ° C, 37 mL (37 mmol) of a 1.0 M solution of NaHMDS in tetrahydrofuran. After 30 minutes, a solution of 3.0 g (9.13 mmol) of the product (21-3) in 100 mL of tetrahydrofuran was added. The reaction mixture was heated to reflux. After 1.0 hour, the reaction mixture was diluted with diethyl ether and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography eluting with 50% ethyl acetate in hexanes to give the product (21-4) as a yellow oil.

A mixture of 3.5 g (9-13 mmol) of product (21-4) and 1.0 g of a 10% palladium on carbon solution in 50 ml of methanol was stirred under a hydrogen atmosphere for 6 hours. After filtration and removal of the solvent by evaporation, the resulting residue was purified by silica gel column chromatography eluting with 3050% ethyl acetate in hexanes to give the product (21-5) as a yellow oil.

144 ...............

TLC R f = 0.43 (silica, 50% ethyl acetate in hexanes) ¹ H NMR (300 MHz, CDCl ₃ ): d 8.79 (d, 1H, J = 2Hz), 8.08 (d, 1H J = 9Hz), 7.93 (s, 1H), 7.79 (d, 1H, J = 8Hz), 7.68 (m, 1H), 7.54 (m, 1H), 4.47 ( s, 1H), 3.57 (s, 3H), 3.30 (m, 1H), 3.04 (m, 2H), 2.73 (m, 2H), 1.78 (m, 2H), 1.45 (m, 2H), 1.39 (s, 9H), 1.26 (m, 2H).

7 - [(5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl-methyl) -amino] -3 (quinolin-3-yl) -heptanoic acid methyl ester (21-7)

A solution of 9.1 mmol of ester (21-5) in 10 mL of a 4 M solution of hydrochloric acid in dioxane was stirred for 30 minutes, and then concentrated to give the amine (21-6) as a yellow oil.

A mixture of 900 mg (2.5 mmol) of compound (21-6), 405 mg (2.5 mmol) of 3-formyl-5,6,7,8-tetrahydro- [1,8] naphthyridine, 2 g of molecular sieves in powder form, 0.35 mL (2.5 mmol) of DIPEA and 100 mL of DCE were stirred for 30 minutes, cooled to 0 ° C, and then 730 mg (3.5 mmol) of Na (OAc) ₃ BH was added. . After 1 hour, the reaction mixture was diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with a 10% 10: 10: 1 mixture of ethanol, ammonium hydroxide and water in 70:20:10 chloroform: ethyl acetate: methanol to give the title product ( 21-7) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 8.79 (d, 1H, J = 2Hz), 8.08 (d, 1H, J = 9Hz), 7.93 (d, 1H, J = 2Hz) 7.78 (d, 1H, J = 8Hz), 7.67 (m, 1H), 7.54 (m, 1H), 7.05 (d, 1H, J = 7Hz), 6.39 (d 1H, J = 7Hz), 4.83 (s, 1H), 3.58 (s, 2H), 3.57 (s, 3H), 3.34 (m, 3H), 2.73 (m, 4H), 2.53 (t, 2H, J = 7 Hz), 1.89 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.24 (m, 2H) ).

7 - [(5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-ylmethyl) -amino] -3- (quinolin-3-yl) -heptanoic acid (21-8) • F f f f f f f f f f f k f f k k f k k k k k k f f f f k k »·

145 ...............

To a solution of 0.8255 mmol of compound (21-7) in 5 mL of ethanol was added 1.0 mL (1.0 mmol) of 1N sodium hydroxide solution. After stirring for 1 hour, the solvent was removed by evaporation and the residue was purified by silica gel column chromatography eluting with a 20: 10: 1: 1 mixture of ethyl acetate, ethanol, water and ammonium hydroxide followed by 15: 10: 1: 1 to give the title product. (21-8) as white solids.

TLC Rf = 0.10 (ethyl acetate: ethanol: water: ammonium hydroxide =

10: 10: 1: 1).

¹ H NMR (300 MHz, CD ₃ OD): d 8.78 (d, 1H, J = 2Hz), 8.20 (d, 1H,

J = 2 Hz), 7.97 (d, 1H, J = 9 Hz), 7.89 (d, 1H, J = 8 Hz), 7.71 (m, 1H), 7.58 (m, 1H), 7 16 (d, 1H, J = 7 Hz), 6.43 (d, 1H, J = 7 Hz), 3.96 (s, 2H), 3.36 (m, 2H), 2.94 (m, 2H) 1.65 (m, 2H), 1.83 (m, 5H), 1.69 (t, 2H, J = 8 Hz),

1.30 (m, 2 H).

Scheme 22

DiBALH

-7-1 tr ·

I nr

4 ·· «9 9 • 99 9 9 * 9 8

9 9 9 9

9 9 9 9

9 9 9> ·>

• 9 1 «« 999999

146

99

Q3>

CH ₂ Cl ₂ TFA

FACE, DBU, CFhCN

22-4

The first H _2, Fd / C

2. LiOH

4- (quinolin-3-yl) but-3-en-2-one (22-1)

To a mixture of 3.1 g (19.1 mmol) of dimethyl (2-oxopropyl) phosphonate, 972 mg (23 mmol) of anhydrous lithium chloride and 3.0 g (19.1 mmol) of 3-quinolinecarboxaldehyde (6-1) in 70 ml of anhydrous acetonitrile was treated with 2.9 ml (19.1 mmol) of DBU and the resulting suspension was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between saturated sodium chloride solution and methylene chloride. The organic portion was removed, dried and concentrated to give a yellow solid which was crystallized from ethyl acetate in hexanes to give the title product (22-1) as an off-white solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.05 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8)

Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.5

Hz, 1H), 7.65 (d, J = 16Hz, 1H), 7.55 (t, J = 7.5Hz, 1H), 6.53 (d, J = 16Hz)

Hz, 1H), 1.44 (s, 3H).

• ·

148 ...........

4- (quinolin-3-yl) but-3-en-2-ol (22-2)

A solution of 1.2 g (6.1 mmol) of the product (22-1) in 50 mL of anhydrous tetrahydrofuran was cooled to -78 ° C and then treated dropwise with 12.75 mL (12.2 mmol) of isobutyl. -aluminium hydride (I-BU2AlH). The solution was stirred at -78 ° C for 20 minutes, then quenched with ethyl acetate (20 mL). After warming to room temperature, the mixture was treated with 25 mL of 1 M sodium potassium tartrate solution and stirred for 4 hours. The mixture was extracted twice with 150 mL of ethyl acetate, dried, filtered and evaporated to give the product (22-2) as a yellow oil.

Rf (silica, ethyl acetate) = 0.30.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.05 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 1.8Hz, 1H), 7.81 (d, J = 7.5Hz, 1H), 7.73 (t, J = 7.5Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 16 Hz, 1H), 6.53 (dd, J = 16, 5.8 Hz, 1H), 4.56 (m, 1H), 1 44 (d, J = 4.6 Hz, 3H).

3- (quinolin-3-yl) -hex-4-enoic acid ethyl ester (22-3)

A solution of 1.2 g (6.1 mmol) of allylic alcohol (22-2) in 50 ml of triethyl orthoacetate was treated with 0.022 ml (0.31 mmol) of propionic acid and refluxed for 2 hours. The cooled mixture was treated with 150 mL of a 1: 1 saturated solution of sodium chloride and 1N hydrochloric acid, and then extracted three times with 125 mL of methylene chloride. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried, filtered and evaporated. Silica gel chromatography eluting with ethyl acetate gave the product (22-3) as a yellow glassy solid.

Rf (silica, ethyl acetate) = 0.65.

¹ H NMR (300 MHz, CDCl ₃ ): d 8.92 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.82 (d, J = 7.5Hz, 1H), 7.71 (t, J = 7.5Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 5.6 (m, 2H), 4.21 (m, 1H), 4.05 (t, J = 7.4 Hz, 2H), 2.79 (m, 2H) 1.91 (d, J = 6Hz, 2H), 1.08 (t, J = 7.4Hz, 3H).

149 4-Oxo-3- (quinolin-3-yl) -butyric acid ethyl ester (22-4)

A solution of 1.0 g (3.7 mmol) of product (22-3), 0.06 mL (3.9 mmol) of trifluoroacetic acid and 0.5 mg sudan red in 50 mL was cooled to -78 ° C. of anhydrous methylene chloride. The reaction solution was treated with ozone until the red color disappeared (approximately 5 min). Solid triphenylphosphine (1.4 g, 5.6 mmol) was added and the solution was warmed to room temperature. After 30 minutes, the solution was washed with saturated sodium bicarbonate solution, dried, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with 10% acetone in ethyl acetate. The title compound (22-4) is obtained as a colorless glass.

Rf (silica, ethyl acetate) = 0.25.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.88 (s, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.82 (d, J = 7.5Hz, 1H), 7.76 (t, J = 7.5Hz, 1H) 7.58 (t, J = 7.5Hz, 1H), 4.4 (m, 1H), 4.05 (t, J = 7.4Hz, 1H), 4.13 (m, 2H) 3.30 (dd, J = 7.6, 16 Hz, 1H), 2.87 (dd, J = 7.2, 16 Hz, 1H), 1.20 (m, 3H).

2-oxo-5- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -pentylphosphonic acid dimethyl ester (22-5)

The cooled solution to -78 ° C, 10.0 g (80.5 mmol) of dimethyl methyl phosphonate in 125 mL of anhydrous tetrahydrofuran was treated dropwise with 32.2 mL of 2.5 M n-butyl lithium solution. After stirring for 45 minutes, a solution of 6.6 g (26.6 mmol) of ester (22-4) in 35 ml of tetrahydrofuran was added dropwise at -78 ° C, and the resulting solution was stirred at -78 ° C for 30 minutes. The reaction was quenched by the addition of 100 mL of saturated ammonium chloride solution and then extracted three times with 150 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to a yellow oil. Silica gel column chromatography eluting with 5% methanol in methylene chloride gave the product (22-5) as a yellow oil.

Rf (silica, 5% methanol in methylene chloride) = 0.20.

150 ...........

¹ H NMR (300 MHz, CDCl ₃ ): d 7.05 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.32 Hz, 1H), 4.80 (br, s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.4 (m, 2H), 3.08 (d, J = 22.7 Hz), 2.72 ( m, 6H), 2.56 (t, 2H), 1.91 (m, 2H).

6-Oxo- (3-quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (22-7)

To a mixture of 1.0 g (3.1 mmol) of ketophosphonate (22-5), 170 mg (4.0 mmol) of anhydrous lithium chloride and 0.797 g (3.1 mmol) of the resulting product (22-4) in 60 ml of anhydrous of acetonitrile was treated with 0.52 mL (3.3 mmol) of DBU and the resulting suspension was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between saturated sodium chloride solution and methylene chloride. The organic portion was removed, dried and concentrated to give the title product (22-6) as a mixture of E and Z olefins. The crude mixture was dissolved in 50 ml of ethanol. The solution was treated with 200 mg of a 10% palladium on charcoal solution, stirred for 4 hours under a hydrogen atmosphere, and then filtered. The filtrate was treated with 2.0 eq. The mixture was stirred at room temperature for 12 hours and then neutralized by addition of 1N hydrochloric acid solution and evaporated. The resulting residue was purified by silica gel chromatography eluting with 10% methanol in methylene chloride to give the title product (22-7) as a white solid.

Rf (silica, 10% methanol in methylene chloride) = 0.20.

¹ H NMR (300 MHz, CDCl ₃ ); d 10.9 (br, s, 1 H), 8.92 (d, J = 1.8 Hz,

H), 8.21 (d, J = 7.5Hz, 1H), 8.05 (d, J = 1.8Hz, 1H), 7.87 (d, J = 7.5Hz, 1H) 7.81 (t, J = 7.5Hz, 1H), 7.58 (t, J = 7.5Hz, 1H), 7.25 (d, J = 7.3Hz, 1H), 6 34 (d, J = 7.3Hz, 1H), 3.81 (m, 1H), 3.44 (m, 2H), 3.0-2.2 (m, 12H), 1.92 (m, 2H), 1.68 (m, 1H), 1.42 (m, 1H).

• ·

151 • ·

Scheme 23

3- (N-oxo-quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (23-2)

A solution of 100 mg (0.22 mmol) of compound (15-6) in 30 mg of 50 aqueous ethanol was treated with 414 mg (0.66 mmol) of Oxone®. The resulting solution was stirred at room temperature for one hour, extracted three times with 60 ml of methylene chloride, dried, filtered and evaporated to give the product (23-1).

152

like a yellow movie. The crude product (23-1) is hydrolyzed with lithium hydroxide and purified by silica gel column chromatography eluting with a 50:50 mixture of solvent system A and ethyl acetate (A = ethanol: ammonium hydroxide: water 20: 1: 1) to give (23-2) as a colorless glass.

R f (silica, 50% A: ethyl acetate) = 0.30 ¹ H NMR (300 MHz, CD ₃ OD): d 8.66 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 8.5Hz, 1H), 8.09 (d, J = 1.8Hz, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7, 32 Hz, 1H), 5.6 (m, 2H), 3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2H), 2.65 (m, 2H) 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H).

Scheme 24

153

Furo- [2,3-b] pyridine-5-carboxaldehyde (24-2)

The alcohol solution (24-1) (M. Bhupathy et al., J. Heterocycl. Chem. 1995, 32,1283-1287) was treated with an excess of manganese dioxide (10 eq.) And stirred at room temperature for 16 hours. filter through celite and evaporate to give the product (24-2) as a white solid.

TLC R f = 0.40 (25% ethyl acetate in hexane) ¹ H NMR (300 MHz, CDCl ₃ ): d 10.22 (s, 1H), 9.05 (d, J = 1.8 Hz, 1H) 8.27 (d, J = 1.7 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H).

3-Furo [2,3-b] pyridin-5-yl-7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - (E) hept-1- en-4-one (24-3)

To a mixture of 0.69 g (2.0 mmol) of ketophosphonate (15-1), 86 mg (2.0 mmol) of anhydrous lithium chloride and 0.25 g (1.7 mmol) of product (24-2) in 25 mL of anhydrous acetonitrile was treated with 0.25 mL (1.8 mmol) of DBU and the resulting suspension was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between saturated sodium chloride solution and methylene chloride.

• ·

The organic portion was removed, dried and concentrated to give a yellow solid which was purified by silica column chromatography eluting with 5% isopropanol / chloroform to give the title product (24-3) as an off-white solid.

Rf (silica, 5% isopropanol in methylene chloride) = 0.45. ¹ H NMR (300 MHz, CDCl ₃ ): d 8.50 (d, J = 2.1Hz, 1H), 8.13 (d, J = 2.1Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 16 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 2.4 Hz) (1H), 6.77 (d, J = 16Hz, 1H), 6.36 (d, J = 7.3Hz, 1H), 4.85 (br, s, 1H), 3.4 (m) 2H, 2.7-2.5 (m, 6H), 1.91 (m, 2H), 1.68 (m, 4H).

3- (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - (E) -non ethyl ester -4-ene (24-4)

The product (24-3) is converted to (24-4) according to the procedure for converting the product (15-4) to the product (15-5).

Rf (silica, 5% isopropanol in methylene chloride) = 0.40. ¹ H NMR (300 MHz, CDCl ₃ ): d 8.18 (d, J = 2.1Hz, 1H), 7.91 (d, J = 2.1Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 7, 3 Hz, 1H), 5.6 (m, 2H), 4.85 (br, s, 1H), 4.05 (q, J = 7.5 Hz, 2H), 4.05 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2H), 2.65 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H) m, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H).

3- (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (24-5a)

A solution of 108 mg (0.25 mmol) of the product (24-4) in ethanol was treated with 30 mg of 10% palladium-on-carbon catalyst and the mixture was stirred under an atmosphere of hydrogen for 6 hours, filtered through celite and evaporated. The crude product is hydrolyzed with lithium hydroxide and purified by silica gel column chromatography eluting with a 50:50 mixture of solvent system A and ethyl acetate (A = ethanol: ammonium hydroxide: water 20: 1: 1) to give the product (24-5a). ) and (24-5b) as white solids.

• • • •

155

Rf (silica, 50% A: ethyl acetate) = 0.45.

¹ H NMR (300 MHz, CDCl ₃ ): d 10.7 (br, s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 1.8) Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 1.7 Hz, 1H), 6.25 (d, J = 7.3Hz, 1H), 3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2H), 2.65 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H) ).

3- (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - nonanoic acid (24-5b)

Rf (silica, 50% A: ethyl acetate) = 0.45.

¹ H NMR (300 MHz, CDCl ₃ ): d 10.8 (br, s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8) Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 4.60 (t, J = 7.4 Hz, 2 H), 3.7 (m, 1H), 3.40 (m, 2H), 3.20 (t, J = 7.4 Hz, 2H), 2.75 (m, 2H), 2, 65 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H) H).

25-1

The first H _2, Pd / C

LiAIH ₄

25x2 (X = CO ₂ Et) 253 (X = CH ₂ OH)

25-4

CHO

156

2,3-dihydro-furo [3,2-b] pyridine-5-ethyl-carboxylate (25-2)

A solution of the ester (25-1) (Jacob M. Hoffman, US Patent No. 4,808,595) in ethanol is treated with 30% by weight of 10% palladium on charcoal and the mixture is stirred under an atmosphere of hydrogen for 22 hours and then filtered and Evaporates to give the product (25-2) as a tan solid.

TLC Rf = 0.40 (25% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.45 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 4.72 (t, J = 7.5Hz, 2H), 4.01 (q, J = 7.4Hz, 2H), 3.42 (t, J = 7.5Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).

2,3-Dihydro-furo [3,2-b] pyridine-5-methanol (25-3)

A solution of 1.93 g (10 mmol) of ester (25-2) in 150 mL of anhydrous tetrahydrofuran was cooled to -78 ° and then treated dropwise with 10.75 mL (10.75 mmol) of LAH. The resulting solution was stirred at -78 ° for 20 minutes, then warmed to 25 ° C, stirred for 4 hours, and then quenched with 20 mL of ethyl acetate. The mixture was treated with 25 ml of 1M sodium tartrate solution and stirred for 4 hours. The mixture was extracted twice with 150 mL of ethyl acetate, dried, filtered and evaporated to give the product (25-3) as a white solid, which was used in the next synthesis step without further purification.

TLC Rf = 0.6 (ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.10 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 1.8 Hz, 1H), 5.10 (s, 2H), 4.65 (t, J = 7.5 Hz, 2H), 3.36 (t, J = 7.5 Hz, 2H).

• «

157

2,3-dihydro-furo [3,2-b] pyridine-5-carboxaldehyde (25-4)

The alcohol solution (25-3) was treated with excess manganese dioxide (10 eq) and the mixture was stirred at room temperature for 16 hours, filtered through celite and evaporated to give the title product (25-4) as a white solid.

TLC Rf = 0.35 (25% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 10.08 (s, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 4.72 (t, J = 7.5Hz, 2H), 3.42 (t, J = 7.5Hz, 2H).

3- (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) ) -nonanoic acid (25-5)

Compound is prepared using aldehyde (25-4) according to the product preparation procedure (15-7).

¹ H NMR (300 MHz, CD ₃ OD): d 7.80 (d, J = 1.5 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.02 (d J = 1.5 Hz, 1H), 6.45 (d, J = 7.3 Hz, 1H), 4.72 (t, J = 7.5 Hz, 2H), 3.56 (m, 1H) ), 3.46 (m, 2H), 3.42 (t, J = 7.5Hz, 2H), 2.75 (m, 2H), 2.62 (m, 2H), 2.50 (m H, 1.95 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H).

Scheme 26 N h ₃ en ^x 'Cl 22E

57% Hl h ₃ en ^-

in

2F-2 ¹ · FdfOACJ ²¹ NE ₃ , DMF 2 K ₂ , Pd / C

1. NH ₃ , THF

2. 6N HCI • ·

158

4-Iodo-2-methyl-thio-pyrimidine (26-2)

To a solution of 50 ml of 57% hydrogen iodide cooled to 0 ° C was added dropwise 10 g (62.3 mmol) of chloride (26-1). After 30 minutes, the ice bath was removed and the resulting orange suspension was stirred at room temperature for 16 hours. The reaction was carefully quenched by the addition of 400 mL of saturated sodium bicarbonate solution, brought to pH = 9 by addition of solid sodium carbonate, and the mixture was extracted twice with 200 mL of ethyl acetate. The combined organic extracts were dried and evaporated to give a colorless oil, which was dissolved in boiling hexane and then cooled to give (26-2) as colorless needle crystals.

TLC Rf = 0.4 (20% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.01 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 5.1)

159 • ·

Hz, 1H), 2.54 (s, 3H).

5- (2-Methylthio-pyrimidin-4-yl) -pentanoic acid ethyl ester (26-3)

A solution of 9.5 g (38 mmol) of the product (26-2) in 150 ml of dimethylformamide is treated with 0.43 g (1.9 mmol) of palladium acetate and 8.0 g (80 mmol) of triethylamine, and the mixture is bubbled with argon and Heat to 50 ° C for 16 hours. The solvent was removed under reduced pressure and the brown residue formed was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was dried, filtered and evaporated. The resulting residue was purified by silica column chromatography eluting with 20% ethyl acetate in hexane to give the product (26-3) as an oil.

TLC Rf = 0.3 (20% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.41 (d, J = 5.1 Hz, 1H), 7.0 (m, 1H), 6.80 (d, J = 5.1 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 4.18 (q, J = 7.3 Hz, 2H), 2.7-2.5 (4H), 2.57 ( s, 3H), 1.25 (t, J = 7.3Hz, 3H).

In the presence of 1.2 g (20% by weight) of 10% palladium on charcoal, 5.6 g (22 mmol) of this material was reduced in ethanol at 10 psi hydrogen. The title product (26-3) is obtained as a colorless oil.

TLC Rf = 0.3 (20% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.41 (d, J = 5.1 Hz, 1H), 6.80 (d, J = 5.1 Hz, 1H), 4.18 (q, J = 7.3 Hz, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.57 (s, 3H), 2.35 (t, J = 7.4 Hz, 2H), 1.7 (4H), 1.25 (t, J = 7.3Hz, 3H).

5- (2-Methanesulfonyl-pyrimidin-4-yl) -pentanoic acid ethyl ester (26-4) To a solution of 2.0 g (8.0 mmol) of the product (26-3) in 100 ml of methanol is added a solution of 14 5 g (24 mmol) of Oxone® in 100 ml of water. The resulting solution was stirred at room temperature for 20 hours and then the methanol was removed under reduced pressure. Dilute the aqueous portion with 100 mL saturated sodium bicarbonate solution and extract twice with 100 mL.

160 ...........

ethyl acetate. The organics were dried, filtered and concentrated to give the title product (26-4) as a colorless oil.

TLC Rf = 0.3 (20% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.75 (d, J = 5.1 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.18 (q, J) = 7.3 Hz, 2H), 3.37 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.25 (t, J = 7.3 Hz, 3H).

5- (2-Amino-pyrimidin-4-yl) -pentanoic acid (26-5)

A solution of 0.19 g (0.67 mmol) of the product (26-4) in 5 mL of tetrahydrofuran was cooled to 0 ° C and saturated with ammonia gas. The mixture was stirred at 0 ° C for 4 hours and then evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was dried, filtered and concentrated to give the amino ester (265).

TLC Rf = 0.3 (ethyl acetate).

¹ H NMR (300 MHz, CD ₃ OD): d 8.16 (d, J = 5.1 Hz, 1H), 6.75 (d, J = 5.1 Hz, 1H), 4.18 (q, J = 7.3 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.7 (4H), 1 25 (t, J = 7.3Hz, 3H).

The above ester was dissolved in 6N hydrochloric acid and stirred at room temperature for 16 hours. After concentration, the product (26-5) is formed as its hydrochloride.

¹ H NMR (300 MHz, CD ₃ OD): d 8.53 (d, J = 5.1 Hz, 1H), 6.85 (d, J = 5.1 Hz, 1H), 2.58 (t, J = 7.4Hz, 2H), 2.35 (t, J = 7.4Hz, 2H), 1.7 (4H).

3- [5- (2-Amino-pyrimidin-4-yl) -pentanoyl-amino] -3 (S) - (quinolin-3-yl) -propionic acid (26-6)

The acid (26-6) is obtained by combining the products (26-5) and (5-7) followed by saponification, the process of which is described in the preparation of the product (19) from compounds (1-6) and (1-7).

¹ H NMR (300 MHz, CD ₃ OD): d 8.53 (s, 1H), 20 (s, 1H), 7.7 (d, J = 7 Hz, 1H), 7.7-7.4 (4H), 6.11 (d, J = 5Hz, 1H), 5.3 (m, 1H), 3.5 (m, 3H), 2.5 (m, 2H), 2.10 (m) 1 H, 1.51 (m, 2H), 1.3 (m, 2H).

161

Scheme 27

3- (4-Amino-butyryl-amino) -3- (S) - (3-fluoro-phenyl) -propionic acid ethyl ester hydrochloride (27-2)

A mixture of 245 mg (2.1 mmol) of compound (27-1), 300 mg (1.21 mmol) of compound (9-1), 300 mg (1.57 mmol) of EDC, 490 mg (50 mmol) was stirred under argon for 16 h. 4.84 mmol) NMM and 213 mg (157 mmol) HOBT in 7 ml dimethylformamide. The mixture is then diluted with 50 ml of ethyl acetate and washed successively with saturated sodium bicarbonate solution, water, 10% potassium hydrogen carbonate solution and 20 ml of saturated sodium chloride solution, dried and concentrated to give the Boc-protected aminoester amino ester.

TLC Rf = 0.7 (90% ethyl acetate in hexane).

¹ H NMR (300 MHz, CDCl ₃ ): d 7.3 (t, J = 7.8 Hz, 1H), 7.1 (d, J = 7.8 Hz,

1H), 7.07 (d, J = 7.8Hz, 1H), 6.92 (t, J = 7.8Hz, 1H), 5.40 (m, 1H), 4.80 (br, t, 1H), 4.18 (q, J = 7.3 Hz, 2H), 3.20 (m, 2H), 2.82 (t, J = 7.4 Hz, 2H),

2.35 (t, J = 7.4Hz, 2H), 1.7 (4H), 1.25 (t, J = 7.3Hz, 3H).

• • • • •

162

Dissolve 440 mg (1.1 mmol) of the Boc protected aminoester in 10 mL of a 2.3 N ethanolic hydrochloric acid solution. The solution was stirred at room temperature for 3 hours and then concentrated to give the product hydrochloride (27-2).

¹ H NMR (300 MHz, CD ₃ OD): d 7.3 (t, J = 7.8 Hz, 1H), 7.1 (d, J = 7.8 Hz, 1H), 7.07 (d J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 5.40 (m, 1H), 4.18 (q, J = 7.3 Hz, 2H) 3.20 (m, 2H), 2.82 (t, J = 7.4Hz, 2H), 2.35 (t, J = 7.4Hz, 2H), 1.7 (4H), 1.25 (t, J = 7.3Hz, 3H).

3 (S) - (3-Fluoro-phenyl) -3- [4 - ([1,8] -naphthyridin-2-ylamino) -butyrylamino-propionic acid ethyl ester (27-4)

A mixture of 350 mg (1.1 mmol) of amine hydrochloride (27-2), 230 mg (1.1 mmol) of bromide (27-3) (W. Roszkiewicz; M. Wozniak; Synthesis 1976) was heated at reflux for 20 h. 691-2) and 355 mg (2.75 mmol) of DIPEA in 5.5 mmol of acetonitrile. The solution was concentrated and the brown residue formed was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium chloride solution, dried, filtered and concentrated. The residue as an oil was purified by silica column chromatography eluting with 5% ethanol in ethyl acetate to give the title compound (27-4) as a colorless glass.

TLC Rf = 0.45 (5% ethanol in ethyl acetate).

¹ H NMR (300 MHz, CDCl ₃ ): d 8.80 (d, J = 1.8 Hz, 1H), 8.50 (br, d, J = 7 Hz, 1H), 7.85 (d, d, J = 1.8, 7.0 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.2-6.8 (5H), 6.62 (d, J) = 7.5 Hz, 1H), 5.61 (m, 1H), 5.31 (br, t, 1H), 4.18 (q, J = 7.3 Hz, 2H), 3.60 (m (2H), 32 (dd, J = 6.0, 10.5 Hz, 1H) 3.02 (dd, J = 5.6, 10.5 Hz, 1H), 2.22 (t, J = 7) 4 Hz, 2H), 1.92 (m, 2H), 1.25 (t, J = 7.3 Hz, 3H).

3- (S) - (3-Fluorophenyl) -3- [4- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylamino) -butyryl-amino] bis-trifluoroacetate - Propionic acids (27-5)

Ίθβ * · ·· »····!

A solution of 90 mg (0.21 mmol) of product (27-4) in 3 mL of ethanol was treated with 60 mg of 10% palladium on charcoal and stirred under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration and the filtrate was concentrated to give the crude reduced ester. This material was hydrolyzed with lithium hydroxide, neutralized by addition of 1N hydrochloric acid solution, concentrated, and the resulting residue was purified by reverse phase chromatography to give the product (27-5) as bistrifluoroacetate.

High resolution mass spectrum:

calcd. = 401.1977;

found = 401.1983.

Scheme 28

28-5 ·

• · · · · · · · · · · · ·

164 • 9 · 4 · 4 and 4 · 4 · 4 · 4 · 4 · 4

COoEí

CO 4 H

LiOH

EtOH / HoO

8-Oxo-nonanal (28-2)

A solution of 5.2 g (41.9 mmol) of 1-methylcyclooctene (28-1) in 200 ml of methylene chloride cooled to -78 ° C was treated with ozone for 30 minutes. The mixture was stirred for 1 hour and argon was bubbled through. The reaction mixture was treated with triphenylphosphine, and then the reaction mixture was concentrated and purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes 1:10 to give the desired product (28-2) as an oil.

¹ H NMR (400 MHz, CDCl ₃ ): d 9.72 (t, J = 2.0 Hz, 1H), 2.38 (m, 4H), 2.09 (s, 3H), 1.61- 1.52 (m, 4H); 1.28 (m, 4H).

Ethyl 10-oxo-undec-2-enoate (28-3)

To a solution cooled to -40 ° C, 10.8 g (69.2 mmol) of the product (28-2) in 150 ml of methylene chloride was gradually added over a period of 15 minutes a solution of 24.1 g (69.2 mmol) (carbethoxymethylene). of triphenylphosphorane in 100 ml of methylene chloride. The reaction mixture was stirred for 12 hours and warmed to room temperature. After removal of the solvent, the residue was purified by silica gel flash column chromatography eluting with 1: 8 to 1: 6 ethyl acetate in hexanes to give the desired product (28-3) as an oil.

·

165 «··· ·· · ¹ H NMR (400 MHz, CDCl _3): d 6.95 (m, 1H), 5.80 (d, J = 15.6 Hz, 1H),

4.18 (d, J = 7.2Hz, 2H), 2.42 (t, J = 7.2, 2H), 2.20 (m, 2H), 2.13 (s, 3H), 1 57 (m, 2H), 1.46 (m, 2H), 1.29 (m, 7H).

9- [1,8] -naphthyridin-2-yl-non-2-enoic acid ethyl ester (28-4)

A mixture of 4.1 g (18.3 mmol) of compound (28-3), 2.7 g (23.8 mmol) of proline and 2.9 g (23.8 mmol) of compound was heated at 110 ° C for 24 h. (1-3) in 50 mL of ethanol. The reaction mixture is concentrated and purified by silica gel column chromatography eluting with 100% ethyl acetate to give the desired product (28-4) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ): d 9.08 (dd, J = 4.4, 2.0 Hz, 1H), 8.15 (dd, J = 8.0, 2.0 Hz, 1H ), 8.09 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.0, 4.4, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.95 (dt, J = 15.6, 7.2 Hz, 1H), 5.80 (dt,

J = 15.6, 1.6Hz, 1H), 4.15 (q, J = 7.2Hz, 2H), 3.05 (t, J = 7.6Hz, 2H),

2.18 (m, 2H), 1.90 (m, 2H), 1.43 (m, 6H), 1.28 (t, J = 7.2 Hz, 3H).

3- (6-Amino-pyridin-3-yl) -9- [1,8] naphthyridin-2-yl-non-2-enoic acid ethyl ester (28-5)

A mixture of 0.3 g (1.0 mmol) of compound (28-4), 0.3 g (1.9 mmol) of 2-amino-5-bromo-pyridine, 0.3 g (2.4 mmol) of potassium acetate and 0 0.022 g (0.1 mmol) of palladium acetate in 6 ml of dimethylformamide was bubbled with argon for 5 minutes and then heated at 90 ° C for 7 hours and at 115 ° C for 48 hours. The mixture was cooled, water (50 ml) was added and extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by silica gel flash column chromatography eluting from 100% ethyl acetate to 10: 1 ethyl acetate in methanol to give the desired product (28-5) as an oil.

¹ H NMR (400 MHz, CDCl ₃ ): d 9.07 (dd, J = 4.4, 2.0 Hz, 1H), 8.18 (d,

J = 2.0 Hz, 1H), 8.14 (dd, J = 8.0, 2.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H),

7.53 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 (dd, J = 8.0, 4.4, 1H), 7.38 (d, J = 8.4 ·· ·· ♦ ·· ····

166

Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.96 (s, 1H), 4.83 (bs, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.02 (m, 4H), 1.85 (m, 2H), 1.43 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H).

3- (6-Amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid ethyl ester (28-6)

A mixture of 0.1 g (0.3 mmol) of compound (28-5) and 0.1 g of 10% palladium on charcoal in 10 mL of methanol was bubbled through argon in vacuo. The reaction mixture was placed under a hydrogen atmosphere for 40 hours. After filtration through celite, the solution was concentrated and the residue was purified by silica gel column chromatography eluting from 100% chloroform to 5: 1 chloroform: methanol to give the desired product (28-6) as an oil.

¹ H NMR (400 MHz, CDCl ₃ ): d 7.88 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7, Δ (d, J = 7.6 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 4.98 ( bs, 1H), 4.34 (bs, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.39 (m, 2H), 2.95 (m, 1H), 2, 68 (m, 2H), 2.60-2.43 (m, 4H), 1.89 (m, 2H), 1.64-1.44 (m, 4H), 1.27 (m, 6H) 1.29 (t, J = 7.2Hz, 3H).

3- (6-Amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid (28-7)

A mixture of 0.04 g (0.1 mmol) of compound (28-6) and 0.3 ml (0.3 mmol) of a 1M solution of lithium hydroxide in 1 ml of ethanol and 0.5 ml of water was stirred at room temperature for 12 hours. The mixture was concentrated and diluted with 2 mL of 1N hydrochloric acid. The mixture was purified by reverse phase HPLC (C18 column; gradient: water: methyl cyanide: trifluoroacetic acid from 95: 5: 0.1 to 5: 95: 0.1 over 45 min) to give the pure product (28-7) as trifluoroacetate .

¹ H NMR (400 MHz, CD ₃ OD): d 7.90 (dd, J = 9.2, 2.0 Hz, 1H), 7.67 (d,

J = 2.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 6.55 (d,

J = 7.6 Hz, 1H), 3.48 (m, 2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.66 (m, 5H),

2.53 (m, 1H), 1.94 (m, 2H), 1.64 (m, 4H), 1.27 (m, 4H).

167

Scheme 29

HCl (g), EtOAc

168 methyl 8-oxo-nonanoate (29-2)

To a stirred suspension of copper (I) cyanide (2.87 g, 32.0 mmol) in tetrahydrofuran (100 mL) was added methyl magnesium bromide (9.9 mL, 3.0 M) in THF at -78 ° C. The reaction mixture was allowed to warm to -15 ° C over 5 minutes and then cooled to -78 ° C. After addition of a solution of 4.9 g (23.7 mmol) of methyl 7- (chloroformyl) heptanoate (29-1) in 20 mL of tetrahydrofuran,

Warm to -10 ° C for 1.5 hours.

200 ml of a saturated aqueous ammonium chloride solution and 9: 1 concentrated aqueous ammonium hydroxide solution were added to the mixture, and the reaction mixture was extracted twice with 200 ml of ethyl acetate. The organic extracts were washed thoroughly with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic extracts were then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the product (29-1) as an oil, which was used in the next synthesis step without further purification.

7- [1,8] Naphthyridin-2-yl-heptanoic acid methyl ester (29-3)

To a stirred solution of 3.8 g (20.4 mmol) of methyl 8-oxo-nonanoate (292) in 100 mL of absolute ethanol was added 2.49 g (20.4 mmol) of 2-aminopyridine-3-carboxaldehyde and 1, 2-aminopyridine. 17 g (10.2 mmol) of L-proline. The mixture was heated at 95 ° C for 18 h, then cooled to room temperature and then concentrated under reduced pressure. The solid formed was purified by flash column chromatography on silica gel eluting with a 95: 5 mixture of ethyl acetate and methanol to give the title product (29-3) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 9.11 (dd, J = 2.0, 4.2 Hz, 1H), 8.17 (dd,

J = 1.9, 8.1Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 7.44 (dd, J = 4.4, 8.1)

Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 3.65 (s, 3H), 3.03 (app t, J = 6.2 Hz,

2H), 2.32 (app t, J = 7.7 Hz, 2H), 1.98-1.84 (m, 2H), 1.70-1.57 (m, •)

169

2H), 1.50-1.33 (m, 4H).

7- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -heptanoic acid methyl ester (29-4)

To a stirred suspension of 600 mg of 10% palladium on charcoal in 25 ml of ethanol is added a solution of 3.6 g of 7- [1,8] naphthyridin-2-yl-heptanoic acid methyl ester (29-3) in 75 ml of ethanol. The mixture was placed under an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title product (29-4) as an oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.06 (d, J = 7.3 Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 5.01 (br s (1H), 3.66 (s, 3H), 3.42-3.37 (m, 2H), 2.69 (app t, J = 6.3 Hz, 2H), 2.53 (app t, J = 7.6 Hz, 2H), 2.29 (app t, J = 7.5 Hz,

2H), 1.94-1.86 (m, 2H), 1.67-1.59 (m, 2H), 1.37-1.33 (m, 4H).

3-Oxo-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29-5)

To a stirred solution of 5.17 ml (36.9 mmol) of diisopropylamine in 100 ml of anhydrous tetrahydrofuran at -78 ° C was added 16.2 ml of a 2.5 M solution of n-butyllithium in a mixture of hexanes. 97 ml (36.9 mmol) of t-butyl acetate. After a further 5 minutes, add 3.4 g (12.3 mmol) of 7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -heptanoic acid methyl ester (29-4) in 30 ml of tetrahydrofuran and the solution was warmed to -40 ° C for 1 h. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The oil formed was purified by silica gel flash column chromatography eluting with ethyl acetate to give the title product (29-5) as a yellowish oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.04 (d, J = 7.3 Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 4.84 (br s 1H, 3.42-3.37 (m, 2H), 3.33 (s, 2H), 2.69 (app t, J)

170 = 6.4 Hz, 1H), 2.58-2.44 (m, 2H), 1.94-1.86 (m, 2H), 1.72-1.52 (m, 4H), 1.47 (s, 9H); 1.39-1.28 (m, 4H).

9- (5,6,7,8-Tetrahydro- [1,8] -naphthyridin-2-yl) -3- (trifluoromethanesulfonyloxy) -non-2-enoic acid tert-butyl ester (29-6)

To a stirred solution of 3-oxo-9 (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29 g, 2.77 mmol) 7.2 ml of a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene was added in 25 ml of anhydrous tetrahydrofuran at 0 ° C. After 5 minutes, 1.49 g (4.17 mmol) of N-phenyl-trifluoromethanesulfonimide was added in one portion and the solution was allowed to warm to room temperature over 2 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel eluting with ethyl acetate: hexanes (3: 2) to give the title product (29-6) as a yellowish semi-solid.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.08 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 5.66 (s, 1H), 5.09 (br s, 1H), 3.44-3.37 (m, 2H), 2.68 (app t, J = 6.2 Hz, 2H), 2.56 (app t, J = 7.7 Hz, 2H), 2.33 (app t, J = 7.6 Hz,

2H), 1.94-1.83 (m, 2H), 1.70-1.48 (m, 4H), 1.49 (s, 9H), 1.37-1.29 (m, 4H) .

3-Phenyl-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -non-2-enoic acid tert-butyl ester (29-7a)

To a stirred solution of 100 mg (0.20 mmol) of tert-butyl ester 9 (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -3- (trifluoromethanesulfonyloxy) non-2- of enoic acid (29-6) in 2.5 mL of toluene was added 23 mg (0.020 mmol) of (tetrakis) -triphenylphosphine-palladium, 50 mg (0.41 mmol) of phenyl boronic acid and 56 mg (0.41 mmol) of potassium carbonate. Created

171 of the suspension was heated at 90-100 ° C for 2 hours and then cooled to room temperature. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel, eluting with ethyl acetate / hexanes (4: 1) to afford (29-7a) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.41-7.15 (m, 5H), 7.02 (d, J = 7.3 Hz,

H), 6.31 (d, J = 7.2 Hz, 1H), 5.77 (brs, 1H), 4.77 (brs, 1H), 3.42-3.34 (m, 2H), 2.69 (app t, J = 6.3 Hz, 2H), 2.50 (app t, J = 7.6 Hz, 2H), 2.39 (app t, J = 7.8 Hz, 2H) 1.95-1.84 (m, 2H), 1.66-1.54 (m, 4H), 1,421.26 (m, 8H), 1.21 (s, 9H).

3-Phenyl-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29-8a)

To a stirred suspension of 15 mg of 10% palladium on charcoal in 2 ml of ethanol was added a solution of 62 mg of 3-phenyl-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2- tert -butyl ester). yl) -non-2-enoic acid (29-7a) in 3 mL of ethanol and the mixture was placed under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title product (29-8a) as an oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.31-7.13 (m, 5H), 7.04 (d, J = 7.3 Hz, 1H), 6.31 (d, J = 7) 2 Hz, 1H), 4.92 (br s, 1H), 3.42-3.35 (m, 2H), 3.062.94 (m, 1H), 2.69 (app t, J = 6, 2 Hz, 2H), 2.58-2.40 (m, 4H), 1.941.85 (m, 2H), 1.66-1.48 (m, 4H), 1.36-1.18 (m , 17H).

3-phenyl-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) nonanoic acid hydrochloride (29-9a)

A stirred solution of 60 mg of 3-phenyl-9- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29-8a) in ethyl acetate at 0 The gaseous was bubbled through for 1 hour

172 hydrogen chloride. The reaction mixture was warmed to room temperature and then concentrated under reduced pressure. The solid formed (29-9a) was dried under vacuum overnight.

¹ H NMR (300 MHz, CD ₃ OD): d 7.78 (d, J = 7.1 Hz, 1H), 7.33-7.11 (m, 5H), 6.58 (d, J = 7) 2 Hz, 1H), 3.52-3.42 (m, 2H), 3.10-2.96 (m, 1H), 2.82 (app t, J = 7.0 Hz, 2H), 2.68-2.43 (m, 4H), 1.98-1.89 (m, 2H), 1.76-1.50 (m, 4H), 1.40-1.05 (m, 8H) ).

3- (Benzo [b] -thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-2-eno-tert-butyl ester acids (29-7b)

To a stirred solution of 100 mg (0.20 mmol) of tert-butyl ester

9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -3- (trifluoromethanesulfonyloxy) non-2-ene (29-6) in 2.5 ml toluene (tetrakis) -triphenylphosphine-palladium (23 mg, 0.020 mmol), benzo [b] thiophene-2-boronic acid (50 mg, 0.41 mmol) and potassium carbonate (56 mg, 0.41 mmol) were added. The resulting suspension was heated at 90-100 ° C for 2 hours and then allowed to cool to room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic portion was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel eluting with ethyl acetate / hexanes (4: 1) to give the title compound (29-7b) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.82-7.70 (m, 2H), 7.53 (s, 1H), 7.397.22 (m, 2H), 7.02 (d, J) = 7.3 Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 5.89 (br s, 1H), 4.78 (br s, 1H), 3.42-3 36 (m, 2H), 2.74 (app t, J = 6.2 Hz, 2H), 2.58-2.42 (m, 2H), 1.95-1.77 (m, 4H) 1.70-1.10 (m, 17H).

3- (Benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29-8b) )

Into a stirred suspension of 45 mg of 10% palladium on activated carbon in 5 ml.

A solution of 220 mg of 3- (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-tert-butyl ester was added to methanol in methanol. The 2-enoic acid (29-7b) in 5 mL of ethanol was placed in a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel, eluting with a 9: 1 mixture of ethyl acetate in methanol to give the title product (29-8b) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.89-7.64 (m, 4H), 7.03 (s, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.29 (d, J = 7.3 Hz, 1H), 4.85 (br s, 1H), 3.44-3.34 (m, 3H), 2.72-2.44 (m, 6H) 1.94-1.84 (m, 2H), 1.72-1.52 (m, 4H), 1.34 (s, 9H), 1.33-1.22 (m, 8H).

3- (Benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid (29-9b)

With a stirred solution of 3- (benzo [b] thiophen-2-yl) -9 (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) nonanoic acid tert-butyl ester (29) -8b) Hydrogen chloride gas is bubbled in ethyl acetate at 0 ° C for 1 hour. The reaction mixture was warmed to room temperature and then concentrated under reduced pressure. The formed solid was neutralized by the addition of concentrated ammonium hydroxide solution, and then the formed free base was purified by flash column chromatography on silica gel eluting with a 25: 3: 2 mixture of chloroform, ethyl acetate and methanol to give the title compound (29-9b) as a colorless oil. .

¹ H NMR (300 MHz, CD ₃ OD): d 7.77-7.62 (m, 2H), 7.38 (d, J = 7.3 Hz, 1H), 7.30-7.18 ( m, 2H), 7.09 (s, 1H), 6.45 (d, J = 7.2 Hz, 1H), 3.60-3.51 (m, 1H), 3.41 (app t, J = 6.4 Hz, 2H), 2.78-2.52 (m, 6H), 1.94-1.56 (m, 8H), 1.44-1.28 (m, 8H).

3- (Benzothiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-2-enoic acid tert-butyl ester (29-7c) )

To a stirred solution of 165 mg (1.22 mmol) of benzthiazole in 5 mL

174

of anhydrous tetrahydrofuran at -78 ° C is added 0.52 ml of a 2.5 M solution of n-butyl lithium in a mixture of hexanes. After 5 minutes, 2.6 mL of a 0.50 M solution of zinc chloride in tetrahydrofuran was added and the reaction mixture was warmed to room temperature. To the solution is added 400 mg (0.81 mmol) of 9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -3- (trifluoromethanesulfonyloxy) tert-butyl ester non-2-ene (29-6) and 94 mg (0.081 mmol) of (tetrakis) -triphenylphosphine-palladium. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash silica gel column chromatography eluting with ethyl acetate: hexanes (4: 1) to give the title compound (29-7c) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 8.10-7.85 (m, 2H), 7.50-7.35 (m, 2H), 7.02 (d, J = 7.2 Hz) 1 H, 6.35 (d, J = 7.2 Hz, 1 H), 6.05 (br s, 1 H), 5.55 (br s, 1 H), 3.45-3.36 (m, 2H), 2.74-2.65 (m, 2H), 2.62-2.42 (m, 2H), 2.28 (app t, J = 7.2 Hz, 2H), 1.95- 1.82 (m, 2H); 1.70-1.15 (m, 17H).

3- (Benzothiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid tert-butyl ester (29-8c)

To a stirred suspension of 50 mg of 10% palladium on charcoal in 5 ml of methanol was added a solution of 190 mg of tert-butyl 3- (benzothiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,3] 8] naphthyridin-2-yl) -non-2-enoic acid (29-7c) in 5 mL of ethanol and the mixture was placed under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel eluting with 4: 1 hexanes / acetone to give the title compound (29-8c) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): d 7.99-7.81 (m, 2H), 7.48-7.31 (m, 2H),

7.04 (d, J = 7.3 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.95 (br s, 1H), 3.66175

3.56 (m, 1H), 3.38 (app t, J = 6.3 Hz, 2H), 2.90-2.63 (m, 6H), 2.48 (app t, J = 7, 6 Hz, 2H), 1.94-1.74 (m, 4H), 1.64-1.52 (m, 2H), 1.36 (s, 9H), 1.34-1.22 (m , 8H).

3- (Benzothiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride (29-9c)

A stirred solution of 80 mg of 3- (benzothiazol-2-yl) -9 (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) nonanoic acid tert-butyl ester (29-9b) hydrogen chloride gas was bubbled in at 0 ° C for 1 hour in ethyl acetate. The reaction mixture was warmed to room temperature and then concentrated under reduced pressure. The solid formed (29-9c) was concentrated in vacuo overnight.

¹ H NMR (300 MHz, CD ₃ OD): d 8.01-7.90 (m, 2H), 7.60-7.41 (m, 3H), 6.58 (d, J = 7.3) Hz, 1H), 3.78-3.62 (m, 1H), 3.49 (app t, J = 6.4 Hz, 2H), 2.98-2.59 (m, 6H), 1, 97-1.82 (m, 4H), 1.70-1.56 (m, 2H), 1,441.28 (m, 6H).

Scheme A

Synthesis of radioligand for SPA test

176

First Er _2, NaOH, ₂ Η Ο

2. HCl

τ

177

co ₂ h

HCHHpN

CO ₂ CH ₂ CH <H 'HNSO ₂ C _with HJ

A-4

EDC, HOBT, NMM, DMF

A-8

O • *

178

N- (4-iodophenylsulfonylamino) -L-asparagine (A-2)

To a stirred solution of 4.39 g, 33.2 mmol of A-1 acid, 1.49 g,

NaOH (37.2 mmol), dioxane (30 ml) and water (30 ml) were added pipsyl chloride (10.34 g, 34.2 mmol) at 0 ° C. After about 5 minutes, a solution of 1.49 g (37.2 mmol) of NaOH in 15 mL of water was added and the cooling bath was removed. After two hours, the reaction mixture was evaporated. The residue was dissolved in 300 ml of water and then washed with ethyl acetate. The aqueous portion was cooled to 0 ° C and acidified with concentrated HCl. The solid was collected and washed with diethyl ether to give acid A-2 as a white solid.

179 ¹ H NMR (300 MHz, D ₂ O) d 7.86 (d, 2H, J = 8Hz), 7.48 (d, 2H, J = 8Hz) 3.70 (m, 1H), 2 39 (m, 2H).

2 (S) - (4-Iodophenylsulfonylamino) -beta-alanine (A-3)

To a stirred solution of 7.14 g, 181.8 mmol NaOH and 40 mL H ₂ O at 0 ° C was added 1.30 mL, 24.9 mmol bromine dropwise over 10 minutes. After about 5 minutes, 9.9 g, 24.9 mmol of A-2 acid, 2.00 g, 49.8 mmol of NaOH and 35 mL of water are added, the mixture is cooled to 0 ° C and stirred at this temperature for 20 minutes, and then heated to 90 ° C for 30 minutes and then recooled to 0 ° C. The pH is adjusted to about 7 by dropwise addition of concentrated hydrochloric acid. The solid was collected, washed with ethyl acetate, and dried in vacuo to give acid A-3 as a white solid.

¹ H NMR (300 MHz, D ₂ O) d 8.02 (d, 2H, J = 8Hz), 7.63 (d, 2H, J = 8Hz), 4.36 (m, 1H), 3.51 (dd, 1H, J = 5Hz, 13Hz) 3.21 (m, 1H).

ethyl 2 (S) - (4-iodophenylsulfonylamino) -beta-alanine hydrochloride (A-4) Hydrogen chloride gas is bubbled through a suspension of 4.0 g,

10.81 mmol of A-3 acid in 50 mL of ethanol at 0 ° C for 10 min. The cooling bath was removed and the reaction mixture was heated to 60 ° C. After 18 hours, the reaction mixture was evaporated to give ester A-4 as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) d 7.98 (d, 2H, J = 8Hz), 7.63 (d, 2H, J = 8Hz), 4.25 (q, 1H, J = 5 Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t, 3H, J = 7 Hz).

ethyl 4- [2- (2-aminopyridin-6-yl) ethyl] benzoate (A-5a)

A mixture of 700 mg, 2.63 mmol of ester A-5, the preparation of which is described in Scheme 9 in PCT publication WO 65/32710, published December 7, 1995, 350 mg of 10% palladium on activated carbon is stirred in ethanol at atmospheric pressure hydrogen. After 20 hours

The reaction mixture was filtered through a pad of celite and evaporated to give ester A-5a as a brown oil.

TLC: R f = 0.23 (silica, 40% ethyl acetate in hexanes) ¹ H NMR (300 MHz, CDCl ₃ ) d 7.95 (d, 2H, J = 8 Hz), 7.26 (m, 3H) 6.43 (d, 1H, J = 7Hz), 6.35 (d, 1H, J = 8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J = 7 Hz).

4- [2- (2-Amino-pyridin-6-yl) -ethyl] -benzoic acid hydrochloride (A-6) A suspension of A-5a ester 625 mg, 2.31 mmol in 12 mL of 6N HCl was heated to 60 ° C. After about 20 hours, the reaction mixture was evaporated to give acid A-6 as an off-white solid.

¹ H NMR (300 MHz, CD ₃ OD) d 7.96 (d, 2H, J = 8Hz), 7.80 (m, 1H), 7.33 (d, 2H, J = 8Hz), 6 84 (d, 1H, J = 9Hz), 6.69 (d, 1H, J = 7Hz), 3.09 (m, 4H).

ethyl 4- [2- (2-aminopyridin-6-yl) ethyl] benzoyl-2 (S) - (4-iodophenylsulfonylamino) -beta-alanine (A-7)

A solution of 400 mg, 1.43 mmol of 15-6 acid, 686 mg, 1.57 mmol of amine A-4, 358 mg, 1.86 mmol EDC, 252 mg, 1.86 mmol HOBT,

632 microliters, 5.72 mmol NMM in 10 mL DMF was stirred for about 20 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Flash chromatography (silica, ethyl acetate and then 5% isopropanol in ethyl acetate) gave amide A-7 as a white solid. TLC: R f = 0.4 (silica, 10% isopropanol / ethyl acetate) ¹ H HMR (300 MHz, CD ₃ OD) d 7.79 (d, 2H, J = 9 Hz), 7.61 (d, 2H) J = 8 Hz), 7.52 (d, 2H, J = 9Hz), 7.29 (m, 1H), 7.27 (d, 2H, J = 8Hz), 4.20 (m, 1H), 3.95 (q, 2H, J = 7Hz), 3.66 (dd, 1H, J = 6Hz, 14Hz), 3.49 (dd, 1H, J = 8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J = 7Hz).

4- [2- (2-Amino-pyridin-6-yl) -ethyl] -benzoyl-2 (S) - (4-

(iodophenylsulfonylamino) -beta-alanine (A-8)

A solution of 200 mg, 0.3213 of ester A-7 in 30 mL of 6N CHI was warmed to 0 ° C. After about 20 hours, the reaction mixture was evaporated. Flash chromatography (silica and a mixture of ethyl acetate, ethanol, ammonium hydroxide and water 20: 20: 1: 1) gave acid A-8 as a white solid.

TLC: R f = 0.45 (silica and a mixture of ethyl acetate, ethanol, ammonium hydroxide and water 20: 20: 1: 1) ¹ H NMR (400 MHz, DMSO) d 8.40 (m, 1H), 8, 14 (Bs, 1H), 7.81 (d, 2H, J = 8Hz), 7.62 (d, 2H, J = 8Hz), 7.48 (d, 2H, J = 8Hz), 7 27 (m, 3H), 6.34 (d, 1H, J = 7Hz), 6.25 (d, 1H, J = 8Hz), 5.85 (bs, 2H), 3.89 (bs) (1H),

3.35 (m, 2H), 2.97 (m, 2H), 2.79 (m, 2H).

4- [2- (2-Amino-pyridin-6-yl) -ethyl] -benzoyl-2 (S) - (4-trimethylstannyl-phenylsulfonylamino) -beta-alanine (A-9)

A solution of 70 mg, 0.1178 mmol of iodide A-8, 49 microliters,

0.2356 mmol of [(CH ₃ ) ₃ Sn] 2.5 mg of Pd (PPh ₃ ) ₄ and 7 ml of dioxane were heated to 90 ° C. After 2 hours, the reaction mixture was evaporated and the residue was purified by preparative HPLC (delta-Pak C ₁₈ 15 microM 100 A, 40 x 100 mm, water: methyl cyanide 95: 5 to 5:95) to give trifluoroacetate. This salt was suspended in 10 ml of water, 5 drops of ammonium hydroxide were added and the mixture was lyophilized to give amide A-9 as a white solid.

¹ H NMR (400 MHz, DMSO) δ 8.40 (m, 1H), 8.18 (d, 1H, J = 8 Hz), 7.67 (m, 5H), 7.56 (d, 2H) J = 8 Hz), 7.29 (d, 2H, J = 8 Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, 1H) 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.86 (m, 2H).

4- [2- (2-aminopyridin-6-yl) ethyl] benzoyl-2 (S) ⁴¹²⁵ jodofenylsulfonylamino-beta-alanine (A-10)

Add iodine beads (Pierce) to a 5 mCi vial

To ¹²⁵ L (Amersham, IMS30) and stir at 5 ° C for 5 minutes.

182 rooms. A solution of 0.1 mg of compound A-9 in 0.05 ml of 10% sulfuric acid in methanol is then added to the vial. The mixture is stirred at room temperature for 3 minutes and then approximately 0.04 to 0.05 ml of ammonium hydroxide is added to adjust the pH of the reaction mixture to 6-7. The resulting reaction mixture is injected into an HPLC column (Vydac peptide-protein C18, 4). , 6 x 250 mm, linear gradient of 10% acetonitrile (0.1% TFA): H ₂ O (0.1% TFA) to 90% acetonitrile (0.1% FTA): H ₂ O (0.1% TFA ) over 30 minutes, flow rate 1 ml / min). The retention time for Compound A-10 is 17 minutes under these conditions. Fractions containing the largest proportion of radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of Compound A-10, which was eluted by HPLC with an authentic sample of A-8.

In a similar manner, the following MS mass spectrum can also be prepared: m / e, M ⁺ or (M + 1) ⁺

Compound No. Name MS (1) 3 (R) - (Quinolin) -3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)) - Pentanoylamino) -propionic acid, 433

OH (2) 3- (quinolin-3-yl) -3- (7- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid bistrifluoroacetate,

461 ♦ ·

(3) 3- (quinolin-3-yl) -3- (6- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 447

(4) 3 (S) - (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -pent-4-enoic acid, 332

(5) 3 (S) - (3-Fluorophenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 400

• · · · · · · · · · · ·

184 (6) 3 (S) - (2,3-Dihydro-benzofuran-6-yl) -3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethylsulfanyl) bistrifluoroacetate (Propionylamino) -propionic acid, 442

(7) 2 (S) - (Benzenesulfonylamino) -10- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) decanoic acid, 460

(8) 2 (S) - (Benzenesulfonylamino) -8- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -octanoic acid, 432

(9) 2 (S) - (Cyclohexylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride, 466

185

(10) 2 (S) - (7,7-Dimethyl-2-oxo-bicyclo [2.2.1] hept-1 (S) -ylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro [ 1,8] naphthyridin-2-yl) nonanoic,

520

Cl

(11) 2 (S) - (phenylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid,

460

(12) 2 (S) - (Cyclohexanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride,

452 • 9 9

• · «

186

(13) 2 (S) - (3-Benzylureido) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid,

439

(14) 2 (S) - (Benzyloxycarbonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid,

440

(15) 2 (S) - (Phenylacetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid,

O

424

187 * · (16) 2 (S) - (acetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 348

(17) 2 (S) - (Benzoylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 410

(18) 3- (quinolin-3-yl) -7- [acetyl- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] heptanoic acid, 461

(19) 3- (quinolin-3-yl) -7- [methanesulfonyl- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] -heptanoic acid, 497

188

(20) 3- (6-oxo-1,6-dihydro-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -bistrifluoroacetate - nonanové,

384

(21) 3- (quinolin-3-yl) -7- (1,2,3,4,6,7,8,9-octahydro-benzo [b] [1,8] naphthyridin-8-yl) hydrochloride ) -Heptane

444

(22) 3- (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid,

368

189

(23) 3- (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid trifluoroacetate , 407

(24) 2- (benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid bistrifluoroacetate,

444

· »

190

The compounds of formulas I-XXX, the structure of which is given below, can also be prepared by the method of Schemes 1 to 29 using the appropriate starting materials with conventional variations of the schemes.

192

Technological equipment:

Analytical and preparative HPLC was performed using a Waters model 600E solvent delivery system, a Rheodyne 7125 injector, a Waters model 900 photodiode spectral system, and a Gilson FC 203 microfraction collector. Protein Vydac C-18, 4.6x250 mm with Brownlee modular protective column C-8. Acetonitrile was FisherOptima. The activity detector was Beckman 170. Peptide and protein separation was performed by analytical and preparative HPLC on a Vydac C-18 column of 3.9 x 250 mm. Solutions containing radioactive material were concentrated using a Speedvac centrifuge. Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV / Vis diode array spectrophotometer. Radioactivity in the sample was determined using a Packard A5530 gamma counter.

The methods used to measure ανβ3 and ανβ5 binding and to measure the inhibitory activity of the compounds of the invention on bone resorption will be described below.

Test for bone resorption

When bone resorption occurs by osteoclasts, recesses are formed at the surface of the bone tissue in which resorption occurs. When the test substances are tested for their ability to cause inhibition of osteoclast activity, it is appropriate to measure the ability of the osteoclasts to leave these resorptive wells after application of the inhibitory substance.

From the bovine femoral shaft, 6 mm diameter cylinders were prepared first, and then cross-sections of 200 microns thickness were prepared using a diamond tool (Isomet, Beuler, Ltd., Lake Bluff, II).

193

The bone sections are placed in 10% ethanol solution and frozen until further use.

Prior to the experiment, the sections are sonicated twice in water for 20 minutes. Clean sections are then placed on 96-well plates to provide 2 control lanes and 1 lane for each dose of drug. There should be three or four culture samples per lane. Bone sections are sterilized in ultraviolet light in the plates. Prior to incubation with osteoclasts, bone sections are hydrated by the addition of 0.1 ml of aMEM pH 6.9 containing 5% fetal bovine serum and 1% penicillin / streptomycin.

The long bones of rabbits aged 7-14 days of New Zealand White Hare are removed, cleaned of soft tissues and placed in αMEM containing 20 mM HEPES. The bones are then divided into pieces less than 1 mm in scissors and placed in a 50 ml tube at 25 ml. The tube is inverted 60 times gently, the tissue is allowed to settle for 1 minute and the supernatant discarded. An additional 25 ml of medium is added and the tube is gently inverted again. The first supernatant is mixed with the second supernatant. The number of cells is determined with the exclusion of erythrocytes, usually about 2 χ 10 ⁷ cells / ml. A cell suspension of 5 x 10 ⁶ / ml in aMEM containing 5% fetal calf serum, nM 1.25 (OH) 2D3 and penicillin and streptomycin was added to the 200 x 6 mm bovine tissue sections. ml of this mixture and the bone slice mixture were incubated for 2 hours at 37 ° C in a humidified atmosphere containing 5% carbon dioxide. The medium is then carefully removed with a micropipette and fresh medium containing the test substance is added. The cultures were incubated for 48 hours and monitored for the presence of c-telopeptide, which is a fragment of the type I collagen type I collagen using Crosslaps (Herlev, Denmark).

194 • ·

Bone tissue sections of cattle are exposed to osteoclasts for 20-24 hours and then processed for staining. The environment used is removed from each section. Each well was washed with 200 ml of water and then the bone sections were fixed for 20 minutes using a solution containing 2.5% glutaraldehyde and 0.1 M cacodylate, pH 7.4. After fixation, any cell debris is removed by sonicating for 2 minutes in the presence of 0.25 M ammonia and then sonicating 2 times 15 minutes in water. Then the bone sections are immediately stained for 6 to 8 minutes with filtered 1% toluidine blue and 1% burax.

After drying of the bone sections, the resorptive wells in the control sections and the experimental sections using the test substances were calculated. The wells are monitored in a Microphot Fx fluorescence microscope (Nikon) using a Nikon IGS polarizing filter. The results for the test substances are compared with the results for the controls and IC ₅₀ values for each test substance are determined.

The possibility of extrapolating the data obtained in these experiments to mammals, including humans, is supported by Sato, M. et al., Journal of Bone and Mineral Research, Volume 5, No. 1, pages 31-40, 1990. This publication states that some bisphosphonates have been used clinically and are effective in the treatment of Paget's disease, elevated calcium levels in malignant tumors, osteolytic lesions in bone metastases and bone loss upon immobilization or low levels of sex hormones. The same bisphosphonates were then used in the above assays, confirming the correlation between their known use and the positive results of the assays.

EIB test

Duong et al., J. Bone Miner. Res. 8, S378, 1993, describes an assay for the expression of human integrin ανβ3. Assumed,

195 that integrin stimulates osteoclast adherence to the bone matrix, since antibodies to integrin or RGD-containing molecules such as echistatin of EP 382 451 can effectively block this bone resorption.

Reaction mixture:

1. 175 microliters of TBS buffer containing 50 mM Tris.HCl at pH 7.2, 150 mM NaCl, 1% BSA, 1 mM CaCl ₂ and 1 mM MgCl ₂ ;

2. 25 microliters of cell extract diluted with 100 mM octyl glucoside buffer until 2000 counts per minute per 25 microliters.

3. ¹²⁵ l-echistatin, 50,000 counts per minute / 25 microliters

4. 25 microliters of binding buffer or unlabeled echistatin for non-specific binding.

The reaction mixture was incubated for 1 hour at room temperature.

Unbound and bound ανβ3 is collected by filtration using a Skatron Cell Harvester. The filters, pre-wetted for 10 minutes in 1.5% polyethyleneimine, were then washed with wash buffer containing 50 mM tris.HCl, 1 mM CaCl ₂ / MgCl ₂ , pH 7.2. The radioactivity of the filter was then determined using a gamma counter.

SPA test

Materials:

Wheat germ agglutinin scintillation beads, SPA (Amersham).

2. Octylglucopyranoside (Calbiochem).

3. HEPES (Calbiochem).

196

4. NaCl (Fisher)

5. CaCI ₂ (Fisher)

6. MgCl ₂ (SIGMA)

7. Phenylmethylsulfonylfluoride PMSF (SIGMA)

8. Plate Optiplate (PACKARD)

9. Compound A-10 (specific activity 500-1000 Ci / mmol)

10. Test substance

11. Purified integrin receptor: ανβ3 was purified from 293 cells expressing ανβ3 expression (Duong et al., J. Bone Min. Res., 8: S378, 1993) according to Pytela, Methods in Enzymology, 144: 475 , 1987.

12. Binding Buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca ²⁺ / Mg ²⁺ , 0.5 mM PMSF

13. 50 mM octyl glucoside in binding buffer, 50-OG buffer.

Execution

1. SPA pre-treatment:

500 mg of lyophilized SPA beads are washed with 400 x 200 ml of 50-OG buffer and 1 x 100 ml of binding buffer, and then the beads are suspended in 12.5 ml of binding buffer.

2. Preparation of SPA beads and receptor mix:

2.5 microliters (40 mg / ml) of pre-treated beads in 97.5 microliters of binding buffer and 20 microliters of 50-OG buffer were suspended in each tube. Then, 5 microliter (~ 30 ng / microliter) of purified receptor was added to the suspension beads with stirring at room temperature for 30 minutes. The mixture is then centrifuged at 2500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4 ° C. The pellet is then resuspended in a mixture of 50 microliters of binding buffer and 25 microliters of 50-OG buffer.

197

3. Reaction:

The following components are added sequentially to the corresponding recesses of the Optiplate:

(i) 75 ml receptor / bead mixture (ii) 25 microliters of test substance and the same amount of binding buffer for total binding or for A-8 non-specific binding up to a final concentration of 1 microM (iii) A-10 in binding buffer; microliters, final concentration of 40 pM (iv) 125 microliters of binding buffer (v), each plate is capped (PACKARD) and incubated overnight at 4 ° C on a shaker.

4. Read plates with PACKARD TOPCOUNT

5. Inhibition in% is calculated as follows:

A = total number

B = non-specific count C =% inhibition reading = [{(A-B) - (C-B)} / (A-B)] / (A-B) x 100

OCFORM test

Cells similar to mouse osteoblasts were plated on CORNING plates with 24 wells in aMEM containing ribo- and deoxyribonucleosides, 10% fetal calf serum and a mixture of penicillin and streptomycin. Cells were seeded at 40,000 / well in the morning. In the afternoon, bone cells from 6 week old Balb / C mice were prepared as follows:

198

Mice were sacrificed, tibia removed and placed in the above environment. The ends of the bones were separated and the bone marrow was flushed out of the cavity into a test tube using a 1 ml syringe and a 27.5 needle. Bone marrow was suspended by multiple aspiration into a pipette followed by drain. The suspension was passed through a nylon mesh with a mesh diameter > 100 microns. The resulting suspension was centrifuged at 350 g for 7 minutes. The pellet was resuspended and the sample diluted with 2% acetic acid to disrupt the red blood cells. The remaining cells were counted in a hemocytometer. The cells were then centrifuged and resuspended at 1 x 10 ⁶ cells / ml. 50 microliters of this suspension was added to each well so that the well contained 50,000 cells. In addition, 1,25-dihydroxyvitamin D ₃ was added to each well to a final concentration of 10 nM. The cultures were incubated at 37 ° C in a humidified atmosphere of 5% carbon dioxide. After 48 hours, the medium was changed, and 72 hours after the addition of bone marrow, the test substances were added in fresh medium containing vitamin D ₃ in quadruplicate. The compounds were re-added after another 48 hours in fresh medium containing vitamin D ₃ , the medium was removed for 48 hours, cells were fixed with 10% formaldehyde in physiological sodium chloride phosphate buffer solution for 10 minutes at room temperature, then the cells were processed for another 1 hour. up to 2 minutes with a 1: 1 mixture of ethanol and acetone and then air dried. The cells were then stained for tartrate-resistant acid phosphatase as follows:

Cells were stained for 10-15 minutes at room temperature using 50 mM acetate buffer pH 5.0 containing 30 mM sodium tartrate, 0.3 mg / ml Fast Red Violet LB salt and 0.1 mg / ml Naftol

AS-MX phosphate. After staining, the plates were washed thoroughly with deionized water and air dried. Then he was in everyone

The number of positively stained cells with multiple nuclei was determined by the wells.

Ανβ5 binding test

Duong et al., J. Bone Miner. Res., 11: S290, 1996 describes a system for the expression of the human α1βδ integrin receptor.

Materials:

1. The media and solutions for this assay were obtained from BRL / Gibco up to BSA, chemicals were obtained from Sigma.

2. Binding medium: HBSS with 1 mg / ml BSA, heat-inactivated and free of fatty acids and 2 mM CaCl2 ·

3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl-N-acetyl-beta-D-glucosamidine, 0.1 M sodium citrate and 0.25% Triton pH 5.0.

4. Glycine-EDTA development solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods:

1. 96 well plates (Nunc Maxi Sorp) were coated with human vitronectin (3 micrograms / ml) in 50 mM carbonate buffer pH 9.6 overnight at 4 ° C, using 100 microliters of solution per well. The plates were then washed twice with DPBS and blocked with 2% BSA in DPBS for a total of 2 hours at room temperature. Then, the plates were washed twice more with DPBS and used to determine cell binding.

2. Cells expressing ανβ5 were grown in MEM in the presence of 10% fetal calf serum until a continuous layer of 90% was formed. Then, the cell material was separated using Trypsin / EDTA solution 1 time and the cells were washed 3 times

200 MEM without serum. Then, the cell material was resuspended in binding buffer at 3 times 10 ⁵ cells / ml.

3. Test substances were prepared in serial dilutions and added at 50 microliters to each well. The same amount of cell suspension was then added to the wells. The plates were incubated at 37 ° C for one hour at 5% carbon dioxide to achieve binding.

4. Cells that did not adhere to the plates were removed by gently washing the plates 3 times using DPBS and then incubated with the substrate for glucosaminidase (100 microliter / well) overnight at room temperature in the dark. To determine the cell number, a standard glucosaminidase activity curve was determined for each experiment by adding cell suspension samples directly to the wells containing the enzyme substrate solution.

5. The next day, the reaction was developed by adding 185 microliters / well of glycine and EDTA solution, and then absorbance at 405 nM was read using a Molecular Devices V-Max reader. The average absorbance from four wells per concentration was calculated for each concentration used. The number of bound cells for each drug concentration was then quantitatively determined and the results were compared to a standard curve (Softmax program).

Pharmaceutical preparations

In a specific embodiment of the pharmaceutical composition for oral administration, 100 mg of the compound of the invention is treated with finely powdered lactose and 580-590 mg of the resulting mixture is placed in hard gelatin capsules of O size.

201

• · · · · · · · · · · · · · · · · · · · · · · ·

Representative compounds of the invention have been tested and shown to be capable of binding to α1β3 human integrin. For these compounds, IC ₅₀ values are usually less than

100 nM in SPA assay.

Representative compounds of the invention have also been tested and have been shown to be capable, at least 50%, of inhibiting the adhesion of cells expressing ανβ5 to vitronecin coated plates at a concentration of approximately 1 microM.

The invention has been described in connection with preferred embodiments, but it will be apparent that many changes and modifications could be made within the scope of the invention. For this reason, the scope of the invention cannot be limited to the embodiments illustrated in the individual examples.

Claims (49)

PATENT CLAIMS An integrin receptor antagonist of formula I R ⁵ R ⁶ XY-Z '^ ^Z \ x ^C0 2 ^R' R ⁷ R ⁸ wherein X is a group R ¹ —C-NR ¹ R ² or is a 5- or 6-membered monocyclic aromatic or non-aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms from N, O and S, wherein the ring nitrogen atoms are unsubstituted or are substituted with one substituent R ¹ and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ^1, or 9- to 14-membered polycyclic ring system wherein one or more rings are aromatic, wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms from the group N, O and S, the nitrogen atoms in the ring being unsubstituted or are substituted with one R ¹ substituent and the ring carbon atoms are unsubstituted or are substituted with one or two R ¹ substituents; 203 »* 4 · 1 1 Y is selected from groups - (CH 2) _m -, - (CH ₂ ) _m -O- (CH ₂ ) n -, - (CH ₂ ) _m -NR ⁴ - (CH ₂ ) _n -, - (CH ₂₎ nrS- (CH2) _n -, - (CH ₂₎ nrSO- _(CH2) n-, - (CH ₂ ) m -SO ₂ - (CH 2) n -, - (CH 2) m -O- (CH 2) n -O- (CH 2) p -, - (CH 2) m O- (CH 2) n -NR 4 ( _C H 2) p -, - (CH 2) m-x NR ⁴ - (CH 2) n -NR ⁴ - (CH 2) p -, - (CH 2) m -O- (CH 2) n -S- (CH 2) p -, - (CH 2) m -S- (CH 2) n -S- (CH 2) p -, - (CH 2) m -NR 4 - (CH 2) n -S- (CH 2) p -, - (CH 2) m -NR 4 - (CH 2) n -O- (CH 2) p -, - (CH 2) m -S- (CH 2) n -O- (CH 2) p -, a - (CH 2) m S- (CH 2) n -NR ⁴ - (CH 2) p -, wherein any carbon atom in the methylene group (CH ₂ ) of the meaning of Y, other than R ⁴ , may be substituted by 1 or 2 substituents R ³ , Z is selected from groups O -CNR ⁴ O II NR ⁴ Co II -NR ⁴ CNR ⁴ ·. -CH ₂ -CH ₂ - and -CH = CH-, wherein any carbon atom may be substituted with 1 or 2 R ³ substituents, R ¹ and R ² are independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, C 3-8 cycloalkyl • • < I * 9 C 1-6 alkyl, C 3-8 cycloheteroalkyl C 1-6 alkyl, aryl, aryl C 1-8 alkyl, amino, aminoC 1-8 alkyl, C 1-3 acylamino, C 1-3 acylaminoC 1-8 alkyl, (C 1-6 alkyl) _p amino, (C 1-6 alkyl) _p aminoC 1 - 8alkyl, C1-4alkoxy, C1-4alkoxyC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-3alkoxycarbonyl, C1-3alkoxycarbonylC1-6alkyl, hydroxycarbonylC1-6alkyloxy, hydroxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, trifluoromethyl, nitro, trifluoromethoxy, trifluoroethoxy, C1-8alkyl-S (O) _p , (C1-8alkyl) _p aminocarbonyl, C1-8alkyloxycarbonylamino, (C1-8alkyl) _p aminocarbonyloxy, (arylC 1-8alkyl) _p amino, (aryl) _p amino, arylC1 -8alkylsulfonylamino and C 1-8alkylsulfonylamino, or form two substituents R ¹ on the same carbon atom together with this atom a carbonyl group, R ³ is independently selected from hydrogen, aryl, C1-1 Oalkyl, aryl- (CH _{2) r} -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy, oxo, trifluoromethyl, C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl, 205 C 1-6 alkylcarbonyloxy, C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC 1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, HC = C- (CH ₂ ) _t -, C 1-6 alkyl-C = C- (CH ₂ ) _t -, C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C? C- (CH _{2) t} -, C1-6alkylaryl-CsC- _(CH2) t- CH ₂ = CH- (CH ₂ ) _t -, C 1-6 alkyl-CH = CH- (CH ₂ ) _t -, 3-7-CH = CH- _{(CH2) t-,} aryl-CH = CH- (CH _{2) t} -, C1-6alkylaryl-CH = CH- (CH _{2) r,} C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -, C1-6alkylaryl-SO ₂ (CH ₂₎ i, C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, (C1-6alkyl) _p aminoC1-6alkyl, (aryl) _p amino, (aryl) _p aminoC1-6alkyl, (arylC1-6alkyl) _p amino, (arylC1-6alkyl) 6alkyl) _p aminoC 1-6 alkyl, arylcarbonyloxy, arylC 1-6 alkylcarbonyloxy, 206 (C 1-6 alkyl) _p aminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonylamino, C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulfonylaminoC1-6alkyl, C1-8alkoxycarbonylamino, C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl, C 1-8 alkylcarbonylamino, C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl. (aryl) _p aminocarbonylaminoC1-6alkyl, (arylC 1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, ( aryl) _p aminosulfonylaminoC1-6alkyl (arylC C8alkyl) _p aminosulfonylaminoskupina (arylC 1-8alkyl) _p aminosulfonylaminoC1-6alkyl C1 -6alkylsulfonyl, C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, arylC1-6alkylsulfonylC1-6alkyl, C 1-6 alkylcarbonyl, C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl, C 1-6 alkylthiocarbonylamino, C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylC1-6alkyl, (aryl) _p aminocarbonylC1-6alkyl, (arylC1-8alkyl) _p aminocarbonyl, 8aikyl) _p aminokarbonylC1-6alkyl or form two R ³ substituents on the same carbon atom, together with that atom a carbonyl or a cyclopropyl group, wherein any alkyl group in R ³ is unsubstituted or substituted by one to three R ¹ substituents, provided that R ³ is selected such that in the resulting compound the carbon atom (s) to which R ³ is attached is linked to at most one heteroatom, R ⁴ is independently selected from hydrogen, aryl, aminocarbonyl, C3-8cycloalkyl, aminoC1-6alkyl, (aryl) _p aminocarbonyl, (arylC1-5alkyl) _p aminocarbonyl, hydroxycarbonylC1-6alkyl, 208 C1-8alkyl, arylC1-6alkyl, (C1-6alkyl) _p aminoC2-6alkyl, (arylC1-6alkyl) _p aminoC2-6alkyl, C 1-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, arylC 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, arylcarbonyl, arylC 1-6 alkylcarbonyl, (C 1-8 alkyl) _p aminocarbonyl, aminosulfonyl, C 1-8 alkylaminosulfonyl, (aryl) _p aminosulfonyl, (arylC 1-8 alkyl) _p aminosulfonyl, arylsulfonyl, arylC 1-6 alkylsulfonyl, C 1-6 alkylthiocarbonyl, arylthiocarbonyl, arylC 1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R ⁴ is unsubstituted or substituted with 1 to 3 substituents R ¹ , R ⁵ and R ⁶ are independently selected from hydrogen, aryl, C1-10 alkyl, aryl- (CH ₂₎ r -O- (CH _{2) s} -, aryl- (CH _{2) r} -S (O) _p - (CH _{2) s} -, aryl- (CH _{2) r} -C ( O) - (CH _{2) s} -, aryl- (CH ₂₎ - C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) f} -N (R ⁴⁾ - C (O) - (CH ₂ ) _s -, 209 aryl- (CH ₂ ) _r -N (R ⁴ ) - (CH ₂ ) _s -, halogen, hydroxy, C 1-8 alkylcarbonylamino, arylC 1-5 -alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, HC = C- (CH ₂ ) _t -, C 1-6 alkyl-C = C- (CH ₂ ) _t -, C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C = C- _(CH2) t- C 1-6 alkylaryl-C = C- (CH ₂ ) t -, CH ₂ = CH- (CH ₂ ) _t -, C 1-6 alkyl-CH = CH- (CH ₂ ) _t -, C 3-7 cycloalkyl-CH = CH- (CH ₂ ) _t -, aryl-CH = CH- (CH ₂ ) _t -, C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -, C 1-6 alkyl-SO ₂ - (CH ₂ ) _t -, C 1-6 alkylaryl-SO ₂ (CH ₂ ) _t -, C1-6alkoxy, arylC1-6alkoxy, arylC1-6alkyl, • 210 (C1 -6alkyl) aminoC 1 -6alkyl _P, (aryl) _p amino, (aryl) _p aminoC1-6alkyl (arylC -6alkyl) _p amino, (arylC -6alkyl) aminoC1-6alkyl _p, arylcarbonyloxy, arylC -6alkylkarbonyloxyskupina, (C 1-6 alkyl) _p aminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonylamino, C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl, C1-8alkoxycarbonylamino, C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl, C 1-8 alkylcarbonylamino, C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl. (aryl) _p aminocarbonylaminoC1-6alkyl, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, • * (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, (aryl) _p aminosulfonylaminoC1-6alkyl (arylC 1-8alkyl) _p aminosulfonylaminoskupina (arylC 1-8alkyl) _p aminosulfonylaminoC1-6alkyl, C 1-6 alkylsulfonyl, C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkylsulfonyl, arylC1-6alkylsulfonylC1-6alkyl, C 1-6 alkylcarbonyl, C1-6alkylcarbonylC1-6alkyl, arylcarbonylC1-6alkyl, arylC1-6alkylcarbonyl, arylC1-6alkylcarbonylC1-6alkyl, C 1-6 alkylthiocarbonylamino, C 1-6 alkylthiocarbonylaminoC 1-6 alkyl, arylthiocarbonylaminoC 1-6 alkyl, arylC 1-6 alkylthiocarbonylamino, arylC 1-6 alkylthiocarbonylaminoC 1-6 alkyl, (C 1-8 alkyl) _p aminocarbonylC 1-6 alkyl, (aryl) _p aminocarbonylC 1-6 alkyl, (arylC 1-8 alkyl) _p aminocarbonyl 1-8alkyl) _p aminocarbonylC 1-6 alkyl, or form R ⁵ and R ⁶ together with the carbon atom to which they are attached a carbonyl group, wherein any R ⁵ or R ⁶ alkyl group is unsubstituted or substituted by 1 to 3 R substituents ¹ , provided that the meanings of R ⁵ and R ^{6 are} chosen such that in the resulting compound the carbon atom to which they are attached is bound to at most one heteroatom, R ⁷ and R ⁸ are independently selected from hydrogen, 212 aryl, C1-1 Oalkyl, aryl- (CH ₂₎ r O- _(CH2) s-, aryl- (CH _{2) r} -S (O) p- _{(CH2) s} -, aryl- (CH _{2) r} -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -C (O) -N (R ⁴⁾ - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ -C (O) - (CH _{2) s} -, aryl- (CH _{2) r} -N (R ⁴⁾ - (CH _{2) s} -, halogen, hydroxy, trifluoromethyl, C 1-8 alkylcarbonylamino, arylC -5-alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl) _p aminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8cycloalkyl, (C1-6alkyl) _p amino, aminoC1-6alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonylC1alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, HC = C- (CH ₂ ) _r , C 1-6 alkyl-C? C- (CH _{2) r,} C 3-7 cycloalkyl-C? C- (CH _{2) t} -, aryl-C = C- _(CH2) t- C 1-6 alkylaryl-C = C- (CH ₂ ) _t -, CH ₂ = CH- (CH ₂ ) t -, C1-6alkyl-CH = CH- (CH _{2) r,} 213 C 3-7 cycloalkyl-CH = CH- (CH ₂ ) _t -, aryl-CH = CH- (CH ₂ ) _t -, C 1-6 alkylaryl-CH = CH- (CH ₂ ) _t -, C 1-6 alkyl-SO ₂ - (CH ₂ ) _r , C 1-6 alkylaryl-SO ₂ (CH ₂ ) 1 -, C 1-6 alkoxy, arylC 1-6 alkoxy, arylC 1-6 alkyl, (C 1-6 alkyl) _p aminoC 1-6 alkyl, (aryl) _p amino, (aryl) _p aminoC 1-6 alkyl, ( arylC1-6alkyl) _p amino, (arylC1-6alkyl) _p aminoC1-6alkyl, arylcarbonyloxy, arylC1-6alkylcarbonyloxy, (C1-6alkyl) _p aminocarbonyloxy, C 1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl, C1-8alkoxycarbonylamino, C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl, C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, 214 aminocarbonylaminoC 1-6 alkyl, arylaminocarbonylamino, (C 1-8 alkyl) _p aminocarbonylamino, (C 1-8 alkyl) _p aminocarbonylaminoC 1-6 alkyl. (aryl) _p aminocarbonylaminoC1-6alkyl, (arylC 1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, (C1-8alkyl) _p aminosulfonylaminoC1-6alkyl, ( aryl) _p aminosulfonylaminoC 1-6 alkyl, (arylC 1-8 alkyl) _p aminosulfonylamino, (arylC 1-8 alkyl) _p aminosulfonylaminoC 1-6 alkyl, C 1-6 alkylsulfonyl, C1-6alkylsulfonylC1-6alkyl, arylsulfonylC1-6alkyl, arylC1-6alkyls Ifonyl, arylC1-6alkylsulfonylC1-6alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylC 1-6 alkyl, arylcarbonylC 1-6 alkyl, arylC 1-6 alkylcarbonyl, arylC 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkylthiocarbonylamino, C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylC1-6alkyl, (aryl) _p aminocarbonylC1-6alkyl, (arylC1-8alkyl) _p aminocarbonyl, (8alkyl) _β aminocarbonylC 1-6 alkyl, 215 C7-20polycyclylC0-8alkylsulfonylamino, wherein any of the alkyl groups R ⁷ and R ⁸ is unsubstituted or substituted with 1 to 3 substituents R ¹ , provided that R ⁷ and R ⁸ are selected such that there is a carbon atom in the resulting compound, to which these symbols are bound, bound by at most one heteroatom, R ⁹ is selected from hydrogen C 1-8 alkyl, aryl arylC 1-8 alkyl, C 1-8 alkylcarbonyloxyC 1-4 alkyl, arylC 1-8 alkylcarbonyloxyC 1-4 alkyl, C 1-8 alkylaminocarbonylmethylene, C 1-8 dialkylaminocarbonylmethylene, m independently represents an integer from 0 to 6, n independently represents an integer from 0 to 6, p independently represents an integer from 0 to 2, r independently represents an integer from 1 to 3, s independently represents an integer from 0 to 3, t independently represents an integer from 0 to 3, as well as pharmacologically acceptable salts thereof. Integrin receptor antagonist compounds of formula I according to claim 1, wherein X is A 6-membered monocyclic aromatic ring system containing 1 or 2 nitrogen atoms, each ring carbon atom being unsubstituted or substituted by one substituent R ¹ , or A 9- to 14-membered polycyclic ring system wherein one or more rings is aromatic, wherein the polycyclic ring system contains 0,1,2,3 or 4 heteroatoms from the group N, O and S, atoms 216 nitrogen atoms are unsubstituted or substituted with one R ¹ substituent and the ring carbon atoms are unsubstituted or substituted with one or two substituents R ^first The integrin receptor antagonist of the formula I according to claim 2, wherein X is selected from the groups and R ¹ is as defined in claim 1. Compounds of formula I according to claim 3, wherein X is a group and R ¹ is as defined in claim 1. The integrin receptor antagonist of formula I according to claim 3, wherein Y is selected from the group - (CH2) nr, - (CH 2) m -O- (CH 2) n -> - (CH 2) m * NR 6 - (CH 2) n ', 0 · 217 - (CH 2) _m -S- (CH 2) n -, - (CH 2) m -SO- (CH 2) n -, - (CH 2) m -SO 2 - (CH 2) _n -, - (CH 2) m -O- (CH 2) n -O- (CH 2) p -, - (CH 2) m -O- (CH 2) n -NR - (CH 2) p -, - (CH 2) m -NR ⁴ - (CH 2) n -NR ⁴ - (CH 2) p -, and - (CH 2) m -NR ⁴ - (CH 2) n O- (CH 2) p - wherein any carbon atom of the methylene group (CH ₂ ) in the meaning of Y, other than R ⁴ , is optionally substituted with 1 or 2 R ³ substituents provided that when Y is - (CH 2) m -NR ⁴ - (CH 2) _n - and _n = 1, then R ³ substituent on a carbon atom of the methylene groups in the chain - (CH _{2) m} -, immediately adjacent to the nitrogen atom is other than oxo, Z is selected from the group "n ^H -CNR- · -NR ⁴ C- · -NR ⁴ CNR ⁴ ·. ’>! -CH ₂ CH ₂ - and -CH = CH-, wherein any carbon atom is optionally substituted with 1 or 2 R ³ substituents. The integrin receptor antagonist of formula I according to claim 5, wherein Y is selected from (CH ₂ ) _m , (CH ₂ ) _m -S- (CH ₂ ) _n , and (CH ₂ ) _m -NR ⁴ - (CH ₂ ) _n , wherein any carbon atom of the methylene (CH ₂ ) radical Y other than R ⁴ is optionally substituted with 1 or 2 R ³ substituents, provided that when Y is - (CH 2) m -NR ⁴ - (CH 2) _n -an = 1, • the substituent R ³ on the carbon atom of the methylene group in the chain - (CH ₂ ) _m -, immediately adjacent to the nitrogen atom, has a different meaning from the oxo group, Z is selected from groups -CNR ⁴ - · -NR ⁴ CNR ⁴ '. _and ^J 1 is -C-CH ₂ CH ₂ - and -CH = CH-, wherein any carbon atom is optionally substituted with 1 or 2 substituents R ³ . 7. Substances integrin receptor antagonist of general formula I according to claim 6, wherein R ³ is independently selected from hydrogen, fluoro, trifluoromethyl, aryl, C 1-8 alkyl, arylC 1-6 alkyl, hydroxy, oxo, arylaminocarbonyl, arylC 1-5 alkylaminocarbonyl, aminocarbonyl and aminocarbonylC 1-6 alkyl, R ⁴ is preferably selected from hydrogen, aryl, 219 C3-8cycloalkyl, C 1-8 alkyl, C 1-8 alkylcarbonyl, arylcarbonyl, C1-6alkylsulfonyl, arylsulfonyl, arylC1-6alkyls Ifony I, arylC1-6alkylcarbonyl, C 1-8 alkylaminocarbonyl, arylC 1-5 alkylaminocarbonyl, arylC 1-8 alkoxycarbonyl and C 1-8 alkoxycarbonyl. The integrin receptor antagonist of formula I according to claim 7, wherein R ⁶ , R ⁷ and R ⁸ are hydrogen and R ⁵ is selected from hydrogen, aryl, C 1-8 alkyl, aryl-C = C- (CH ₂ ) r, arylC 1-6 alkyl, CH ₂ = CH- (CH _{2) t} -, and HC = C- (CH ₂ ) _t -. Integrin receptor antagonists of the formula I according to claim 8, wherein R ⁹ is hydrogen, methyl or ethyl. 10th antagonists of integrin formula I according to claim 9, wherein R ⁹ is hydrogen. • 1 220 · · · · • • 220 · · * • • • 220 • • • • The integrin receptor antagonist of formula I according to claim 7, wherein R ^5, R ⁶ and R ⁸ are hydrogen and R ⁷ is selected from: hydrogen, aryl, C 1-8 alkylcarbonylamino, arylcarbonylamino, C 1-8 alkylsulfonylamino, arylsulfonylamino, C1-8alkylsulfonylaminoC1-6alkyl, arylsulfonylaminoC1-6alkyl, arylC1-6alkylsulfonylamino, arylC1-6alkylsulphnylaminoC1-6alkyl, C1-8alkoxycarbonylamino, C1-8alkoxycarbonylaminoC1-8alkyl, aryloxycarbonylaminoC1-8alkyl, arylC1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylaminoC1-8alkyl, C1-8alkylcarbonylaminoC1-6alkyl, arylcarbonylaminoC1-6alkyl, arylC1-6alkylcarbonylamino, arylC1-6alkylcarbonylaminoC1-6alkyl, aminocarbonylaminoC1-6alkyl, (C1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminocarbonylaminoC1-6alkyl. (aryl) _p aminocarbonylaminoC1-6alkyl, arylaminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylaminoC1-6alkyl, aminosulfonylaminoC1-6alkyl, (C1-8alkyl) _p aminosulfonylamino, 221 (C1-8alkyl) _p- aminosulfonylaminoC1-6alkyl, (aryl) _p- aminosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p- aminosulfonylaminoC1-6alkyl, (arylC1-8alkyl) _p- aminosulfonylaminoC1-6alkyl, C 1-6 alkylthiocarbonylamino, C1-6alkylthiocarbonylaminoC1-6alkyl, arylthiocarbonylaminoC1-6alkyl, arylC1-6alkylthiocarbonylamino, arylC1-6alkylthiocarbonylaminoC1-6alkyl, and C7-20polycyclylC0-C8alkylsulfonylamino. 12. Substances integrin receptor antagonist of general formula I according to claim 11, wherein R ^5, R ⁶ and R ⁸ are hydrogen and R ⁷ is selected from: hydrogen, aryl, C 1-8 alkylcarbonylamino, arylC 1-6 alkylcarbonylamino, arylcarbonylamino, C 1-8 alkylsulfonylamino, arylC 1-6 alkylsulfonylamino, arylsulfonylamino, C1-8alkoxycarbonylamino, arylC1-8alkoxycarbonylamino, arylaminocarbonylamino, (C1-8alkyl) _p aminocarbonylamino, (arylC1-8alkyl) _p aminocarbonylamino, (C1-8alkyl) _p aminosulfonylamino and (arylC1-8alkyl) _p . Compounds of formula (I) as claimed in claim 12, wherein R ⁹ is hydrogen, methyl or ethyl. • · · · · · · · · · · · · · · · · · · · · · 222 ······· · · 14th antagonists, integrin receptor of general formula I according to claim 13, wherein R ⁹ is hydrogen. 15. The integrin receptor antagonist of formula (I) according to claim 7, selected from the group consisting of: 3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3 (S) - (pyridin-3-yl) -3- ( 5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3 (S) - (5,6,7,8-tetrahydroquinolin-3-yl) trifluoroacetate -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 2 (S) -benzenesulfonylamino-3- (5- (5) -propionic acid trifluoroacetate) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (quinolin-3-yl) -3- (5- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (R) - (quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro) [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 3- (quinolin-3-yl) -3- (7- (5,6,7,8-tetrahydro- [1,8] naphthyridine) -bistrifluoroacetate) -2-yl) -pentanoylamino) -propionic acid 3- (quinolin-3-yl) -3- (6- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) 3-S (3) - (3-fluorophenyl) -3- (4- (5,6,7,8223)) -propionic acid bistrifluoroacetate 3-S-5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid - pentanoylamino) -pent-4-enoic acid 3 (S) - (3-fluorophenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 2- (3-fluorophenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid trifluoroacetate, 3 (S) - (benzo [1,3] dioxol-5-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 ( S) - (2,3-Dihydro-benzofuran-6-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, trifluoroacetate 3 (S) - (2-Oxo-2,3-dihydro-benzoxazol-6-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)) -pentanoylamino) -propionic acid 3 (S) - (3-fluorophenyl) -3- {3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino] -propionylamino 3 (S) - (3-fluorophenyl) -3- (2- {propyl- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)) - propionic acid, trifluoroacetate - ethyl] -amino} -acetylam Ino) -propionic acid, 3 (S) - (3-fluorophenyl) -3- (2- {phenethyl- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionic acid trifluoroacetate) -ethyl] -amino} -acetylamino) -propionic acid 3 (S) - (3-fluorophenyl) -3- {3 (S) - [(5,6,7,8-tetrahydro- [1,8] naphthyridine- 2-ylmethyl) amino] pent-4-ynoylamino-propionic acid, 224 3 (S) - (3-Fluorophenyl) -3- {3 (S) - (3-fluorophenyl) -3 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-) bistrifluoroacetate 3-S (3) - (3-fluoro-4-phenyl-phenyl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridine) trifluoroacetate) methyl-amino] -propionylamino-propionic acid trifluoroacetate -2-yl) -pentanoylamino) -propionic acid 2 (S) - (2-thienylsulfonylamino) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) trifluoroacetate) -pentanoylamino) -propionic acid 3 (S) - (3-fluorophenyl) -3- {3-methyl-3 [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) -amino 3-S - (3-fluorophenyl) -3- {2- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethylamino] -propionylamino} -propionic acid 3-S (3-fluorophenyl) -3 {[3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -ureido] -acetylamino} -propionic acid -propionic acid 2 (S) - (methanesulfonylamino) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 (R or S), 9-octahydrobenzo [b] [1,8] ] nafthyridin- 8-yl) -propionylamino] -propionic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 ( S or R), 9-octahydrobenzo [b] [1,8] naphthyridin-8-yl) -propionylamino] -propionic acid; 225 • 3 (S) - (6-methoxy-pyridin-3-yl) -3- [N-methyl-3- (1,2,3,4,6,7,8,9-octahydrobenzoic acid) [b] [1,8] Naphthyridin-8-yl-propionyl) -amino] -propionic acid, 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- (5,6, 5-hydroxybenzofuran-6-yl) -bistrifluoroacetate] 7,8-tetrahydro- [1,8] naphthyridin-2-ylmethylsulfanyl) -propionylamino] -propionic acid 3- (quinolin-3-yl) -7 - [(5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] heptanoic acid 3- (quinolin-3-yl) -7- [acetyl- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] 3- (quinolin-3-yl) -7- [methanesulfonyl- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl) amino] -heptanoic acid, 3- [5] - (2-Amino-pyrimidin-4-yl) -pentanoylamino] -3 (S) - (quinolin-3-yl) -propionic acid 9- (5,6,7,8-tetrahydro- [1,8] naphthyridine -2-yl) -nonanoic acid 2- (benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid bistrifluoroacetate 2 (S ) - (Benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (R) - (Benzenesulfonylamine) o) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (benzenesulfonylamino) -10- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) decanoic acid, 226 2 (S) - (Benzenesulfonylamino) -8- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -octanoic acid 2 (S) - (cyclohexylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept- 1 (S) -ylmethanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 2 (S) - (phenylmethanesulfonylamino) -9- (5,6) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 2 (S) - (cyclohexanesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl) -nonanoic acid 2 (S) - (butane-1-sulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid hydrochloride 2 (S) - (3-Benzylureido) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (benzyloxycarbonylamino) -9- (5) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 2 (S) - (phenylacetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin) -2-yl) -nonanoic acid 2 (S) - (acetylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyride n-2-yl) nonanoic, 227 2 (S) - (Benzoylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro) [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) 3- (quinolin-3-yl) -7- (1,2,3,4,6,7,8,9-octahydro-benzo [b] [1,8] naphthyridine-8-) -nonanoic acid, bis-hydrochloride yl) -heptanoic acid, 6-oxo- (quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (N- oxo-quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (phenyl) -9- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin) -2-yl) -nonanoic acid 3 (R) - (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - nonanoic acid, 3 (S) - (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 228 3- (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (pyridin-3-yl) ) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (pyridin-3-yl) -9- (5,6, 5, 7, 8, 8, 8, 11, 11, 11, 11, 11, 11); 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (3-fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -nonanoic acid 3 (R) - (3-fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - ( 3-Fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8) 3- (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid trifluoroacetate naphthyridin-2-yl) -non-4-enoic acid 3- (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8- tetrahydro- [1,8] naphthyrid n-2-yl) -nonano; 229 3 (R) - (2,3-Dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -nonanoic acid 3 (S) - (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) ) -nonanoic acid 3 (R) - (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - nonanoic acid, 3 (S) - (furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid , 3 (R) - (2,3-Dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -nonanoic acid 3 (S) - (2,3-dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] 3- (6-methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, naphthyridin-2-yl) -nonanoic acid, 3 (S) - (6-Methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid Acid, 3 (R) - (6-methoxy-pyridin-3-yl) -9- (5,6,7,8230 · ·· .. .. · ·. -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) trifluoroacetate (3) - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid trifluoroacetate 3 (S) -nonanoic acid trifluoroacetate - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3- (6-amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (6-Amino-pyridin-3-yl) -9- (5, 6-amino-pyridin-3-yl) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-amino-pyridin-3-yl) -9- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3- (benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl) -nonanoic acid, 3 (R) - (Benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) - Nonanoic acid, 3 (S) - (Benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, bistrifluoroacetate 3 - (6-oxo-1,6-dihydro-pyridin-3-yl) -9- (5 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, and pharmaceutically acceptable salts thereof. 231 • * 16. The integrin receptor antagonist of the formula of claim 15 selected from the group consisting of: 3 (S) - (Pyridin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid trifluoroacetate 2 ( S) -benzenesulfonylamino-3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (quinolin-3-yl) -3- (5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (R) - (quinolin-3-yl) -3- ( 5- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid, 2 (S) - (2-thienylsulfonylamino) -3- (5- (5, 5, 7, 8-thienylsulfonylamino) trifluoroacetate) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -pentanoylamino) -propionic acid 3 (S) - (2,3-dihydro-benzofuran-6-yl) -3- [3- ( 1,2,3,4,6,7,8 (R or S), 9-octahydrobenzo [b] [1,8] naphthyridin-8-yl) -propionamino-propionic acid, 3 (S) - (2, 3-Dihydro-benzofuran-6-yl) -3- [3- (1,2,3,4,6,7,8 (S or R)), 9-octahydrobenzo [b] [1,8] naphthyridin-8 -yl) -propionamino] -propionic acid 3 (S) - (6-methoxy-pyridin-3-yl) -3- [N-methyl-3- (1,2,3,4,6,7,8) 9-octahydrobenzo [b] [1,8] naphthyridin-8-yl-propionyl) -amino] -propionic acid 3- [5- (2-Amino-pyrimidin-4-yl) -pentanoylamino] -3 (S) - (quinolin-3-yl) -propionic acid, 232 2- (Benzenesulfonylamino) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -non-4-enoic acid trifluoroacetate, as well as pharmacologically acceptable salts thereof. 17. The integrin receptor antagonist of formula (I) according to claim 15 selected from the group consisting of: 3 (R) - (Quinolin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (quinolin-3) -yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (benzo [b] thiophen-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (benzo [b] thiophen-2-yl) -9- (5,6,7) 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin) -2-yl) -nonanoic acid 3 (S) - (pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (3-Fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-benzofuran) -6-yl) -9- (5,6,7,8-acid 3 (S) - (3-fluorophenyl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonan, 233 3-S (2,3-dihydro-benzofuran-6-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid; 1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9- (5,6,7, 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (2,3-dihydro-furo [3,2-b] pyridin-5-yl) -9- (5, 7-fluoro-2,3-dihydro-furo [3,2-b] pyridin-5-yl) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (furo [2,3b] pyridin-5-yl) -9- (5,6,7, 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (furo [2,3b] pyridin-5-yl) -9- (5,6,7,8-tetrahydro [ 1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (2,3-dihydro-furo [2,3-b] pyridin-5-yl) -9- (5,6,7, 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (2,3-dihydro-furo [2,3-b] pyridin-5-yl) -9- (5, 5-methyl-2-fluoro-2,3-dihydro-furo [2,3-b] pyridin-5-yl) 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (6-methoxy-pyridin-3-yl) -9- (5,6,7,8- tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-methoxy-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (R) - (pyridin-5-yl) -9- (5,6,7,8-tetrahydro [ 1,8] naphthyridin-2-yl) nonanoic acid, 234 3 (S) - (Pyridin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (6- amino-pyridin-3-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-amino-pyridin-3- yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (benzo [b] thiazol-2-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (benzo [b] thiazol-2-yl) -9- (5,6, 7,8-tetrahydro [1,8] naphthyridin-2-yl) 7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acids and their pharmaceutically acceptable salts. 18. A pharmaceutical composition comprising, as an active ingredient, an integrin receptor antagonist of the formula I as claimed in claim 1 together with a pharmaceutically acceptable carrier. 19. A pharmaceutical composition which is obtainable by admixing the integrin receptor antagonist of formula (I) according to claim 1 and a pharmaceutically acceptable carrier. 20. A process for the manufacture of a pharmaceutical composition comprising admixing the compounds of claim 1 with a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 18, characterized in that it contains an additional active ingredient from the group night, zoo. (a) organic bisphosphonates and their salts or esters; (b) estrogen receptor modulators; c) cytotoxic and antiproliferative substances, d) matrix metalloproteinase inhibitors, (e) inhibitors of epidermis, fibroblast or platelet-derived growth factors; (f) VEGF inhibitors; g) Flk-1 / KDR inhibitor, Flt-1, Tck / Tie-2, or Tie-1; h) cathepsin K inhibitors; and i) prenylation inhibitors, e.g., a farnesyltransferase or geranylgeranyltransferase inhibitor or a farnesyl / geranylgeranyltransferase double inhibitor, and mixtures thereof. 22. A pharmaceutical composition according to claim 21, wherein the additional active ingredient is selected from the group consisting of (a) organic bisphosphonates and their salts or esters; (b) estrogen receptor modulators; and c) cathepsin K inhibitors and mixtures thereof. 23. A pharmaceutical composition according to claim 22 wherein the organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium salt trihydrate. 24. A pharmaceutical composition according to claim 21 wherein the additional active ingredient is selected from the group consisting of: a) cytotoxic and antiproliferative substances, b) matrix metalloproteinase inhibitors, (c) inhibitors of growth factors derived from epidermis, fibroblasts or platelets; (d) VEGF inhibitors; (e) inhibitor of Flk-1 / KDR, Flt-1, Tck / Tie-2, or Tie-1; f) cathepsin K inhibitors and mixtures thereof. 25. A method of antagonizing an integrin receptor in a mammal comprising administering an effective amount of a compound of formula (I) according to claim 1. 26. The method of claim 25, wherein the α1β3 receptor antagonist effect. 27. The method of claim 26, wherein the α1β3 receptor antagonist effect is an effect on inhibiting bone resorption, restenosis, vascular formation, diabetic rethinopathy, macular degeneration, inflammation, viral diseases, tumor growth. and metastasis formation. 28. The method of claim 27, wherein the α1β3 receptor antagonizing effect is to antagonize bone resorption. 29. The method of claim 25, wherein the α1βδ receptor antagonist effect. 30. The method of claim 29, wherein the α1βδ receptor antagonizing effect is inhibition of restenosis, vascular formation, diabetic retinopathy, macular regeneration, inflammation, tumor growth, and metastasis. 31. The method of claim 25, wherein the integrin receptor antagonist effect is a ανβ3 / ανβ5 receptor double effect. 237 32. The method of claim 31, wherein the dual effect on α1β3 / α1β5 receptors is selected from inhibiting bone resorption, restenosis, vascular formation, diabetic retinopathy, macular degeneration, inflammation, viral diseases, tumor growth, and metastasis. 33. The method of claim 25, wherein the antagonizing effect is an αββ6 receptor effect. 34. The method of claim 33, wherein the α1β6 receptor effect is selected from inhibition of angiogenesis, inflammatory reactions, or erroneous wound healing. 35. A method of inducing an integrin receptor antagonist effect in a mammal, comprising administering an effective amount of the pharmaceutical composition of claim 18. 36. A method of treating or preventing an integrin receptor mediated condition in a mammal, comprising administering an effective amount of the pharmaceutical composition of claim 18. 37. A method of inhibiting bone resorption in a mammal, comprising administering an effective amount of a pharmaceutical composition of claim 18. 38. A method of inhibiting bone resorption in a mammal, comprising administering an effective amount of a pharmaceutical composition of claim 22. 238 39. A method of treating tumor growth in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 24. 40. A method of treating tumor growth in a mammal, comprising administering an effective amount of a compound of formula I according to claim 1 in combination with radiation. 41. The integrin receptor antagonist of claim 17 selected from the group consisting of: 3 (S) - (2-Methoxy-pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (2) -methoxypyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (R) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro) [1,8] naphthyridin-2-yl) -nonanoic acid, 3 (S) - (2-methylpyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2) -yl) -nonanoic acid 3 (R) - (2-methylpyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid 3 (S) - (6-Methoxy-pyridin-3-yl) -7-oxo-9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid and 3 (R) - (6-methoxypyridin-3-yl) -7-hydroxy-9- (5,6,7,8). 240 • «•« -tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate, and pharmaceutically acceptable salts thereof. The integrin receptor antagonist of claim 41 which is 3 (R) - (2-methoxypyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridine-2- acid). yl) -nonano. The integrin receptor antagonist of claim 41 which is 3 (R) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) acid. -nonan. The integrin receptor antagonist of claim 41 which is 3 (R) - (2-methylpyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -nonano. The integrin receptor antagonist of claim 41 which is 3 (S) - (2-methoxypyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2- yl) -nonano. The integrin receptor antagonist of claim 41 which is 3 (S) - (pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) acid. -nonan. The integrin receptor antagonist of claim 41 which is 3 (S) - (2-methylpyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridine-2- yl) -nonano. 240 ·· · 4 · 4 · 4 · 4 · 4 48. The method of claim 27, wherein 3 (S) - (2-methoxypyrimidin-5-yl) -9- (5,6,7,8-tetrahydro [ 1,8] naphthyridin-2-yl) -nonanoate. 3 (S) - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid. 3 (S) - (2-Methyl-pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, or a pharmaceutically acceptable salt thereof. 49. The method of claim 40, wherein said 3 (S) - (2-methoxypyrimidin-5-yl) -9- (5,6,7, 3, 4, 5, 6, 7, 8, 11, 12, 13, 18, 21, 30, 30) acid is administered. 8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoate. 3 (S) - (Pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid. 3 (S) - (2-Methyl-pyrimidin-5-yl) -9- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -nonanoic acid, or a pharmaceutically acceptable salt thereof.